U.S. patent application number 17/416108 was filed with the patent office on 2022-09-01 for modulators of hsd17b13 expression.
This patent application is currently assigned to Ionis Pharmaceuticals, Inc.. The applicant listed for this patent is Ionis Pharmaceuticals, Inc.. Invention is credited to Susan M. Freier, Susan F. MURRAY.
Application Number | 20220273691 17/416108 |
Document ID | / |
Family ID | 1000006365176 |
Filed Date | 2022-09-01 |
United States Patent
Application |
20220273691 |
Kind Code |
A1 |
Freier; Susan M. ; et
al. |
September 1, 2022 |
MODULATORS OF HSD17B13 EXPRESSION
Abstract
Methods, compounds, and compositions useful for inhibiting HSD
expression are provided. Such compounds, compositions, and methods
are useful for treating, preventing, or ameliorating a disease
associated with HSD 17B 13.
Inventors: |
Freier; Susan M.; (San
Diego, CA) ; MURRAY; Susan F.; (San Diego,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Ionis Pharmaceuticals, Inc. |
Carlsbad |
CA |
US |
|
|
Assignee: |
Ionis Pharmaceuticals, Inc.
Carlsbad
CA
|
Family ID: |
1000006365176 |
Appl. No.: |
17/416108 |
Filed: |
December 20, 2019 |
PCT Filed: |
December 20, 2019 |
PCT NO: |
PCT/US2019/068051 |
371 Date: |
June 18, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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62827524 |
Apr 1, 2019 |
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62825581 |
Mar 28, 2019 |
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62783680 |
Dec 21, 2018 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C12N 15/1137 20130101;
A61K 31/7088 20130101; A61P 1/16 20180101 |
International
Class: |
A61K 31/7088 20060101
A61K031/7088; C12N 15/113 20060101 C12N015/113; A61P 1/16 20060101
A61P001/16 |
Claims
1-108. (canceled)
109. An oligomeric compound, according to the following chemical
structure: ##STR00068## or a pharmaceutically acceptable salt
thereof.
110. An oligomeric compound, according to the following chemical
structure: ##STR00069##
111. An oligomeric compound comprising a modified oligonucleotide
consisting of 16 linked nucleosides having a nucleobase sequence
SEQ ID NO: 1448, wherein the modified oligonucleotide comprises a
gap segment consisting of ten linked deoxynucleosides; a 5' wing
segment consisting of three linked nucleosides; and a 3' wing
segment consisting of three linked nucleosides; wherein the gap
segment is positioned between the 5' wing segment and the 3' wing
segment; wherein the 5' wing segment and the 3' wing segment
comprise cEt sugars; wherein each internucleoside linkage is a
phosphorothioate linkage; and wherein each cytosine is a
5-methylcytosine.
112. The oligomeric compound of claim 109, which is a sodium salt
or a potassium salt.
113. A pharmaceutical composition comprising the oligomeric
compound of any one of claims 109-112 and a pharmaceutically
acceptable diluent.
114. The pharmaceutical composition of claim 113, wherein the
pharmaceutically acceptable diluent is water.
115. A method of treating a disease associated with HSD17B13 in an
individual comprising administering to the individual a compound of
any one of claims 109-112, thereby treating the disease.
116. The method of claim 115, wherein the individual has a liver
disease, NAFLD, NASH, alcoholic steatohepatitis (ASH), alcoholic
liver disease, nonalcoholic liver disease, alcoholic cirrhosis,
nonalcoholic cirrhosis, steatohepatisis, hepatic steatosis,
hepatocellular carcinoma, alcoholic liver disease, HCV hepatitis,
chronic hepatitis, hereditary hemochromatosis, or primary
sclerosing cholangitis.
117. A method of inhibiting expression of HSD17B13 in a cell
comprising contacting the cell with an oligomeric compound of any
one of claims 109-112, thereby inhibiting expression of HSD17B13 in
the cell.
118. The method of claim 117, wherein the cell is in the liver of
an individual.
119. The method of claim 118, wherein the individual has, or is at
risk of having, liver disease, NAFLD, NASH, alcoholic
steatohepatitis (ASH), alcoholic liver disease, nonalcoholic liver
disease, alcoholic cirrhosis, nonalcoholic cirrhosis,
steatohepatisis, hepatic steatosis, hepatocellular carcinoma,
alcoholic liver disease, HCV hepatitis, chronic hepatitis,
hereditary hemochromatosis, or primary sclerosing cholangitis.
120. A method of ameliorating liver damage, steatosis, liver
fibrosis, liver inflammation, liver scarring or cirrhosis, liver
failure, liver enlargement, elevated transaminases, or hepatic fat
accumulation in an individual, comprising administering an
oligomeric compound of any one of claims 109-112 to the individual,
thereby ameliorating liver damage, steatosis, liver fibrosis, liver
inflammation, liver scarring or cirrhosis, liver failure, liver
enlargement, elevated transaminases, or hepatic fat accumulation in
the individual.
121. The method of claim 120, wherein the individual has, or is at
risk of having, liver disease, NAFLD, NASH, alcoholic
steatohepatitis (ASH), alcoholic liver disease, nonalcoholic liver
disease, alcoholic cirrhosis, nonalcoholic cirrhosis,
steatohepatisis, hepatic steatosis, hepatocellular carcinoma,
alcoholic liver disease, HCV hepatitis, chronic hepatitis,
hereditary hemochromatosis, or primary sclerosing cholangitis.
Description
SEQUENCE LISTING
[0001] The present application is being filed along with a Sequence
Listing in electronic format. The Sequence Listing is provided as a
file entitled BIOL0350WOSEQ_ST25.txt created Dec. 13, 2019, which
is 640 kb in size. The information in the electronic format of the
sequence listing is incorporated herein by reference in its
entirety.
FIELD
[0002] The present embodiments provide methods, compounds, and
compositions useful for inhibiting hydroxysteroid 17-beta
dehydrogenase 13 (LOC345275; 17-beta hydroxysteroid dehydrogenase;
HSD17B13; HSD17.beta.13) expression, and in certain instances,
reducing the amount of HSD17B13 protein in a cell or animal, which
can be useful for treating, preventing, or ameliorating a disease
associated with HSD17B13.
BACKGROUND
[0003] Non-alcoholic fatty liver disease (NAFLD) covers a spectrum
of liver disease from steatosis to nonalcoholic steatohepatitis
(NASH) and cirrhosis. NAFLD is defined as fat accumulation in the
liver exceeding 5% by weight, in the absense of significant alcohol
consumption, steatogenic medication, or hereditary disorders
(Kotronen et al, Arterioscler Thromb. Vasc. Biol. 2008, 28:
27-38).
[0004] Non-alcoholic steatohepatitis (NASH) is NAFLD with signs of
inflammation and hepatic injury. NASH is defined histologically by
macrovesicular steatosis, hepatocellular ballooning, and lobular
inflammatory infiltrates (Sanyal, Hepatol. Res. 2011. 41: 670-4).
NASH is estimated to affect 2-3% of the general population. In the
presence of other pathologies, such as obesity or diabetes, the
estimated prevalence increases to 7% and 62% respectively
(Hashimoto et al, J. Gastroenterol. 2011. 46(1): 63-69).
SUMMARY
[0005] Certain embodiments provided herein are compounds and
methods for reducing the amount or activity of HSD17B13 mRNA, and
in certain embodiments, reducing the amount or activity of HSD17B13
protein in a cell or animal. In certain embodiments, the animal has
a liver disease. In certain embodiments, the disease is NASH. In
certain embodiments, the disease is alcoholic steatohepatitis
(ASH). In certain embodiments, the disease is NAFLD. In certain
embodiments, the disease is hepatic steatosis. In certain
embodiments, the disease is cirrhosis. In certain embodiments, the
disease is hepatocellular carcinoma. In certain embodiments, the
disease is alcoholic liver disease. In certain embodiments, the
disease is HCV hepatitis. In certain embodiments, the disease is
chronic hepatitis. In certain embodiments, the disease is
hereditary hemochromatosis. In certain embodiments, the disease is
primary sclerosing cholangitis. Certain compounds provided herein
are directed to compounds and compositions that reduce liver
damage, steatosis, liver fibrosis, liver inflammation, liver
scarring or cirrhosis, liver failure, liver enlargement, elevated
transaminases, or hepatic fat accumulation in an animal.
[0006] Certain embodiments provided herein are directed to potent
and tolerable compounds and compositions useful for inhibiting
HSD17B13 expression, which can be useful for treating, preventing,
ameliorating, or slowing progression of liver diseases. Certain
embodiments provided herein are directed to compounds and
compositions that are more potent or have greater therapeutic value
than compounds publicly disclosed.
DETAILED DESCRIPTION
[0007] It is to be understood that both the foregoing general
description and the following detailed description are exemplary
and explanatory only and are not restrictive of the embodiments, as
claimed. Herein, the use of the singular includes the plural unless
specifically stated otherwise. As used herein, the use of "or"
means "and/or" unless stated otherwise. Furthermore, the use of the
term "including" as well as other forms, such as "includes" and
"included", is not limiting.
[0008] The section headings used herein are for organizational
purposes only and are not to be construed as limiting the subject
matter described. All documents, or portions of documents, cited in
this application, including, but not limited to, patents, patent
applications, articles, books, treatises, and GenBank and NCBI
reference sequence records are hereby expressly incorporated by
reference for the portions of the document discussed herein, as
well as in their entirety.
[0009] It is understood that the sequence set forth in each SEQ ID
NO in the examples contained herein is independent of any
modification to a sugar moiety, an internucleoside linkage, or a
nucleobase. As such, compounds defined by a SEQ ID NO may comprise,
independently, one or more modifications to a sugar moiety, an
internucleoside linkage, or a nucleobase. Compounds described by
ION number indicate a combination of nucleobase sequence, chemical
modification, and motif.
Definitions
[0010] Unless otherwise indicated, the following terms have the
following meanings:
[0011] "2'-deoxyfuranosyl sugar moiety" or "2'-deoxyfuranosyl
sugar" means a furanosyl sugar moiety having two hydrogens at the
2'-position. 2'-deoxyfuranosyl sugar moieties may be unmodified or
modified and may be substituted at positions other than the
2'-position or unsubstituted. A .beta.-D-2'-deoxyribosyl sugar
moiety in the context of an oligonucleotide is an unsubstituted,
unmodified 2'-deoxyfuranosyl and is found in naturally occurring
deoxyribonucleic acids (DNA).
[0012] "2'-deoxynucleoside" means a nucleoside comprising 2'-H(H)
furanosyl sugar moiety, as found in naturally occurring
deoxyribonucleic acids (DNA). In certain embodiments, a
2'-deoxynucleoside may comprise a modified nucleobase or may
comprise an RNA nucleobase (uracil).
[0013] "2'-O-methoxyethyl" (also 2'-MOE) refers to a
2'-O(CH.sub.2).sub.2--OCH.sub.3) in the place of the 2'-OH group of
a ribosyl ring. A 2'-O-methoxyethyl modified sugar is a modified
sugar.
[0014] "2'-MOE nucleoside" (also 2'-O-methoxyethyl nucleoside)
means a nucleoside comprising a 2'-MOE modified sugar moiety.
[0015] "2'-substituted nucleoside" or "2-modified nucleoside" means
a nucleoside comprising a 2'-substituted or 2'-modified sugar
moiety. As used herein, "2'-substituted" or "2-modified" in
reference to a sugar moiety means a sugar moiety comprising at
least one 2'-substituent group other than H or OH.
[0016] "3' target site" refers to the nucleotide of a target
nucleic acid which is complementary to the 3'-most nucleotide of a
particular compound.
[0017] "5' target site" refers to the nucleotide of a target
nucleic acid which is complementary to the 5'-most nucleotide of a
particular compound.
[0018] "5-methylcytosine" means a cytosine with a methyl group
attached to the 5 position.
[0019] "About" means within .+-.10% of a value. For example, if it
is stated, "the compounds affected about 70% inhibition of
HSD17B13", it is implied that HSD17B13 levels are inhibited within
a range of 60% and 80%.
[0020] "Administration" or "administering" refers to routes of
introducing a compound or composition provided herein to an
individual to perform its intended function. An example of a route
of administration that can be used includes, but is not limited to
parenteral administration, such as subcutaneous, intravenous, or
intramuscular injection or infusion.
[0021] "Administered concomitantly" or "co-administration" means
administration of two or more compounds in any manner in which the
pharmacological effects of both are manifest in the patient.
Concomitant administration does not require that both compounds be
administered in a single pharmaceutical composition, in the same
dosage form, by the same route of administration, or at the same
time. The effects of both compounds need not manifest themselves at
the same time. The effects need only be overlapping for a period of
time and need not be coextensive. Concomitant administration or
co-administration encompasses administration in parallel or
sequentially.
[0022] "Amelioration" refers to an improvement or lessening of at
least one indicator, sign, or symptom of an associated disease,
disorder, or condition. In certain embodiments, amelioration
includes a delay or slowing in the progression or severity of one
or more indicators of a condition or disease. The progression or
severity of indicators may be determined by subjective or objective
measures, which are known to those skilled in the art.
[0023] "Animal" refers to a human or non-human animal, including,
but not limited to, mice, rats, rabbits, dogs, cats, pigs, and
non-human primates, including, but not limited to, monkeys and
chimpanzees.
[0024] "Antisense activity" means any detectable and/or measurable
activity attributable to the hybridization of an antisense compound
to its target nucleic acid. In certain embodiments, antisense
activity is a decrease in the amount or expression of a target
nucleic acid or protein encoded by such target nucleic acid
compared to target nucleic acid levels or target protein levels in
the absence of the antisense compound to the target.
[0025] "Antisense compound" means a compound comprising an
oligonucleotide and optionally one or more additional features,
such as a conjugate group or terminal group. Examples of antisense
compounds include single-stranded and double-stranded compounds,
such as, oligonucleotides, ribozymes, siRNAs, shRNAs, ssRNAs, and
occupancy-based compounds.
[0026] "Antisense inhibition" means reduction of target nucleic
acid levels in the presence of an antisense compound complementary
to a target nucleic acid compared to target nucleic acid levels in
the absence of the antisense compound.
[0027] "Antisense mechanisms" are all those mechanisms involving
hybridization of a compound with target nucleic acid, wherein the
outcome or effect of the hybridization is either target degradation
or target occupancy with concomitant stalling of the cellular
machinery involving, for example, transcription or splicing.
[0028] "Antisense oligonucleotide" means an oligonucleotide having
a nucleobase sequence that is complementary to a target nucleic
acid or region or segment thereof. In certain embodiments, an
antisense oligonucleotide is specifically hybridizable to a target
nucleic acid or region or segment thereof.
[0029] "Bicyclic nucleoside" or "BNA" means a nucleoside comprising
a bicyclic sugar moiety. "Bicyclic sugar" or "bicyclic sugar
moiety" means a modified sugar moiety comprising two rings, wherein
the second ring is formed via a bridge connecting two of the atoms
in the first ring thereby forming a bicyclic structure. In certain
embodiments, the first ring of the bicyclic sugar moiety is a
furanosyl moiety. In certain embodiments, the bicyclic sugar moiety
does not comprise a furanosyl moiety.
[0030] "Branching group" means a group of atoms having at least 3
positions that are capable of forming covalent linkages to at least
3 groups. In certain embodiments, a branching group provides a
plurality of reactive sites for connecting tethered ligands to an
oligonucleotide via a conjugate linker and/or a cleavable
moiety.
[0031] "Cell-targeting moiety" means a conjugate group or portion
of a conjugate group that is capable of binding to a particular
cell type or particular cell types.
[0032] "cEt" or "constrained ethyl" means a ribosyl bicyclic sugar
moiety wherein the second ring of the bicyclic sugar is formed via
a bridge connecting the 4'-carbon and the 2'-carbon, wherein the
bridge has the formula: 4'-CH(CH.sub.3)--O-2', and wherein the
methyl group of the bridge is in the S configuration.
[0033] "cEt nucleoside" means a nucleoside comprising a cEt
modified sugar moiety.
[0034] "Chemical modification" in a compound describes the
substitutions or changes through chemical reaction, of any of the
units in the compound relative to the original state of such unit.
"Modified nucleoside" means a nucleoside having, independently, a
modified sugar moiety and/or modified nucleobase. "Modified
oligonucleotide" means an oligonucleotide comprising at least one
modified internucleoside linkage, a modified sugar, and/or a
modified nucleobase.
[0035] "Chemically distinct region" refers to a region of a
compound that is in some way chemically different than another
region of the same compound. For example, a region having
2'-O-methoxyethyl nucleotides is chemically distinct from a region
having nucleotides without 2'-O-methoxyethyl modifications.
[0036] "Chimeric antisense compounds" means antisense compounds
that have at least 2 chemically distinct regions, each position
having a plurality of subunits.
[0037] "Cleavable bond" means any chemical bond capable of being
split. In certain embodiments, a cleavable bond is selected from
among: an amide, a polyamide, an ester, an ether, one or both
esters of a phosphodiester, a phosphate ester, a carbamate, a
di-sulfide, or a peptide.
[0038] "Cleavable moiety" means a bond or group of atoms that is
cleaved under physiological conditions, for example, inside a cell,
an animal, or a human.
[0039] "Complementary" in reference to an oligonucleotide means the
nucleobase sequence of such oligonucleotide or one or more regions
thereof matches the nucleobase sequence of another oligonucleotide
or nucleic acid or one or more regions thereof when the two
nucleobase sequences are aligned in opposing directions. Nucleobase
matches or complementary nucleobases, as described herein, are
limited to the following pairs: adenine (A) and thymine (T),
adenine (A) and uracil (U), cytosine (C) and guanine (G), and
5-methyl cytosine (.sup.mC) and guanine (G) unless otherwise
specified. Complementary oligonucleotides and/or nucleic acids need
not have nucleobase complementarity at each nucleoside and may
include one or more nucleobase mismatches. By contrast, "fully
complementary" or "100% complementary" in reference to
oligonucleotides means that such oligonucleotides have nucleobase
matches at each nucleoside without any nucleobase mismatches.
[0040] "Conjugate group" means a group of atoms that is attached to
an oligonucleotide. Conjugate groups include a conjugate moiety and
a conjugate linker that attaches the conjugate moiety to the
oligonucleotide.
[0041] "Conjugate linker" means a group of atoms comprising at
least one bond that connects a conjugate moiety to an
oligonucleotide.
[0042] "Conjugate moiety" means a group of atoms that is attached
to an oligonucleotide via a conjugate linker.
[0043] "Contiguous" in the context of an oligonucleotide refers to
nucleosides, nucleobases, sugar moieties, or internucleoside
linkages that are immediately adjacent to each other. For example,
"contiguous nucleobases" means nucleobases that are immediately
adjacent to each other in a sequence.
[0044] "Designing" or "Designed to" refer to the process of
designing a compound that specifically hybridizes with a selected
nucleic acid molecule.
[0045] "Diluent" means an ingredient in a composition that lacks
pharmacological activity, but is pharmaceutically necessary or
desirable. For example, the diluent in an injected composition can
be a liquid, e.g. saline solution.
[0046] "Differently modified" means chemical modifications or
chemical substituents that are different from one another,
including absence of modifications. Thus, for example, a MOE
nucleoside and an unmodified DNA nucleoside are "differently
modified," even though the DNA nucleoside is unmodified. Likewise,
DNA and RNA are "differently modified," even though both are
naturally-occurring unmodified nucleosides. Nucleosides that are
the same but for comprising different nucleobases are not
differently modified. For example, a nucleoside comprising a 2'-OMe
modified sugar and an unmodified adenine nucleobase and a
nucleoside comprising a 2'-OMe modified sugar and an unmodified
thymine nucleobase are not differently modified.
[0047] "Dose" means a specified quantity of a compound or
pharmaceutical agent provided in a single administration, or in a
specified time period. In certain embodiments, a dose may be
administered in two or more boluses, tablets, or injections. For
example, in certain embodiments, where subcutaneous administration
is desired, the desired dose may require a volume not easily
accommodated by a single injection. In such embodiments, two or
more injections may be used to achieve the desired dose. In certain
embodiments, a dose may be administered in two or more injections
to minimize injection site reaction in an individual. In other
embodiments, the compound or pharmaceutical agent is administered
by infusion over an extended period of time or continuously. Doses
may be stated as the amount of pharmaceutical agent per hour, day,
week or month.
[0048] "Dosing regimen" is a combination of doses designed to
achieve one or more desired effects.
[0049] "Double-stranded antisense compound" means an antisense
compound comprising two oligomeric compounds that are complementary
to each other and form a duplex, and wherein one of the two said
oligomeric compounds comprises an oligonucleotide.
[0050] "Effective amount" means the amount of compound sufficient
to effectuate a desired physiological outcome in an individual in
need of the compound. The effective amount may vary among
individuals depending on the health and physical condition of the
individual to be treated, the taxonomic group of the individuals to
be treated, the formulation of the composition, assessment of the
individual's medical condition, and other relevant factors.
[0051] "Efficacy" means the ability to produce a desired
effect.
[0052] "Expression" includes all the functions by which a gene's
coded information is converted into structures present and
operating in a cell. Such structures include, but are not limited
to, the products of transcription and translation.
[0053] "Gapmer" means an oligonucleotide comprising an internal
region having a plurality of nucleosides that support RNase H
cleavage positioned between external regions having one or more
nucleosides, wherein the nucleosides comprising the internal region
are chemically distinct from the nucleoside or nucleosides
comprising the external regions. The internal region may be
referred to as the "gap" and the external regions may be referred
to as the "wings."
[0054] "HSD17B13" means any nucleic acid or protein of HSD17B13.
"HSD17B13 nucleic acid" means any nucleic acid encoding HSD17B13.
For example, in certain embodiments, a HSD17B13 nucleic acid
includes a DNA sequence encoding HSD17B13, an RNA sequence
transcribed from DNA encoding HSD17B13 (including genomic DNA
comprising introns and exons), and an mRNA sequence encoding
HSD17B13. "HSD17B13 mRNA" means an mRNA encoding a HSD17B13
protein. The target may be referred to in either upper or lower
case.
[0055] "HSD17B13 specific inhibitor" refers to any agent capable of
specifically inhibiting HSD17B13 RNA and/or HSD17B13 protein
expression or activity at the molecular level. For example,
HSD17B13 specific inhibitors include nucleic acids (including
antisense compounds), peptides, antibodies, small molecules, and
other agents capable of inhibiting the expression of HSD17B13 RNA
and/or HSD17B13 protein.
[0056] "Hybridization" means the annealing of oligonucleotides
and/or nucleic acids. While not limited to a particular mechanism,
the most common mechanism of hybridization involves hydrogen
bonding, which may be Watson-Crick, Hoogsteen or reversed Hoogsteen
hydrogen bonding, between complementary nucleobases. In certain
embodiments, complementary nucleic acid molecules include, but are
not limited to, an antisense compound and a nucleic acid target. In
certain embodiments, complementary nucleic acid molecules include,
but are not limited to, an oligonucleotide and a nucleic acid
target.
[0057] "Immediately adjacent" means there are no intervening
elements between the immediately adjacent elements of the same kind
(e.g. no intervening nucleobases between the immediately adjacent
nucleobases).
[0058] "Individual" means a human or non-human animal selected for
treatment or therapy.
[0059] "Inhibiting the expression or activity" refers to a
reduction or blockade of the expression or activity relative to the
expression of activity in an untreated or control sample and does
not necessarily indicate a total elimination of expression or
activity.
[0060] "Internucleoside linkage" means a group or bond that forms a
covalent linkage between adjacent nucleosides in an
oligonucleotide. "Modified internucleoside linkage" means any
internucleoside linkage other than a naturally occurring, phosphate
internucleoside linkage. Non-phosphate linkages are referred to
herein as modified internucleoside linkages.
[0061] "Lengthened oligonucleotides" are those that have one or
more additional nucleosides relative to an oligonucleotide
disclosed herein, e.g. a parent oligonucleotide.
[0062] "Linked nucleosides" means adjacent nucleosides linked
together by an internucleoside linkage.
[0063] "Linker-nucleoside" means a nucleoside that links an
oligonucleotide to a conjugate moiety. Linker-nucleosides are
located within the conjugate linker of a compound.
Linker-nucleosides are not considered part of the oligonucleotide
portion of a compound even if they are contiguous with the
oligonucleotide.
[0064] "Mismatch" or "non-complementary" means a nucleobase of a
first oligonucleotide that is not complementary to the
corresponding nucleobase of a second oligonucleotide or target
nucleic acid when the first and second oligonucleotides are
aligned. For example, nucleobases including but not limited to a
universal nucleobase, inosine, and hypoxanthine, are capable of
hybridizing with at least one nucleobase but are still mismatched
or non-complementary with respect to nucleobase to which it
hybridized. As another example, a nucleobase of a first
oligonucleotide that is not capable of hybridizing to the
corresponding nucleobase of a second oligonucleotide or target
nucleic acid when the first and second oligonucleotides are aligned
is a mismatch or non-complementary nucleobase.
[0065] "Modulating" refers to changing or adjusting a feature in a
cell, tissue, organ or organism. For example, modulating HSD17B13
RNA can mean to increase or decrease the level of HSD17B13 RNA
and/or HSD17B13 protein in a cell, tissue, organ or organism. A
"modulator" effects the change in the cell, tissue, organ or
organism. For example, a HSD17B13 compound can be a modulator that
decreases the amount of HSD17B13 RNA and/or HSD17B13 protein in a
cell, tissue, organ or organism.
[0066] "MOE" means methoxyethyl.
[0067] "Monomer" refers to a single unit of an oligomer. Monomers
include, but are not limited to, nucleosides and nucleotides.
[0068] "Motif" means the pattern of unmodified and/or modified
sugar moieties, nucleobases, and/or internucleoside linkages, in an
oligonucleotide.
[0069] "Natural" or "naturally occurring" means found in
nature.
[0070] "Non-bicyclic modified sugar" or "non-bicyclic modified
sugar moiety" means a modified sugar moiety that comprises a
modification, such as a substituent, that does not form a bridge
between two atoms of the sugar to form a second ring.
[0071] "Nucleic acid" refers to molecules composed of monomeric
nucleotides. A nucleic acid includes, but is not limited to,
ribonucleic acids (RNA), deoxyribonucleic acids (DNA),
single-stranded nucleic acids, and double-stranded nucleic
acids.
[0072] "Nucleobase" means a heterocyclic moiety capable of pairing
with a base of another nucleic acid. As used herein a "naturally
occurring nucleobase" is adenine (A), thymine (T), cytosine (C),
uracil (U), and guanine (G). A "modified nucleobase" is a naturally
occurring nucleobase that is chemically modified. A "universal
base" or "universal nucleobase" is a nucleobase other than a
naturally occurring nucleobase and modified nucleobase, and is
capable of pairing with any nucleobase.
[0073] "Nucleobase sequence" means the order of contiguous
nucleobases in a nucleic acid or oligonucleotide independent of any
sugar or internucleoside linkage.
[0074] "Nucleoside" means a compound comprising a nucleobase and a
sugar moiety. The nucleobase and sugar moiety are each,
independently, unmodified or modified. "Modified nucleoside" means
a nucleoside comprising a modified nucleobase and/or a modified
sugar moiety. Modified nucleosides include abasic nucleosides,
which lack a nucleobase.
[0075] "Oligomeric compound" means a compound comprising a single
oligonucleotide and, optionally, one or more additional features,
such as a conjugate group or terminal group.
[0076] "Oligonucleotide" means a polymer of linked nucleosides each
of which can be modified or unmodified, independent one from
another. Unless otherwise indicated, oligonucleotides consist of
8-80 linked nucleosides. "Modified oligonucleotide" means an
oligonucleotide, wherein at least one sugar, nucleobase, or
internucleoside linkage is modified. "Unmodified oligonucleotide"
means an oligonucleotide that does not comprise any sugar,
nucleobase, or internucleoside modification.
[0077] "Parent oligonucleotide" means an oligonucleotide whose
sequence is used as the basis of design for more oligonucleotides
of similar sequence but with different lengths, motifs, and/or
chemistries. The newly designed oligonucleotides may have the same
or overlapping sequence as the parent oligonucleotide.
[0078] "Parenteral administration" means administration through
injection or infusion. Parenteral administration includes
subcutaneous administration, intravenous administration,
intramuscular administration, intraarterial administration,
intraperitoneal administration, or intracranial administration,
e.g. intrathecal or intracerebroventricular administration.
[0079] "Pharmaceutically acceptable carrier or diluent" means any
substance suitable for use in administering to an individual. For
example, a pharmaceutically acceptable carrier can be a sterile
aqueous solution, such as PBS or water-for-injection.
[0080] "Pharmaceutically acceptable salts" means physiologically
and pharmaceutically acceptable salts of compounds, such as
oligomeric compounds or oligonucleotides, i.e., salts that retain
the desired biological activity of the parent compound and do not
impart undesired toxicological effects thereto.
[0081] "Pharmaceutical agent" means a compound that provides a
therapeutic benefit when administered to an individual.
[0082] "Pharmaceutical composition" means a mixture of substances
suitable for administering to an individual. For example, a
pharmaceutical composition may comprise one or more compounds or
salt thereof and a sterile aqueous solution.
[0083] "Phosphorothioate linkage" means a modified phosphate
linkage in which one of the non-bridging oxygen atoms is replaced
with a sulfur atom. A phosphorothioate internucleoside linkage is a
modified internucleoside linkage.
[0084] "Phosphorus moiety" means a group of atoms comprising a
phosphorus atom. In certain embodiments, a phosphorus moiety
comprises a mono-, di-, or tri-phosphate, or phosphorothioate.
[0085] "Portion" means a defined number of contiguous (i.e.,
linked) nucleobases of a nucleic acid. In certain embodiments, a
portion is a defined number of contiguous nucleobases of a target
nucleic acid. In certain embodiments, a portion is a defined number
of contiguous nucleobases of an oligomeric compound.
[0086] "Prevent" refers to delaying or forestalling the onset,
development or progression of a disease, disorder, or condition for
a period of time from minutes to indefinitely.
[0087] "Prodrug" means a compound in a form outside the body which,
when administered to an individual, is metabolized to another form
within the body or cells thereof. In certain embodiments, the
metabolized form is the active, or more active, form of the
compound (e.g., drug). Typically conversion of a prodrug within the
body is facilitated by the action of an enzyme(s) (e.g., endogenous
or viral enzyme) or chemical(s) present in cells or tissues, and/or
by physiologic conditions.
[0088] "Reduce" means to bring down to a smaller extent, size,
amount, or number.
[0089] "RefSeq No." is a unique combination of letters and numbers
assigned to a sequence to indicate the sequence is for a particular
target transcript (e.g., target gene). Such sequence and
information about the target gene (collectively, the gene record)
can be found in a genetic sequence database. Genetic sequence
databases include the NCBI Reference Sequence database, GenBank,
the European Nucleotide Archive, and the DNA Data Bank of Japan
(the latter three forming the International Nucleotide Sequence
Database Collaboration or INSDC).
[0090] "Region" is defined as a portion of the target nucleic acid
having at least one identifiable structure, function, or
characteristic.
[0091] "RNAi compound" means an antisense compound that acts, at
least in part, through RISC or Ago2, but not through RNase H, to
modulate a target nucleic acid and/or protein encoded by a target
nucleic acid. RNAi compounds include, but are not limited to
double-stranded siRNA, single-stranded RNA (ssRNA), and microRNA,
including microRNA mimics.
[0092] "Segments" are defined as smaller or sub-portions of regions
within a nucleic acid.
[0093] "Side effects" means physiological disease and/or conditions
attributable to a treatment other than the desired effects. In
certain embodiments, side effects include injection site reactions,
liver function test abnormalities, renal function abnormalities,
liver toxicity, renal toxicity, central nervous system
abnormalities, myopathies, and malaise. For example, increased
aminotransferase levels in serum may indicate liver toxicity or
liver function abnormality. For example, increased bilirubin may
indicate liver toxicity or liver function abnormality.
[0094] "Single-stranded" in reference to a compound means the
compound has only one oligonucleotide.
[0095] "Self-complementary" means an oligonucleotide that at least
partially hybridizes to itself. A compound consisting of one
oligonucleotide, wherein the oligonucleotide of the compound is
self-complementary, is a single-stranded compound. A
single-stranded compound may be capable of binding to a
complementary compound to form a duplex.
[0096] "Sites" are defined as unique nucleobase positions within a
target nucleic acid.
[0097] "Specifically hybridizable" refers to an oligonucleotide
having a sufficient degree of complementarity between the
oligonucleotide and a target nucleic acid to induce a desired
effect, while exhibiting minimal or no effects on non-target
nucleic acids. In certain embodiments, specific hybridization
occurs under physiological conditions.
[0098] "Specifically inhibit" with reference to a target nucleic
acid means to reduce or block expression of the target nucleic acid
while exhibiting fewer, minimal, or no effects on non-target
nucleic acids. Reduction does not necessarily indicate a total
elimination of the target nucleic acid's expression.
[0099] "Standard cell assay" means assay(s) described in the
Examples and reasonable variations thereof
[0100] "Standard in vivo experiment" means the procedure(s)
described in the Example(s) and reasonable variations thereof.
[0101] "Stereorandom chiral center" in the context of a population
of molecules of identical molecular formula means a chiral center
having a random stereochemical configuration. For example, in a
population of molecules comprising a stereorandom chiral center,
the number of molecules having the (S) configuration of the
stereorandom chiral center may be but is not necessarily the same
as the number of molecules having the (R) configuration of the
stereorandom chiral center. The stereochemical configuration of a
chiral center is considered random when it is the result of a
synthetic method that is not designed to control the stereochemical
configuration. In certain embodiments, a stereorandom chiral center
is a stereorandom phosphorothioate internucleoside linkage.
[0102] "Sugar moiety" means an unmodified sugar moiety or a
modified sugar moiety. As used herein, "unmodified sugar moiety"
means a .beta.-D-ribosyl moiety, as found in naturally occurring
RNA, or a .beta.-D-2'-deoxyribosyl sugar moiety as found in
naturally occurring DNA. As used herein, "modified sugar moiety" or
"modified sugar" means a sugar surrogate or a furanosyl sugar
moiety other than a .beta.-D-ribosyl or a .beta.-D-2'-deoxyribosyl.
Modified furanosyl sugar moieties may be modified or substituted at
a certain position(s) of the sugar moiety, substituted, or
unsubstituted, and they may or may not have a stereoconfiguration
other than .beta.-D-ribosyl. Modified furanosyl sugar moieties
include bicyclic sugars and non-bicyclic sugars.
[0103] "Sugar surrogate" means a modified sugar moiety that does
not comprise a furanosyl or tetrahydrofuranyl ring (is not a
"furanosyl sugar moiety") and that can link a nucleobase to another
group, such as an internucleoside linkage, conjugate group, or
terminal group in an oligonucleotide. Modified nucleosides
comprising sugar surrogates can be incorporated into one or more
positions within an oligonucleotide and such oligonucleotides are
capable of hybridizing to complementary oligomeric compounds or
nucleic acids.
[0104] "Synergy" or "synergize" refers to an effect of a
combination that is greater than additive of the effects of each
component alone at the same doses.
[0105] "Target gene" refers to a gene encoding a target.
[0106] "Targeting" means the specific hybridization of a compound
to a target nucleic acid in order to induce a desired effect.
[0107] "Target nucleic acid," "target RNA," "target RNA transcript"
and "nucleic acid target" all mean a nucleic acid capable of being
targeted by compounds described herein.
[0108] "Target region" means a portion of a target nucleic acid to
which one or more compounds is targeted.
[0109] "Target segment" means the sequence of nucleotides of a
target nucleic acid to which a compound is targeted. "5' target
site" refers to the 5'-most nucleotide of a target segment. "3'
target site" refers to the 3'-most nucleotide of a target
segment.
[0110] "Terminal group" means a chemical group or group of atoms
that is covalently linked to a terminus of an oligonucleotide.
[0111] "Therapeutically effective amount" means an amount of a
compound, pharmaceutical agent, or composition that provides a
therapeutic benefit to an individual.
[0112] "Treat" refers to administering a compound or pharmaceutical
composition to an animal in order to effect an alteration or
improvement of a disease, disorder, or condition in the animal.
Certain Embodiments
[0113] Certain embodiments provide methods, compounds and
compositions for inhibiting HSD17B13 expression.
[0114] Certain embodiments provide compounds targeted to a HSD17B13
nucleic acid. In certain embodiments, the HSD17B13 nucleic acid has
the sequence set forth in RefSeq or GENBANK Accession No.
NM_178135.4 (incorporated by reference, disclosed herein as SEQ ID
NO: 1), the complement of GENBANK Accession No. NC_000004.12
truncated from nucleotides 87301001 to U.S. Pat. No. 87,326,000
(incorporated by reference, disclosed herein as SEQ ID NO: 2), the
sequence listed as SEQ ID NO: 3, or GENBANK Accession No.
NM_001136230.2 (incorporated by reference, disclosed herein as SEQ
ID NO: 4). In certain embodiments, the compound is an antisense
compound or oligomeric compound. In certain embodiments, the
compound is single-stranded. In certain embodiments, the compound
is double-stranded.
[0115] Certain embodiments provide a compound comprising a modified
oligonucleotide consisting of 8 to 80 linked nucleosides and having
a nucleobase sequence comprising at least 8 contiguous nucleobases
of any of the nucleobase sequences of 8-2896. In certain
embodiments, the compound is an antisense compound or oligomeric
compound. In certain embodiments, the compound is single-stranded.
In certain embodiments, the compound is double-stranded. In certain
embodiments, the modified oligonucleotide consists of 10 to 30
linked nucleosides.
[0116] Certain embodiments provide a compound comprising a modified
oligonucleotide consisting of 9 to 80 linked nucleosides and having
a nucleobase sequence comprising at least 9 contiguous nucleobases
of any of the nucleobase sequences of 8-2896. In certain
embodiments, the compound is an antisense compound or oligomeric
compound. In certain embodiments, the compound is single-stranded.
In certain embodiments, the compound is double-stranded. In certain
embodiments, the modified oligonucleotide consists of 10 to 30
linked nucleosides.
[0117] Certain embodiments provide a compound comprising a modified
oligonucleotide consisting of 10 to 80 linked nucleosides and
having a nucleobase sequence comprising at least 10 contiguous
nucleobases of any of the nucleobase sequences of 8-2896. In
certain embodiments, the compound is an antisense compound or
oligomeric compound. In certain embodiments, the compound is
single-stranded. In certain embodiments, the compound is
double-stranded. In certain embodiments, the modified
oligonucleotide consists of 10 to 30 linked nucleosides.
[0118] Certain embodiments provide a compound comprising a modified
oligonucleotide consisting of 11 to 80 linked nucleosides and
having a nucleobase sequence comprising at least 11 contiguous
nucleobases of any of the nucleobase sequences of 8-2896. In
certain embodiments, the compound is an antisense compound or
oligomeric compound. In certain embodiments, the compound is
single-stranded. In certain embodiments, the compound is
double-stranded. In certain embodiments, the modified
oligonucleotide consists of 11 to 30 linked nucleosides.
[0119] Certain embodiments provide a compound comprising a modified
oligonucleotide consisting of 12 to 80 linked nucleosides and
having a nucleobase sequence comprising at least 12 contiguous
nucleobases of any of the nucleobase sequences of 8-2896. In
certain embodiments, the compound is an antisense compound or
oligomeric compound. In certain embodiments, the compound is
single-stranded. In certain embodiments, the compound is
double-stranded. In certain embodiments, the modified
oligonucleotide consists of 12 to 30 linked nucleosides.
[0120] Certain embodiments provide a compound comprising a modified
oligonucleotide consisting of 16 to 80 linked nucleosides and
having a nucleobase sequence comprising the nucleobase sequence of
any one of 8-2896. In certain embodiments, the compound is an
antisense compound or oligomeric compound. In certain embodiments,
the compound is single-stranded. In certain embodiments, the
compound is double-stranded. In certain embodiments, the modified
oligonucleotide consists of 16 to 30 linked nucleosides.
[0121] Certain embodiments provide a compound comprising a modified
oligonucleotide having a nucleobase sequence consisting of the
nucleobase sequence of any one of 8-2896. In certain embodiments,
the compound is an antisense compound or oligomeric compound. In
certain embodiments, the compound is single-stranded. In certain
embodiments, the compound is double-stranded.
[0122] Certain embodiments provide a compound comprising a modified
oligonucleotide consisting of 12 to 30 linked nucleosides and
having at least an 8, 9, 10, 11, 12, 13, 14, 15, or 16 contiguous
nucleobase portion complementary to an equal length portion within
nucleobases 3095-3369, 3371-7564, 7565-7672, 7673-8777, 8778-8909,
8910-10401, 10402-10508, 10509-12040, 12041-12178, 12179-15641,
15642-15758, 15759-20692, or 20693-22212 of SEQ ID NO: 2, wherein
said modified oligonucleotide is at least 85%, at least 90%, at
least 95%, or 100% complementary to SEQ ID NO: 2. In certain
embodiments, the compound is an antisense compound or oligomeric
compound. In certain embodiments, the compound is single-stranded.
In certain embodiments, the compound is double-stranded. In certain
embodiments, the modified oligonucleotide consists of 10 to 30
linked nucleosides. In certain embodiments, the modified
oligonucleotide consists of 16 to 30 linked nucleosides.
[0123] In certain embodiments, a compound comprises a modified
oligonucleotide consisting of 8 to 80 linked nucleosides and having
at least an 8, 9, 10, 11, 12, 13, 14, 15, or 16 contiguous
nucleobase portion complementary to an equal length portion within
nucleobases 1-46, 58-142, 1-142, 74-89, 154-197, 154-234, 200-232,
218-234, 240-345, 254-269, 354-746, 354-830, 519-534, 565-580,
603-628, 693-716, 734-750, 734-830, 749-828, 835-862, 835-957,
966-1044, 1017-1043, 1054-1106, 1055-1070, 1075-1169, 1074-1132,
1136-1169, 1175-1218, 1180-1217, 1250-1292, 1251-1279, 1296-1146,
1296-1448, 1308-1448, 1461-1481, 1461-1519, 1461-1647, 1461-1646,
1483-1535, 1538-1646, 1544-1561, 1597-1645, 1654-1685, 1654-1817,
1702-1817, 1705-1741, 1748-2211, 2174-2219, 2240-2272, 2244-2272,
2349-2370, 2350-2371, or 2378-2394 of an HSD17B13 nucleic acid
having the nucleobase sequence of SEQ ID NO: 1.
[0124] In certain embodiments, a compound comprises a modified
oligonucleotide consisting of 8 to 80 linked nucleosides and having
at least an 8, 9, 10, 11, 12, 13, 14, 15, or 16 contiguous
nucleobase portion complementary to an equal length portion within
nucleobases 1-46, 58-142, 1-142, 74-89, 154-197, 154-234, 200-232,
218-234, 240-345, 254-269, 354-746, 354-830, 519-534, 565-580,
603-628, 693-716, 734-750, 734-830, 749-828, 835-862, 835-957,
966-1044, 1017-1043, 1054-1106, 1055-1070, 1075-1169, 1074-1132,
1136-1169, 1175-1218, 1180-1217, 1250-1292, 1251-1279, 1296-1146,
1296-1448, 1308-1448, 1461-1481, 1461-1519, 1461-1647, 1461-1646,
1483-1535, 1538-1646, 1544-1561, 1597-1645, 1654-1685, 1654-1817,
1702-1817, 1705-1741, 1748-2211, 2174-2219, 2240-2272, 2244-2272,
2349-2370, 2350-2371, or 2378-2394 of an HSD17B13 nucleic acid
having the nucleobase sequence of SEQ ID NO: 1.
[0125] In certain embodiments, compounds target within nucleobases
3095-3454, 3095-3140, 3152-3236, 3168-3183, 3248-3328, 3312-3328,
3334-3390, 3348-3390, 3401-3420, 3429-3451, 3429-3454, 3474-3719,
3474-3644, 3478-3494, 3505-3531, 3544-3559, 3568-3634, 3671-3736,
3676-3717, 3721-3799, 3741-3771, 3750-3770, 3782-3799, 3834-3849,
3834-4154, 3877-3897, 3902-3917, 3933-3967, 3933-3979, 3988-4005,
3988-4017, 4068-4091, 4103-4118, 4123-4155, 4133-4155, 4220-4240,
4220-4264, 4249-4264, 4222-4240, 4296-4311, 4360-4378, 4389-4427,
4389-4431, 4405-4449, 4476-4496, 4517-4588, 4517-4552, 4537-4552,
4572-4588, 4640-4678, 4640-4879, 4641-4667, 4862-4879, 4991-5006,
4991-5305, 5029-5098, 5046-5098, 5104-5120, 5121-5141, 5125-5141,
5156-5256, 5158-5217, 5223-5242, 5267-5319, 5268-5319, 5395-5950,
5646-5695, 5655-5858, 5712-5752, 5712-5777, 5758-5777, 5782-5797,
5782-5862, 5804-5862, 5870-5910, 5871-6005, 5870-5910, 5870-5911,
5916-6007, 5935-5950, 5974-6007, 6029-6048, 6029-6055, 6035-6164,
6084-6099, 6084-6104, 6134-6164, 6170-6248, 6170-6275, 6170-6277,
6191-6218, 6221-6243, 6246-6275, 6284-6350, 6284-6352, 6298-6372,
6357-6372, 6388-6406, 6422-6493, 6422-6497, 6426-6621, 6567-6758,
6567-6582, 6597-6653, 6626-6653, 6710-6779, 6784-6811, 6785-6800,
6795-6811, 6913-6930, 6914-6929, 6914-6930, 6915-6930, 7101-7138,
7101-7441, 7125-7145, 7426-7441, 7473-7494, 7473-7498, 7481-7498,
7526-7543, 7550-7565, 7550-7634, 7563-7699, 7643-7676, 7680-7698,
7680-7699, 7708-7723, 7751-7819, 7768-7796, 7828-7866, 7834-7969,
7938-7968, 7938-7969, 7973-7994, 8017-8032, 8039-8186, 8039-8065,
8040-8065, 8121-8156, 8125-8151, 8164-8185, 8164-8186, 8205-8297,
8205-8220, 8236-8252, 8236-8271, 8256-8294, 8279-8297, 8487-8502,
8487-8627, 8529-8579, 8587-8628, 8636-8732, 8643-8910, 8744-8762,
8786-8910, 8939-9027, 8939-8996, 9000-9027, 9057-9096, 9080-9230,
9110-9173, 9188-9240, 9256-9275, 9312-9365, 9372-9401, 9373-9394,
9410-9446, 9410-9491, 9476-9555, 9497-9555, 9588-9678, 9588-9681,
9712-9737, 9712-9742, 9751-9811, 9751-10040, 9887-9902, 9908-10017,
10025-10040, 10058-10079, 10112-10160, 10124-10160, 10138-10160,
10180-10227, 10180-10233, 10258-10279, 10292-10310, 10293-10310,
10335-10375, 10335-10538, 10380-10538, 10554-10569, 10584-10599,
10728-10745, 10831-10870, 10930-10946, 10931-10946, 10970-10993,
10971-11015, 1100-11015, 11030-11045, 11073-11094, 11074-11094,
11115-11132, 11117-11132, 11155-11171, 11210-11228, 11210-11276,
11235-11276, 11290-11323, 11308-11323, 11384-11407, 11385-11443,
11428-11443, 11468-11529, 11542-11605, 11621-11636, 11621-11638,
11621-11668, 11652-11668, 11742-11808, 11742-11811, 11853-11881,
11853-11909, 11892-11912, 11924-11940, 11925-12226, 11953-12027,
12038-12226, 12238-12270, 12337-12531, 12337-12368, 12410-12448,
12465-12531, 12598-12642, 12598-12742, 12647-12742, 12758-12832,
12761-12832, 12862-12904, 13548-13627, 13551-13654, 13638-13674,
13688-13798, 13704-13798, 13813-13932, 13949-14064, 13951-13969,
13975-14064, 14077-14107, 14089-14107, 14126-14147, 14165-14221,
14166-14221, 14243-14298, 14243-14299, 14315-14336, 14316-14336,
14362-14414, 14432-14454, 14461-14514, 14465-14514, 14541-14815,
14541-14636, 14724-14746, 1400-14815, 14905-14951, 14916-14951,
15019-15039, 15022-15039, 15170-15185, 15200-15232, 15211-15268,
15244-15268, 15279-15295, 15279-15399, 15312-15343, 15350-15399,
15405-15460, 15492-15526, 15570-15586, 15633-15808, 15641-15657,
15643-15711, 15716-15765, 15771-15802, 16116-16144, 16116-16149,
16189-16206, 16189-16342, 16218-16240, 16254-16310, 16327-16352,
16377-16397, 16377-16400, 16407-16439, 16407-16440, 16461-16476,
16533-16548, 16755-16770, 16895-16920, 16905-16920, 16956-16984,
16956-17092, 17014-17034, 17135-17159, 17041-17062, 17077-17092,
17135-17159, 17227-17254, 17672-17795, 17675-17872, 17802-17817,
17857-17872, 17909-17945, 17909-17971, 17953-17971, 17954-17971,
17984-18061, 17985-18048, 18075-18117, 18087-18115, 18138-18160,
18176-18193, 18505-18555, 18506-18536, 18585-18600, 18658-18712,
18662-18762, 18720-18763, 18798-18864, 18871-18888, 18901-18940,
18925-18940, 18958-18983, 18958-19013, 19388-19460, 19467-19513,
19474-19505, 19531-19626, 19533-19626, 19649-19717, 19649-19726,
19731-19801, 19731-19842, 19815-19875, 19860-19951, 19887-19951,
19970-19985, 19970-20054, 19999-20024, 20037-20061, 20087-20102,
20109-20153, 20087-20207, 20172-20212, 20356-20438, 20248-20437,
20248-20264, 20470-20508, 20481-20507, 20571-20623, 20571-20644,
20685-20700, 20706-21032, 20706-20772, 20781-20859, 20869-20984,
20990-21033, 21065-21102, 21065-21263, 21092-21632, 21276-21500,
21517-21632, 21989-22034, 22059-22087, or 22164-22209 of an
HSD17B13 nucleic acid having the nucleobase sequence of SEQ ID NO:
2.
[0126] In certain embodiments, compounds have at least an 8, 9, 10,
11, 12, 13, 14, 15, or 16 contiguous nucleobase portion
complementary to an equal length portion within nucleobases
3095-3454, 3095-3140, 3152-3236, 3168-3183, 3248-3328, 3312-3328,
3334-3390, 3348-3390, 3401-3420, 3429-3451, 3429-3454, 3474-3719,
3474-3644, 3478-3494, 3505-3531, 3544-3559, 3568-3634, 3671-3736,
3676-3717, 3721-3799, 3741-3771, 3750-3770, 3782-3799, 3834-3849,
3834-4154, 3877-3897, 3902-3917, 3933-3967, 3933-3979, 3988-4005,
3988-4017, 4068-4091, 4103-4118, 4123-4155, 4133-4155, 4220-4240,
4220-4264, 4249-4264, 4222-4240, 4296-4311, 4360-4378, 4389-4427,
4389-4431, 4405-4449, 4476-4496, 4517-4588, 4517-4552, 4537-4552,
4572-4588, 4640-4678, 4640-4879, 4641-4667, 4862-4879, 4991-5006,
4991-5305, 5029-5098, 5046-5098, 5104-5120, 5121-5141, 5125-5141,
5156-5256, 5158-5217, 5223-5242, 5267-5319, 5268-5319, 5395-5950,
5646-5695, 5655-5858, 5712-5752, 5712-5777, 5758-5777, 5782-5797,
5782-5862, 5804-5862, 5870-5910, 5871-6005, 5870-5910, 5870-5911,
5916-6007, 5935-5950, 5974-6007, 6029-6048, 6029-6055, 6035-6164,
6084-6099, 6084-6104, 6134-6164, 6170-6248, 6170-6275, 6170-6277,
6191-6218, 6221-6243, 6246-6275, 6284-6350, 6284-6352, 6298-6372,
6357-6372, 6388-6406, 6422-6493, 6422-6497, 6426-6621, 6567-6758,
6567-6582, 6597-6653, 6626-6653, 6710-6779, 6784-6811, 6785-6800,
6795-6811, 6913-6930, 6914-6929, 6914-6930, 6915-6930, 7101-7138,
7101-7441, 7125-7145, 7426-7441, 7473-7494, 7473-7498, 7481-7498,
7526-7543, 7550-7565, 7550-7634, 7563-7699, 7643-7676, 7680-7698,
7680-7699, 7708-7723, 7751-7819, 7768-7796, 7828-7866, 7834-7969,
7938-7968, 7938-7969, 7973-7994, 8017-8032, 8039-8186, 8039-8065,
8040-8065, 8121-8156, 8125-8151, 8164-8185, 8164-8186, 8205-8297,
8205-8220, 8236-8252, 8236-8271, 8256-8294, 8279-8297, 8487-8502,
8487-8627, 8529-8579, 8587-8628, 8636-8732, 8643-8910, 8744-8762,
8786-8910, 8939-9027, 8939-8996, 9000-9027, 9057-9096, 9080-9230,
9110-9173, 9188-9240, 9256-9275, 9312-9365, 9372-9401, 9373-9394,
9410-9446, 9410-9491, 9476-9555, 9497-9555, 9588-9678, 9588-9681,
9712-9737, 9712-9742, 9751-9811, 9751-10040, 9887-9902, 9908-10017,
10025-10040, 10058-10079, 10112-10160, 10124-10160, 10138-10160,
10180-10227, 10180-10233, 10258-10279, 10292-10310, 10293-10310,
10335-10375, 10335-10538, 10380-10538, 10554-10569, 10584-10599,
10728-10745, 10831-10870, 10930-10946, 10931-10946, 10970-10993,
10971-11015, 1100-11015, 11030-11045, 11073-11094, 11074-11094,
11115-11132, 11117-11132, 11155-11171, 11210-11228, 11210-11276,
11235-11276, 11290-11323, 11308-11323, 11384-11407, 11385-11443,
11428-11443, 11468-11529, 11542-11605, 11621-11636, 11621-11638,
11621-11668, 11652-11668, 11742-11808, 11742-11811, 11853-11881,
11853-11909, 11892-11912, 11924-11940, 11925-12226, 11953-12027,
12038-12226, 12238-12270, 12337-12531, 12337-12368, 12410-12448,
12465-12531, 12598-12642, 12598-12742, 12647-12742, 12758-12832,
12761-12832, 12862-12904, 13548-13627, 13551-13654, 13638-13674,
13688-13798, 13704-13798, 13813-13932, 13949-14064, 13951-13969,
13975-14064, 14077-14107, 14089-14107, 14126-14147, 14165-14221,
14166-14221, 14243-14298, 14243-14299, 14315-14336, 14316-14336,
14362-14414, 14432-14454, 14461-14514, 14465-14514, 14541-14815,
14541-14636, 14724-14746, 1400-14815, 14905-14951, 14916-14951,
15019-15039, 15022-15039, 15170-15185, 15200-15232, 15211-15268,
15244-15268, 15279-15295, 15279-15399, 15312-15343, 15350-15399,
15405-15460, 15492-15526, 15570-15586, 15633-15808, 15641-15657,
15643-15711, 15716-15765, 15771-15802, 16116-16144, 16116-16149,
16189-16206, 16189-16342, 16218-16240, 16254-16310, 16327-16352,
16377-16397, 16377-16400, 16407-16439, 16407-16440, 16461-16476,
16533-16548, 16755-16770, 16895-16920, 16905-16920, 16956-16984,
16956-17092, 17014-17034, 17135-17159, 17041-17062, 17077-17092,
17135-17159, 17227-17254, 17672-17795, 17675-17872, 17802-17817,
17857-17872, 17909-17945, 17909-17971, 17953-17971, 17954-17971,
17984-18061, 17985-18048, 18075-18117, 18087-18115, 18138-18160,
18176-18193, 18505-18555, 18506-18536, 18585-18600, 18658-18712,
18662-18762, 18720-18763, 18798-18864, 18871-18888, 18901-18940,
18925-18940, 18958-18983, 18958-19013, 19388-19460, 19467-19513,
19474-19505, 19531-19626, 19533-19626, 19649-19717, 19649-19726,
19731-19801, 19731-19842, 19815-19875, 19860-19951, 19887-19951,
19970-19985, 19970-20054, 19999-20024, 20037-20061, 20087-20102,
20109-20153, 20087-20207, 20172-20212, 20356-20438, 20248-20437,
20248-20264, 20470-20508, 20481-20507, 20571-20623, 20571-20644,
20685-20700, 20706-21032, 20706-20772, 20781-20859, 20869-20984,
20990-21033, 21065-21102, 21065-21263, 21092-21632, 21276-21500,
21517-21632, 21989-22034, 22059-22087, or 22164-22209 of an
HSD17B13 nucleic acid having the nucleobase sequence of SEQ ID NO:
2. In certain embodiments, these compounds are antisense compounds,
oligomeric compounds, or oligonucleotides. In certain embodiments,
the modified oligonucleotide consists of 10 to 30 linked
nucleosides. In certain embodiments, the modified oligonucleotide
consists of 16 to 30 linked nucleosides.
[0127] In certain embodiments, compounds have a nucleobase sequence
complementary to nucleobases 1323-1338, 1600-1615, 1627-1642, or
1782-1797 of an HSD17B13 nucleic acid having the nucleobase
sequence of SEQ ID NO: 1.
[0128] In certain embodiments, compounds have a nucleobase sequence
comprising a portion of at least 8, 9, 10, 11, 12, 13, 14, 15, or
16 contiguous nucleobases complementary within an equal length
portion of nucleobases 1323-1338, 1600-1615, 1627-1642, or
1782-1797 of an HSD17B13 nucleic acid having the nucleobase
sequence of SEQ ID NO: 1. In certain embodiments, these compounds
are antisense compounds, oligomeric compounds, or oligonucleotides.
In certain embodiments, the modified oligonucleotide consists of 10
to 30 linked nucleosides. In certain embodiments, the modified
oligonucleotide consists of 16 to 30 linked nucleosides.
[0129] In certain embodiments, compounds have a nucleobase sequence
complementary to nucleobases 3439-3454, 3552-3567, 3754-3769,
3963-3978, 4406-4421, 4123-4138, 4139-4154, 4991-5006, 5045-5060,
5662-5677, 6476-6491, 6478-6493, 17992-18007, 21138-21153,
21415-21430, 21442-21457, or 21597-21612 of an HSD17B13 nucleic
acid having the nucleobase sequence of SEQ ID NO: 2.
[0130] In certain embodiments, compounds have a nucleobase sequence
comprising a portion of at least 8, 9, 10, 11, 12, 13, 14, 15, or
16 contiguous nucleobases complementary within an equal length
portion of nucleobases 3439-3454, 3552-3567, 3754-3769, 3963-3978,
4406-4421, 4123-4138, 4139-4154, 4991-5006, 5045-5060, 5662-5677,
6476-6491, 6478-6493, 17992-18007, 21138-21153, 21415-21430,
21442-21457, or 21597-21612 of an HSD17B13 nucleic acid having the
nucleobase sequence of SEQ ID NO: 2. In certain embodiments, these
compounds are antisense compounds, oligomeric compounds, or
oligonucleotides. In certain embodiments, the modified
oligonucleotide consists of 10 to 30 linked nucleosides. In certain
embodiments, the modified oligonucleotide consists of 16 to 30
linked nucleosides.
[0131] In certain embodiments, any of the foregoing modified
oligonucleotides has at least one modified internucleoside linkage,
at least one modified sugar, and/or at least one modified
nucleobase.
[0132] In certain embodiments, at least one nucleoside of any of
the foregoing modified oligonucleotides comprises a modified sugar.
In certain embodiments, the modified sugar comprises a
2'-O-methoxyethyl group. In certain embodiments, the modified sugar
is a bicyclic sugar, such as a 4'-CH(CH3)-O-2' group, a 4'-CH2-O-2'
group, or a 4'-(CH2)2-O-2'group.
[0133] In certain embodiments, at least one internucleoside linkage
of the modified oligonucleotide comprises a modified
internucleoside linkage, such as a phosphorothioate internucleoside
linkage.
[0134] In certain embodiments, at least one nucleobase of any of
the foregoing modified oligonucleotides comprises a modified
nucleobase, such as 5-methylcytosine.
[0135] In certain embodiments, any of the foregoing modified
oligonucleotides has: [0136] a gap segment consisting of linked
deoxynucleosides; [0137] a 5' wing segment consisting of linked
nucleosides; and [0138] a 3' wing segment consisting of linked
nucleosides; wherein the gap segment is positioned between the 5'
wing segment and the 3' wing segment and wherein each nucleoside of
each wing segment comprises a modified sugar. In certain
embodiments, the modified oligonucleotide consists of 12 to 30
linked nucleosides and has a nucleobase sequence comprising the
sequence recited in any one of SEQ ID NOs: 8-2896. In certain
embodiments, the modified oligonucleotide is 16 to 30 linked
nucleosides in length having a nucleobase sequence comprising the
nucleobase sequence recited in any one of SEQ ID NOs: 8-2896. In
certain embodiments, the modified oligonucleotide is 16 linked
nucleosides in length having a nucleobase sequence consisting of
the sequence recited in any one of SEQ ID NOs: 8-2896.
[0139] In certain embodiments, a compound comprises or consists of
a modified oligonucleotide consisting of 16 to 80 linked
nucleobases and having a nucleobase sequence comprising the
nucleobase sequence recited in any one of 8-2896, wherein the
modified oligonucleotide has: [0140] a gap segment consisting of
linked 2'-deoxynucleosides; [0141] a 5' wing segment consisting of
linked nucleosides; and [0142] a 3' wing segment consisting of
linked nucleosides;
[0143] wherein the gap segment is positioned between the 5' wing
segment and the 3' wing segment and wherein each nucleoside of each
wing segment comprises a modified sugar. In certain embodiments,
the modified oligonucleotide consists of 16 to 30 linked
nucleosides. In certain embodiments, the modified oligonucleotide
consists of 16 linked nucleosides
[0144] In certain embodiments, a compound comprises or consists of
a modified oligonucleotide 12-30 linked nucleobases in length
having a nucleobase sequence comprising the sequence recited in any
one of SEQ ID NOs: 286, 817, 983, 1215, 747, 43, 355, 1602, 201,
734, 1249, 208, 513, 1449, 1448, and 1595, wherein the modified
oligonucleotide has:
[0145] a gap segment consisting of ten linked
2'-deoxynucleosides;
[0146] a 5' wing segment consisting of three linked nucleosides;
and
[0147] a 3' wing segment consisting of three linked
nucleosides;
wherein the gap segment is positioned between the 5' wing segment
and the 3' wing segment, wherein each nucleoside of each wing
segment comprises a cEt sugar; wherein each internucleoside linkage
is a phosphorothioate linkage and wherein each cytosine is a
5-methylcytosine. In certain embodiments, the modified
oligonucleotide consists of 16-30 linked nucleosides. In certain
embodiments, the modified oligonucleotide consists of 16 linked
nucleosides.
[0148] In certain embodiments, a compound comprises or consists of
a modified oligonucleotide 12-30 linked nucleobases in length
having a nucleobase sequence comprising the sequence recited in any
one of SEQ ID NOs: 819, wherein the modified oligonucleotide
has:
[0149] a gap segment consisting of nine linked
2'-deoxynucleosides;
[0150] a 5' wing segment consisting of three linked nucleosides;
and
[0151] a 3' wing segment consisting of four linked nucleosides;
wherein the gap segment is positioned between the 5' wing segment
and the 3' wing segment, wherein each nucleoside of the 5' wing
segment comprises a cEt sugar; wherein the sugar residues of the
nucleosides of the 3' wing segment are 5'-cEt-cEt-cEt-MOE-3';
wherein each internucleoside linkage is a phosphorothioate linkage
and wherein each cytosine is a 5-methylcytosine. In certain
embodiments, the modified oligonucleotide consists of 16-30 linked
nucleosides. In certain embodiments, the modified oligonucleotide
consists of 16 linked nucleosides.
[0152] In certain embodiments, a compound comprises or consists of
a modified oligonucleotide 12-30 linked nucleobases in length
having a nucleobase sequence comprising the sequence recited in any
one of SEQ ID NOs: 1595, wherein the modified oligonucleotide
has:
[0153] a gap segment consisting of ten linked nucleosides;
[0154] a 5' wing segment consisting of three linked nucleosides;
and
[0155] a 3' wing segment consisting of four linked nucleosides;
wherein the gap segment is positioned between the 5' wing segment
and the 3' wing segment and wherein the gap segment consists of
5'-one deoxy, one 2'-O-methyl nucleoside, and eight
deoxynucleosides-3', wherein each nucleoside of each of the wing
segments comprises a cEt sugar; wherein each internucleoside
linkage is a phosphorothioate linkage and wherein each cytosine is
a 5-methylcytosine. In certain embodiments, the modified
oligonucleotide consists of 16-30 linked nucleosides. In certain
embodiments, the modified oligonucleotide consists of 16 linked
nucleosides.
[0156] In any of the foregoing embodiments, the compound or
oligonucleotide can be at least 85%, at least 90%, at least 95%, at
least 98%, at least 99%, or 100% complementary to a nucleic acid
encoding HSD17B13.
[0157] In any of the foregoing embodiments, the compound can be
single-stranded. In certain embodiments, the compound comprises
deoxyribonucleotides. In certain embodiments, the compound is
double-stranded. In certain embodiments, the compound is
double-stranded and comprises ribonucleotides. In any of the
foregoing embodiments, the compound can be an antisense compound or
oligomeric compound.
[0158] In any of the foregoing embodiments, the compound can
consist of 8 to 80, 10 to 30, 12 to 50, 13 to 30, 13 to 50, 14 to
30, 14 to 50, 15 to 30, 15 to 50, 16 to 30, 16 to 50, 17 to 30, 17
to 50, 18 to 22, 18 to 24, 18 to 30, 18 to 50, 19 to 22, 19 to 30,
19 to 50, or 20 to 30 linked nucleosides. In certain embodiments,
the compound comprises or consists of an oligonucleotide.
[0159] In certain embodiments, a compound comprises a modified
oligonucleotide described herein and a conjugate group. In certain
embodiments, the conjugate group is linked to the modified
oligonucleotide at the 5' end of the modified oligonucleotide. In
certain embodiments, the conjugate group is linked to the modified
oligonucleotide at the 3' end of the modified oligonucleotide. In
certain embodiments, the conjugate group comprises at least one
N-Acetylgalactosamine (GalNAc), at least two N-Acetylgalactosamines
(GalNAcs), or at least three N-Acetylgalactosamines (GalNAcs).
[0160] In certain embodiments, compounds or compositions provided
herein comprise a pharmaceutically acceptable salt of the modified
oligonucleotide. In certain embodiments, the salt is a sodium salt.
In certain embodiments, the salt is a potassium salt.
[0161] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00001##
or a salt thereof. In certain embodiments, the compound is a sodium
salt. In certain embodiments, the compound is a potassium salt.
[0162] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00002##
[0163] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00003##
or a salt thereof. In certain embodiments, the compound is a sodium
salt. In certain embodiments, the compound is a potassium salt.
[0164] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00004##
[0165] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00005##
or a salt thereof. In certain embodiments, the compound is a sodium
salt. In certain embodiments, the compound is a potassium salt.
[0166] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00006##
[0167] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00007##
or a salt thereof. In certain embodiments, the compound is a sodium
salt. In certain embodiments, the compound is a potassium salt.
[0168] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00008##
[0169] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00009##
or a salt thereof. In certain embodiments, the compound is a sodium
salt. In certain embodiments, the compound is a potassium salt.
[0170] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00010##
[0171] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00011##
or a salt thereof. In certain embodiments, the compound is a sodium
salt. In certain embodiments, the compound is a potassium salt.
[0172] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00012##
[0173] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00013##
or a salt thereof. In certain embodiments, the compound is a sodium
salt. In certain embodiments, the compound is a potassium salt.
[0174] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00014##
[0175] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00015##
or a salt thereof. In certain embodiments, the compound is a sodium
salt. In certain embodiments, the compound is a potassium salt.
[0176] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00016##
[0177] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00017##
or a salt thereof. In certain embodiments, the compound is a sodium
salt. In certain embodiments, the compound is a potassium salt.
[0178] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00018##
[0179] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00019##
or a salt thereof. In certain embodiments, the compound is a sodium
salt. In certain embodiments, the compound is a potassium salt.
[0180] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00020##
[0181] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00021##
or a salt thereof. In certain embodiments, the compound is a sodium
salt. In certain embodiments, the compound is a potassium salt.
[0182] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00022##
[0183] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00023##
or a salt thereof. In certain embodiments, the compound is a sodium
salt. In certain embodiments, the compound is a potassium salt.
[0184] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00024##
[0185] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00025##
or a salt thereof. In certain embodiments, the compound is a sodium
salt. In certain embodiments, the compound is a potassium salt.
[0186] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00026##
[0187] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00027##
or a salt thereof. In certain embodiments, the compound is a sodium
salt. In certain embodiments, the compound is a potassium salt.
[0188] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00028##
[0189] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00029##
or a salt thereof. In certain embodiments, the compound is a sodium
salt. In certain embodiments, the compound is a potassium salt.
[0190] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00030##
[0191] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00031##
or a salt thereof. In certain embodiments, the compound is a sodium
salt. In certain embodiments, the compound is a potassium salt.
[0192] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00032##
[0193] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00033##
or a salt thereof. In certain embodiments, the compound is a sodium
salt. In certain embodiments, the compound is a potassium salt.
[0194] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00034##
[0195] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00035##
or a salt thereof. In certain embodiments, the compound is a sodium
salt. In certain embodiments, the compound is a potassium salt.
[0196] In certain embodiments, a compound provided herein is
according to the following chemical structure:
##STR00036##
[0197] Under certain conditions, certain compounds disclosed herein
act as acids. Although such compounds may be drawn or described in
protonated (free acid) form, or ionized and in association with a
cation (salt) form, aqueous solutions of such compounds exist in
equilibrium among such forms. For example, a phosphate linkage of
an oligonucleotide in aqueous solution exists in equilibrium among
free acid, anion and salt forms. Unless otherwise indicated,
compounds described herein are intended to include all such forms.
Moreover, certain oligonucleotides have several such linkages, each
of which is in equilibrium. Thus, oligonucleotides in solution
exist in an ensemble of forms at multiple positions all at
equilibrium. The term "oligonucleotide" is intended to include all
such forms. Drawn structures necessarily depict a single form.
Nevertheless, unless otherwise indicated, such drawings are
likewise intended to include corresponding forms. Herein, a
structure depicting the free acid of a compound followed by the
term "or a salt thereof" expressly includes all such forms that may
be fully or partially protonated/de-protonated/in association with
a cation. In certain instances, one or more specific cation is
identified.
[0198] In certain embodiments, modified oligonucleotides or
oligomeric compounds are in aqueous solution with sodium. In
certain embodiments, modified oligonucleotides or oligomeric
compounds are in aqueous solution with potassium. In certain
embodiments, modified oligonucleotides or oligomeric compounds are
in PBS. In certain embodiments, modified oligonucleotides or
oligomeric compounds are in water. In certain such embodiments, the
pH of the solution is adjusted with NaOH and/or HCl to achieve a
desired pH. In certain embodiments, the compounds or compositions
as described herein are active by virtue of having at least one of
an in vitro IC.sub.50 of less than 2 .mu.M, less than 1.5 .mu.M,
less than 1 .mu.M, less than 0.9 .mu.M, less than 0.8 .mu.M, less
than 0.7 .mu.M, less than 0.6 .mu.M, less than 0.5 .mu.M, less than
0.4 .mu.M, less than 0.3 .mu.M, less than 0.2 .mu.M, less than 0.1
.mu.M, less than 0.05 .mu.M, less than 0.04 .mu.M, less than 0.03
.mu.M, less than 0.02 .mu.M, or less than 0.01 .mu.M.
[0199] In certain embodiments, the compounds or compositions as
described herein are highly tolerable as demonstrated by having at
least one of an increase in alanine transaminase (ALT) or aspartate
transaminase (AST) value of no more than 4 fold, 3 fold, or 2 fold
over control animals, or an increase in liver, spleen, or kidney
weight of no more than 30%, 20%, 15%, 12%, 10%, 5%, or 2% compared
to control animals. In certain embodiments, the compounds or
compositions as described herein are highly tolerable as
demonstrated by having no increase of ALT or AST over control
animals. In certain embodiments, the compounds or compositions as
described herein are highly tolerable as demonstrated by having no
increase in liver, spleen, or kidney weight over control
animals.
[0200] Certain embodiments provide a composition comprising the
compound of any of the aforementioned embodiments or any
pharmaceutically acceptable salt thereof and at least one of a
pharmaceutically acceptable carrier or diluent. In certain
embodiments, the composition has a viscosity less than about 40
centipoise (cP), less than about 30 centipose (cP), less than about
20 centipose (cP), less than about 15 centipose (cP), or less than
about 10 centipose (cP). In certain embodiments, the composition
having any of the aforementioned viscosities comprises a compound
provided herein at a concentration of about 100 mg/mL, about 125
mg/mL, about 150 mg/mL, about 175 mg/mL, about 200 mg/mL, about 225
mg/mL, about 250 mg/mL, about 275 mg/mL, or about 300 mg/mL. In
certain embodiments, the composition having any of the
aforementioned viscosities and/or compound concentrations has a
temperature of room temperature, or about 20.degree. C., about
21.degree. C., about 22.degree. C., about 23.degree. C., about
24.degree. C., about 25.degree. C., about 26.degree. C., about
27.degree. C., about 28.degree. C., about 29.degree. C., or about
30.degree. C.
[0201] Non-limiting numbered embodiments include:
[0202] Embodiment 1: Certain embodiments provide a compound
comprising a modified oligonucleotide consisting of 8 to 80 linked
nucleosides and having a nucleobase sequence comprising at least 8,
at least 9, at least 10, at least 11, or at least 12 contiguous
nucleobases of any of the nucleobase sequences of SEQ ID NOs:
8-2896. Certain embodiments provide a compound comprising a
modified oligonucleotide consisting of 12 to 30 linked nucleosides,
wherein wherein the modified oligonucleotide has a nucleobase
sequence comprising at least 8, at least 9, at least 10, at least
11, or at least 12 contiguous nucleobases of any of the nucleobase
sequences of SEQ ID NOs: 8-2896.
[0203] Embodiment 2: Certain embodiments provide a compound
comprising modified oligonucleotide consisting of 8 to 80 linked
nucleosides and having a nucleobase sequence comprising the
nucleobase sequence of any one of SEQ ID NOs: 8-2896. Certain
embodiments provide a compound comprising modified oligonucleotide
consisting of 12 to 30 linked nucleosides and having a nucleobase
sequence comprising the nucleobase sequence of any one of SEQ ID
NOs: 8-2896.
[0204] Embodiment 3: Certain embodiments provide a compound
comprising a modified oligonucleotide having a nucleobase sequence
consisting of any one of SEQ ID NOs: 8-2896.
[0205] Embodiment 4: Certain embodiments provide a compound
comprising modified oligonucleotide consisting of 8 to 80 linked
nucleosides, or consisting of 12 to 30 linked nucleosides, wherein
the modified oligonucleotide has a nucleobase sequence comprising a
portion of at least 8 contiguous nucleobases complementary to an
equal length portion of nucleobases 3095-3454, 3095-3140,
3152-3236, 3168-3183, 3248-3328, 3312-3328, 3334-3390, 3348-3390,
3401-3420, 3429-3451, 3429-3454, 3474-3719, 3474-3644, 3478-3494,
3505-3531, 3544-3559, 3568-3634, 3671-3736, 3676-3717, 3721-3799,
3741-3771, 3750-3770, 3782-3799, 3834-3849, 3834-4154, 3877-3897,
3902-3917, 3933-3967, 3933-3979, 3988-4005, 3988-4017, 4068-4091,
4103-4118, 4123-4155, 4133-4155, 4220-4240, 4220-4264, 4249-4264,
4222-4240, 4296-4311, 4360-4378, 4389-4427, 4389-4431, 4405-4449,
4476-4496, 4517-4588, 4517-4552, 4537-4552, 4572-4588, 4640-4678,
4640-4879, 4641-4667, 4862-4879, 4991-5006, 4991-5305, 5029-5098,
5046-5098, 5104-5120, 5121-5141, 5125-5141, 5156-5256, 5158-5217,
5223-5242, 5267-5319, 5268-5319, 5395-5950, 5646-5695, 5655-5858,
5712-5752, 5712-5777, 5758-5777, 5782-5797, 5782-5862, 5804-5862,
5870-5910, 5871-6005, 5870-5910, 5870-5911, 5916-6007, 5935-5950,
5974-6007, 6029-6048, 6029-6055, 6035-6164, 6084-6099, 6084-6104,
6134-6164, 6170-6248, 6170-6275, 6170-6277, 6191-6218, 6221-6243,
6246-6275, 6284-6350, 6284-6352, 6298-6372, 6357-6372, 6388-6406,
6422-6493, 6422-6497, 6426-6621, 6567-6758, 6567-6582, 6597-6653,
6626-6653, 6710-6779, 6784-6811, 6785-6800, 6795-6811, 6913-6930,
6914-6929, 6914-6930, 6915-6930, 7101-7138, 7101-7441, 7125-7145,
7426-7441, 7473-7494, 7473-7498, 7481-7498, 7526-7543, 7550-7565,
7550-7634, 7563-7699, 7643-7676, 7680-7698, 7680-7699, 7708-7723,
7751-7819, 7768-7796, 7828-7866, 7834-7969, 7938-7968, 7938-7969,
7973-7994, 8017-8032, 8039-8186, 8039-8065, 8040-8065, 8121-8156,
8125-8151, 8164-8185, 8164-8186, 8205-8297, 8205-8220, 8236-8252,
8236-8271, 8256-8294, 8279-8297, 8487-8502, 8487-8627, 8529-8579,
8587-8628, 8636-8732, 8643-8910, 8744-8762, 8786-8910, 8939-9027,
8939-8996, 9000-9027, 9057-9096, 9080-9230, 9110-9173, 9188-9240,
9256-9275, 9312-9365, 9372-9401, 9373-9394, 9410-9446, 9410-9491,
9476-9555, 9497-9555, 9588-9678, 9588-9681, 9712-9737, 9712-9742,
9751-9811, 9751-10040, 9887-9902, 9908-10017, 10025-10040,
10058-10079, 10112-10160, 10124-10160, 10138-10160, 10180-10227,
10180-10233, 10258-10279, 10292-10310, 10293-10310, 10335-10375,
10335-10538, 10380-10538, 10554-10569, 10584-10599, 10728-10745,
10831-10870, 10930-10946, 10931-10946, 10970-10993, 10971-11015,
1100-11015, 11030-11045, 11073-11094, 11074-11094, 11115-11132,
11117-11132, 11155-11171, 11210-11228, 11210-11276, 11235-11276,
11290-11323, 11308-11323, 11384-11407, 11385-11443, 11428-11443,
11468-11529, 11542-11605, 11621-11636, 11621-11638, 11621-11668,
11652-11668, 11742-11808, 11742-11811, 11853-11881, 11853-11909,
11892-11912, 11924-11940, 11925-12226, 11953-12027, 12038-12226,
12238-12270, 12337-12531, 12337-12368, 12410-12448, 12465-12531,
12598-12642, 12598-12742, 12647-12742, 12758-12832, 12761-12832,
12862-12904, 13548-13627, 13551-13654, 13638-13674, 13688-13798,
13704-13798, 13813-13932, 13949-14064, 13951-13969, 13975-14064,
14077-14107, 14089-14107, 14126-14147, 14165-14221, 14166-14221,
14243-14298, 14243-14299, 14315-14336, 14316-14336, 14362-14414,
14432-14454, 14461-14514, 14465-14514, 14541-14815, 14541-14636,
14724-14746, 1400-14815, 14905-14951, 14916-14951, 15019-15039,
15022-15039, 15170-15185, 15200-15232, 15211-15268, 15244-15268,
15279-15295, 15279-15399, 15312-15343, 15350-15399, 15405-15460,
15492-15526, 15570-15586, 15633-15808, 15641-15657, 15643-15711,
15716-15765, 15771-15802, 16116-16144, 16116-16149, 16189-16206,
16189-16342, 16218-16240, 16254-16310, 16327-16352, 16377-16397,
16377-16400, 16407-16439, 16407-16440, 16461-16476, 16533-16548,
16755-16770, 16895-16920, 16905-16920, 16956-16984, 16956-17092,
17014-17034, 17135-17159, 17041-17062, 17077-17092, 17135-17159,
17227-17254, 17672-17795, 17675-17872, 17802-17817, 17857-17872,
17909-17945, 17909-17971, 17953-17971, 17954-17971, 17984-18061,
17985-18048, 18075-18117, 18087-18115, 18138-18160, 18176-18193,
18505-18555, 18506-18536, 18585-18600, 18658-18712, 18662-18762,
18720-18763, 18798-18864, 18871-18888, 18901-18940, 18925-18940,
18958-18983, 18958-19013, 19388-19460, 19467-19513, 19474-19505,
19531-19626, 19533-19626, 19649-19717, 19649-19726, 19731-19801,
19731-19842, 19815-19875, 19860-19951, 19887-19951, 19970-19985,
19970-20054, 19999-20024, 20037-20061, 20087-20102, 20109-20153,
20087-20207, 20172-20212, 20356-20438, 20248-20437, 20248-20264,
20470-20508, 20481-20507, 20571-20623, 20571-20644, 20685-20700,
20706-21032, 20706-20772, 20781-20859, 20869-20984, 20990-21033,
21065-21102, 21065-21263, 21092-21632, 21276-21500, 21517-21632,
21989-22034, 22059-22087, or 22164-22209 of SEQ ID NO: 2, and
wherein the nucleobase sequence of the modified oligonucleotide is
at least 85%, at least 90%, at least 95%, or 100% complementary to
SEQ ID NO: 2.
[0206] Embodiment 5: Certain embodiments provide a compound
comprising a modified oligonucleotide consisting of 8 to 80 linked
nucleosides, wherein the modified oligonucleotide has a nucleobase
sequence complementary within nucleobases 3095-3454, 3095-3140,
3152-3236, 3168-3183, 3248-3328, 3312-3328, 3334-3390, 3348-3390,
3401-3420, 3429-3451, 3429-3454, 3474-3719, 3474-3644, 3478-3494,
3505-3531, 3544-3559, 3568-3634, 3671-3736, 3676-3717, 3721-3799,
3741-3771, 3750-3770, 3782-3799, 3834-3849, 3834-4154, 3877-3897,
3902-3917, 3933-3967, 3933-3979, 3988-4005, 3988-4017, 4068-4091,
4103-4118, 4123-4155, 4133-4155, 4220-4240, 4220-4264, 4249-4264,
4222-4240, 4296-4311, 4360-4378, 4389-4427, 4389-4431, 4405-4449,
4476-4496, 4517-4588, 4517-4552, 4537-4552, 4572-4588, 4640-4678,
4640-4879, 4641-4667, 4862-4879, 4991-5006, 4991-5305, 5029-5098,
5046-5098, 5104-5120, 5121-5141, 5125-5141, 5156-5256, 5158-5217,
5223-5242, 5267-5319, 5268-5319, 5395-5950, 5646-5695, 5655-5858,
5712-5752, 5712-5777, 5758-5777, 5782-5797, 5782-5862, 5804-5862,
5870-5910, 5871-6005, 5870-5910, 5870-5911, 5916-6007, 5935-5950,
5974-6007, 6029-6048, 6029-6055, 6035-6164, 6084-6099, 6084-6104,
6134-6164, 6170-6248, 6170-6275, 6170-6277, 6191-6218, 6221-6243,
6246-6275, 6284-6350, 6284-6352, 6298-6372, 6357-6372, 6388-6406,
6422-6493, 6422-6497, 6426-6621, 6567-6758, 6567-6582, 6597-6653,
6626-6653, 6710-6779, 6784-6811, 6785-6800, 6795-6811, 6913-6930,
6914-6929, 6914-6930, 6915-6930, 7101-7138, 7101-7441, 7125-7145,
7426-7441, 7473-7494, 7473-7498, 7481-7498, 7526-7543, 7550-7565,
7550-7634, 7563-7699, 7643-7676, 7680-7698, 7680-7699, 7708-7723,
7751-7819, 7768-7796, 7828-7866, 7834-7969, 7938-7968, 7938-7969,
7973-7994, 8017-8032, 8039-8186, 8039-8065, 8040-8065, 8121-8156,
8125-8151, 8164-8185, 8164-8186, 8205-8297, 8205-8220, 8236-8252,
8236-8271, 8256-8294, 8279-8297, 8487-8502, 8487-8627, 8529-8579,
8587-8628, 8636-8732, 8643-8910, 8744-8762, 8786-8910, 8939-9027,
8939-8996, 9000-9027, 9057-9096, 9080-9230, 9110-9173, 9188-9240,
9256-9275, 9312-9365, 9372-9401, 9373-9394, 9410-9446, 9410-9491,
9476-9555, 9497-9555, 9588-9678, 9588-9681, 9712-9737, 9712-9742,
9751-9811, 9751-10040, 9887-9902, 9908-10017, 10025-10040,
10058-10079, 10112-10160, 10124-10160, 10138-10160, 10180-10227,
10180-10233, 10258-10279, 10292-10310, 10293-10310, 10335-10375,
10335-10538, 10380-10538, 10554-10569, 10584-10599, 10728-10745,
10831-10870, 10930-10946, 10931-10946, 10970-10993, 10971-11015,
1100-11015, 11030-11045, 11073-11094, 11074-11094, 11115-11132,
11117-11132, 11155-11171, 11210-11228, 11210-11276, 11235-11276,
11290-11323, 11308-11323, 11384-11407, 11385-11443, 11428-11443,
11468-11529, 11542-11605, 11621-11636, 11621-11638, 11621-11668,
11652-11668, 11742-11808, 11742-11811, 11853-11881, 11853-11909,
11892-11912, 11924-11940, 11925-12226, 11953-12027, 12038-12226,
12238-12270, 12337-12531, 12337-12368, 12410-12448, 12465-12531,
12598-12642, 12598-12742, 12647-12742, 12758-12832, 12761-12832,
12862-12904, 13548-13627, 13551-13654, 13638-13674, 13688-13798,
13704-13798, 13813-13932, 13949-14064, 13951-13969, 13975-14064,
14077-14107, 14089-14107, 14126-14147, 14165-14221, 14166-14221,
14243-14298, 14243-14299, 14315-14336, 14316-14336, 14362-14414,
14432-14454, 14461-14514, 14465-14514, 14541-14815, 14541-14636,
14724-14746, 1400-14815, 14905-14951, 14916-14951, 15019-15039,
15022-15039, 15170-15185, 15200-15232, 15211-15268, 15244-15268,
15279-15295, 15279-15399, 15312-15343, 15350-15399, 15405-15460,
15492-15526, 15570-15586, 15633-15808, 15641-15657, 15643-15711,
15716-15765, 15771-15802, 16116-16144, 16116-16149, 16189-16206,
16189-16342, 16218-16240, 16254-16310, 16327-16352, 16377-16397,
16377-16400, 16407-16439, 16407-16440, 16461-16476, 16533-16548,
16755-16770, 16895-16920, 16905-16920, 16956-16984, 16956-17092,
17014-17034, 17135-17159, 17041-17062, 17077-17092, 17135-17159,
17227-17254, 17672-17795, 17675-17872, 17802-17817, 17857-17872,
17909-17945, 17909-17971, 17953-17971, 17954-17971, 17984-18061,
17985-18048, 18075-18117, 18087-18115, 18138-18160, 18176-18193,
18505-18555, 18506-18536, 18585-18600, 18658-18712, 18662-18762,
18720-18763, 18798-18864, 18871-18888, 18901-18940, 18925-18940,
18958-18983, 18958-19013, 19388-19460, 19467-19513, 19474-19505,
19531-19626, 19533-19626, 19649-19717, 19649-19726, 19731-19801,
19731-19842, 19815-19875, 19860-19951, 19887-19951, 19970-19985,
19970-20054, 19999-20024, 20037-20061, 20087-20102, 20109-20153,
20087-20207, 20172-20212, 20356-20438, 20248-20437, 20248-20264,
20470-20508, 20481-20507, 20571-20623, 20571-20644, 20685-20700,
20706-21032, 20706-20772, 20781-20859, 20869-20984, 20990-21033,
21065-21102, 21065-21263, 21092-21632, 21276-21500, 21517-21632,
21989-22034, 22059-22087, or 22164-22209 of SEQ ID NO: 2, and
wherein said modified oligonucleotide is at least 85%, at least
90%, at least 95%, or 100% complementary to SEQ ID NO: 2.
[0207] Embodiment 6: Certain embodiments provide a compound
comprising a modified oligonucleotide consisting of 8 to 80 linked
nucleosides, wherein the modified oligonucleotide has a nucleobase
sequence comprising a portion of at least 8 contiguous nucleobases
100% complementary to an equal length portion of nucleobases 1-46,
58-142, 1-142, 74-89, 154-197, 154-234, 200-232, 218-234, 240-345,
254-269, 354-746, 354-830, 519-534, 565-580, 603-628, 693-716,
734-750, 734-830, 749-828, 835-862, 835-957, 966-1044, 1017-1043,
1054-1106, 1055-1070, 1075-1169, 1074-1132, 1136-1169, 1175-1218,
1180-1217, 1250-1292, 1251-1279, 1296-1146, 1296-1448, 1308-1448,
1461-1481, 1461-1519, 1461-1647, 1461-1646, 1483-1535, 1538-1646,
1544-1561, 1597-1645, 1654-1685, 1654-1817, 1702-1817, 1705-1741,
1748-2211, 2174-2219, 2240-2272, 2244-2272, 2349-2370, 2350-2371,
or 2378-2394 of SEQ ID NO: 1, and wherein the nucleobase sequence
of the modified oligonucleotide is at least 85%, at least 90%, at
least 95%, or 100% complementary to SEQ ID NO: 1.
[0208] Embodiment 7: Certain embodiments provide a compound
comprising a modified oligonucleotide consisting of 8 to 80 linked
nucleosides, wherein the modified oligonucleotide has a nucleobase
sequence complementary within nucleobases 1-46, 58-142, 1-142,
74-89, 154-197, 154-234, 200-232, 218-234, 240-345, 254-269,
354-746, 354-830, 519-534, 565-580, 603-628, 693-716, 734-750,
734-830, 749-828, 835-862, 835-957, 966-1044, 1017-1043, 1054-1106,
1055-1070, 1075-1169, 1074-1132, 1136-1169, 1175-1218, 1180-1217,
1250-1292, 1251-1279, 1296-1146, 1296-1448, 1308-1448, 1461-1481,
1461-1519, 1461-1647, 1461-1646, 1483-1535, 1538-1646, 1544-1561,
1597-1645, 1654-1685, 1654-1817, 1702-1817, 1705-1741, 1748-2211,
2174-2219, 2240-2272, 2244-2272, 2349-2370, 2350-2371, or 2378-2394
of SEQ ID NO: 1, and wherein said modified oligonucleotide is at
least 85%, at least 90%, at least 95%, or 100% complementary to SEQ
ID NO: 1.
[0209] Embodiment 8: Certain embodiments provide a compound
comprising a modified oligonucleotide consisting of 12 to 30 linked
nucleosides, wherein the modified oligonucleotide has a nucleobase
sequence comprising a portion of at least 8, at least 9, at least
10, at least 11, at least 12, at least 13, at least 14, at least
15, at least 16 contiguous nucleobases 100% complementary to an
equal length portion of nucleobases 3439-3454, 3552-3567,
3754-3769, 3963-3978, 4406-4421, 4123-4138, 4139-4154, 4991-5006,
5045-5060, 5662-5677, 6476-6491, 6478-6493, 17992-18007,
21138-21153, 21415-21430, 21442-21457, or 21597-21612 of SEQ ID NO:
2, and wherein the nucleobase sequence of the modified
oligonucleotide is at least 85%, at least 90%, at least 95%, or
100% complementary to SEQ ID NO: 2.
[0210] Embodiment 9: Certain embodiments provide a compound
comprising a modified oligonucleotide consisting of 12 to 30 linked
nucleosides, wherein the modified oligonucleotide has a nucleobase
sequence comprising any one of SEQ ID NOs: 286, 817, 983, 1215,
747, 43, 355, 1602, 201, 734, 1249, 208, 513, 1449, 1448, 1595, and
819.
[0211] Embodiment 10: Certain embodiments provide a compound
comprising a modified oligonucleotide having a nucleobase sequence
consisting of any one of SEQ ID NO: 286, 817, 983, 1215, 747, 43,
355, 1602, 201, 734, 1249, 208, 513, 1449, 1448, 1595, and 819.
[0212] Embodiment 11: Certain embodiments provide the compound of
embodiments 1-6, wherein the oligonucleotide is at least 80%, at
least 85%, at least 90%, at least 95% or 100% complementary to SEQ
ID NO: 2 over the entire length of the oligonucleotide.
[0213] Embodiment 12: Certain embodiments provide the compound of
any one of the preceding embodiments, wherein the modified
oligonucleotide comprises at least one modification selected from
at least one modified internucleoside linkage, at least one
modified nucleoside comprising a modified sugar moiety, and at
least one modified nucleoside comprising a modified nucleobase.
[0214] Embodiment 13: Certain embodiments provide the compound of
embodiment 12, wherein the modified internucleoside linkage is a
phosphorothioate internucleoside linkage.
[0215] Embodiment 14: Certain embodiments provide the compound of
embodiments 12 or 13, wherein at least one nucleoside of the
modified oligonucleotide is a 2'-substituted nucleoside or a
bicyclic nucleoside.
[0216] Embodiment 15: Certain embodiments provide the compound of
embodiment 14, wherein the bicyclic sugar moiety of the bicyclic
nucleoside is selected from the group consisting of:
4'-(CH.sub.2)--O-2' (LNA); 4'-(CH.sub.2).sub.2--O-2' (ENA); and
4'-CH(CH.sub.3)--O-2' (cEt).
[0217] Embodiment 16: Certain embodiments provide the compound of
any one of embodiments 12-15, wherein the modified nucleoside is
2'-O-methoxyethyl nucleoside.
[0218] Embodiment 17: Certain embodiments provide the compound of
any one of embodiments 12-16, wherein the modified nucleobase is a
5-methylcytosine.
[0219] Embodiment 18: Certain embodiments provide the compound of
any one of embodiments 1-17, wherein the modified oligonucleotide
has: [0220] a gap segment consisting of linked 2'-deoxynucleosides;
[0221] a 5' wing segment consisting of linked nucleosides; and
[0222] a 3' wing segment consisting of linked nucleosides;
[0223] wherein the gap segment is positioned immediately adjacent
to and between the 5' wing segment and the 3' wing segment and
wherein each nucleoside of each wing segment comprises a modified
sugar.
[0224] Embodiment 19: Certain embodiments provide the compound of
any one of claims 1-18, wherein the modified sugar moiety of each
nucleoside of each wing segment is selected from 2'-O-Me, 2'-MOE,
and cEt sugar moieties.
[0225] Embodiment 20: Certain embodiments provide the compound of
any of one claims 1-19, wherein the modified oligonucleotide
comprises: [0226] a gap segment consisting of ten linked
deoxynucleosides; [0227] a 5' wing segment consisting of three
linked nucleosides; and [0228] a 3' wing segment consisting of
three linked nucleosides;
[0229] wherein the gap segment is positioned between the 5' wing
segment and the 3' wing segment, wherein each nucleoside of each
wing segment comprises a cEt nucleoside; wherein each
internucleoside linkage is a phosphorothioate linkage and wherein
each cytosine is a 5-methylcytosine.
[0230] Embodiment 21: Certain embodiments provide the compound of
any of one claims 1-20, wherein the modified oligonucleotide
comprises: [0231] a gap segment consisting of ten linked
deoxynucleosides; [0232] a 5' wing segment consisting of three
linked nucleosides; and [0233] a 3' wing segment consisting of
three linked nucleosides;
[0234] wherein the gap segment is positioned between the 5' wing
segment and the 3' wing segment, wherein each nucleoside of each
wing segment comprises a cEt nucleoside; wherein at least one
internucleoside linkage is a phosphorothioate linkage and wherein
each cytosine is a 5-methylcytosine.
[0235] Embodiment 22: Certain embodiments provide the compound of
any of the preceding embodiments, wherein the modified
oligonucleotide comprises: [0236] a gap segment consisting of nine
linked 2'-deoxynucleosides; [0237] a 5' wing segment consisting of
three linked nucleosides; and [0238] a 3' wing segment consisting
of four linked nucleosides;
[0239] wherein the gap segment is positioned between the 5' wing
segment and the 3' wing segment, wherein each nucleoside of the 5'
wing segment comprises a cEt nucleoside; wherein the sugar moieties
of the nucleosides of the 3' wing segment are
5'-cEt-cEt-cEt-MOE-3'; wherein each internucleoside linkage is a
phosphorothioate linkage and wherein each cytosine is a
5-methylcytosine.
[0240] Embodiment 23: Certain embodiments provide the compound of
any of the preceding embodiments, wherein the modified
oligonucleotide comprises: [0241] a gap segment consisting of nine
linked 2'-deoxynucleosides; [0242] a 5' wing segment consisting of
three linked nucleosides; and [0243] a 3' wing segment consisting
of four linked nucleosides;
[0244] wherein the gap segment is positioned between the 5' wing
segment and the 3' wing segment, wherein each nucleoside of the 5'
wing segment comprises a cEt nucleoside; wherein each sugar moiety
of the nucleosides of the 3' wing segment are selected from cEt and
2'-MOE sugar moieties; wherein each internucleoside linkage is a
phosphorothioate linkage and wherein each cytosine is a
5-methylcytosine.
[0245] Embodiment 24: Certain embodiments provide the compound of
any one of the preceding embodiments, wherein the modified
oligonucleotide comprises: [0246] a gap segment consisting of ten
linked nucleosides; [0247] a 5' wing segment consisting of three
linked nucleosides; and [0248] a 3' wing segment consisting of four
linked nucleosides;
[0249] wherein the gap segment is positioned between the 5' wing
segment and the 3' wing segment and wherein the gap segment
consists of 5'-one deoxy, one 2'-O-methyl nucleoside, and eight
deoxynucleosides-3', wherein each nucleoside of each of the wing
segments comprises a cEt nucleoside; wherein each internucleoside
linkage is a phosphorothioate linkage and wherein each cytosine is
a 5-methylcytosine.
[0250] Embodiment 25: Embodiment 24: Certain embodiments provide
the compound of any one of the preceding embodiments, wherein the
modified oligonucleotide comprises: [0251] a gap segment consisting
of ten linked nucleosides; [0252] a 5' wing segment consisting of
three linked nucleosides; and [0253] a 3' wing segment consisting
of four linked nucleosides;
[0254] wherein the gap segment is positioned between the 5' wing
segment and the 3' wing segment and wherein the nucleosides of the
gap segment are selected from deoxynucleosides, cEt nucleosides and
2'-MOE nucleosides, wherein each nucleoside of each of the wing
segments comprises a cEt nucleoside; wherein each internucleoside
linkage is a phosphorothioate linkage and wherein each cytosine is
a 5-methylcytosine.
[0255] Embodiment 26: Certain embodiments provide the compound of
any one of embodiments 1-25, wherein the compound is
single-stranded.
[0256] Embodiment 27: Certain embodiments provide the compound of
any one of embodiments 1-25, wherein the modified oligonucleotide
is hybridized to a second oligonucleotide to form a double-stranded
antisense compound.
[0257] Embodiment 28: Certain embodiments provide the compound of
any one of embodiments 1-27, wherein at least one of the
nucleotides of the modified oligonucleotide is a
ribonucleotide.
[0258] Embodiment 29: Certain embodiments provide the compound of
any one of embodiments 1-27, wherein at least one of the
nucleotides of the modified oligonucleotide is a
deoxyribonucleotide.
[0259] Embodiment 30: Certain embodiments provide the compound of
any one of embodiments 1-23, wherein the modified oligonucleotide
consists of 10 to 30 linked nucleosides.
[0260] Embodiment 31: Certain embodiments provide the compound of
any one of embodiments 1-30, wherein the modified oligonucleotide
consists of 10 to 30 linked nucleosides.
[0261] Embodiment 32: Certain embodiments provide the compound of
any one of embodiments 1-30, wherein the modified oligonucleotide
consists of 16 to 30 linked nucleosides.
[0262] Embodiment 33: Certain embodiments provide a compound
comprising a modified oligonucleotide consisting of 16 linked
nucleosides, wherein the modified oligonucleotide has a nucleobase
sequence selected from any one of SEQ ID NOs: 286, 817, 983, 1215,
747, 43, 355, 1602, 201, 734, 1249, 208, 513, 1449, 1448, 1595, and
819, wherein the modified oligonucleotide comprises: [0263] a gap
segment consisting of linked deoxynucleosides; [0264] a 5' wing
segment consisting of linked nucleosides; and [0265] a 3' wing
segment consisting of linked nucleosides;
[0266] wherein the gap segment is positioned between the 5' wing
segment and the 3' wing segment and wherein each nucleoside of each
wing segment comprises a modified sugar.
[0267] Embodiment 34: Certain embodiments provide a compound
comprising a modified oligonucleotide consisting of 16 linked
nucleosides, wherein the modified oligonucleotide has a nucleobase
sequence selected from any one of SEQ ID NOs: 286, 817, 983, 1215,
747, 43, 355, 1602, 201, 734, 1249, 208, 513, 1449, 1448, and 1595,
wherein the modified oligonucleotide comprises [0268] a gap segment
consisting of ten linked deoxynucleosides; [0269] a 5' wing segment
consisting of three linked nucleosides; and [0270] a 3' wing
segment consisting of three linked nucleosides;
[0271] wherein the gap segment is positioned between the 5' wing
segment and the 3' wing segment; wherein the 5' wing segment and
the 3' wing segment comprise cEt sugars; wherein each
internucleoside linkage is a phosphorothioate linkage; and wherein
each cytosine is a 5-methylcytosine.
[0272] Embodiment 35: Certain embodiments provide a compound
comprising a modified oligonucleotide consisting of 16 linked
nucleosides, wherein the modified oligonucleotide has a nucleobase
sequence consisting of SEQ ID NO: 819, wherein the modified
oligonucleotide comprises: [0273] a gap segment consisting of nine
linked 2'-deoxynucleosides; [0274] a 5' wing segment consisting of
three linked nucleosides; and [0275] a 3' wing segment consisting
of four linked nucleosides;
[0276] wherein the gap segment is positioned between the 5' wing
segment and the 3' wing segment, wherein each nucleoside of the 5'
wing segment comprises a cEt sugar; wherein the sugar residues of
the nucleosides of the 3' wing segment are 5'-cEt-cEt-cEt-MOE-3';
wherein each internucleoside linkage is a phosphorothioate linkage
and wherein each cytosine is a 5-methylcytosine.
[0277] Embodiment 36: Certain embodiments provide a a modified
oligonucleotide consisting of 16 linked nucleosides, wherein the
modified oligonucleotide has a nucleobase sequence consisting of
SEQ ID NO: 1595, wherein the modified oligonucleotide
comprises:
[0278] a gap segment consisting of ten linked nucleosides;
[0279] a 5' wing segment consisting of three linked nucleosides;
and
[0280] a 3' wing segment consisting of four linked nucleosides;
[0281] wherein the gap segment is positioned between the 5' wing
segment and the 3' wing segment and wherein the gap segment
consists of 5'-one deoxy, one 2'-O-methyl nucleoside, and eight
deoxynucleosides-3', wherein each nucleoside of each of the wing
segments comprises a cEt sugar; wherein each internucleoside
linkage is a phosphorothioate linkage and wherein each cytosine is
a 5-methylcytosine.
[0282] Embodiment 37: Certain embodiments provide the compound of
any preceding embodiment, comprising a conjugate group.
[0283] Embodiment 38: Certain embodiments provide the compound of
embodiment 37, wherein the conjugate group comprises a GalNAc
cluster comprising 1-3 GalNAc ligands.
[0284] Embodiment 39: Certain embodiments provide the compound of
embodiment 37 or embodiment 38, wherein the conjugate group
comprises a conjugate linker consisting of a single bond.
[0285] Embodiment 40: Certain embodiments provide the compound of
any one of embodiments 37-39, wherein the conjugate group comprises
a cleavable linker.
[0286] Embodiment 41: Certain embodiments provide the compound of
any one of embodiments 37-40, wherein the conjugate group comprises
a conjugate linker comprising 1-3 linker-nucleosides.
[0287] Embodiment 42: Certain embodiments provide the compound of
any one of embodiments 37-41, wherein the conjugate group is
attached to the modified oligonucleotide at the 5'-end of the
modified oligonucleotide.
[0288] Embodiment 42: Certain embodiments provide the compound of
any one of embodiments 37-41, wherein the conjugate group is
attached to the modified oligonucleotide at the 3'-end of the
modified oligonucleotide.
[0289] Embodiment 43: Certain embodiments provide the compound
having the following chemical structure or salt thereof:
##STR00037##
[0290] Embodiment 44: Certain embodiments provide the compound
having the following chemical structure or salt thereof:
##STR00038##
[0291] Embodiment 45: Certain embodiments provide the compound
having the following chemical structure or salt thereof:
##STR00039##
[0292] Embodiment 46: Certain embodiments provide the compound
having the following chemical structure or salt thereof:
##STR00040##
[0293] Embodiment 47: Certain embodiments provide the compound
having the following chemical structure or salt thereof:
##STR00041##
[0294] Embodiment 48: Certain embodiments provide the compound
having the following chemical structure or salt thereof:
##STR00042##
[0295] Embodiment 49: Certain embodiments provide the compound
having the following chemical structure or salt thereof:
##STR00043##
[0296] Embodiment 50: Certain embodiments provide the compound
having the following chemical structure or salt thereof:
##STR00044##
[0297] Embodiment 51: Certain embodiments provide the compound
having the following chemical structure or salt thereof:
##STR00045##
[0298] Embodiment 52: Certain embodiments provide the compound
having the following chemical structure or salt thereof:
##STR00046##
[0299] Embodiment 53: Certain embodiments provide the compound
having the following chemical structure or salt thereof:
##STR00047##
[0300] Embodiment 54: Certain embodiments provide the compound
having the following chemical structure or salt thereof:
##STR00048##
[0301] Embodiment 55: Certain embodiments provide the compound
having the following chemical structure or salt thereof:
##STR00049##
[0302] Embodiment 56: Certain embodiments provide the compound
having the following chemical structure or salt thereof:
##STR00050##
[0303] Embodiment 57: Certain embodiments provide the compound
having the following chemical structure or salt thereof:
##STR00051##
[0304] Embodiment 58: Certain embodiments provide the compound
having the following chemical structure or salt thereof:
##STR00052##
[0305] Embodiment 59: Certain embodiments provide the compound
having the following chemical structure or salt thereof:
##STR00053##
[0306] Embodiment 60: Certain embodiments provide the compound
having the following chemical structure or salt thereof:
##STR00054##
[0307] Embodiment 61: Certain embodiments provide the compound of
any one of the embodiments 43-60, wherein the compound is a sodium
salt.
[0308] Embodiment 62: Certain embodiments provide the compound of
any one of the embodiments 43-60, wherein the compound is a
potassium salt.
[0309] Embodiment 63: Certain embodiments provide the chirally
enriched population of the compound of any one of embodiments 1-62,
wherein the population is enriched for compounds having a modified
oligonucleotide comprising at least one particular phosphorothioate
internucleoside linkage having a particular stereochemical
configuration.
[0310] Embodiment 64: Certain embodiments provide the chirally
enriched population of embodiment 63, wherein the population is
enriched for compounds having a modified oligonucleotide comprising
at least one particular phosphorothioate internucleoside linkage
having the (Sp) configuration.
[0311] Embodiment 65: Certain embodiments provide the chirally
enriched population of embodiment 63 or embodiment 64, wherein the
population is enriched for compounds having a modified
oligonucleotide comprising at least one particular phosphorothioate
internucleoside linkage having the (Rp) configuration.
[0312] Embodiment 66: Certain embodiments provide the chirally
enriched population of claim 63, wherein the population is enriched
for compounds having a modified oligonucleotide having a
particular, independently selected stereochemical configuration at
each phosphorothioate internucleoside linkage.
[0313] Embodiment 67: Certain embodiments provide the chirally
enriched population of embodiment 66, wherein the population is
enriched for oligomeric compounds having a modified oligonucleotide
having the (Sp) configuration at each phosphorothioate
internucleoside linkage.
[0314] Embodiment 68: Certain embodiments provide the chirally
enriched population of embodiment 66, wherein the population is
enriched for oligomeric compounds having a modified oligonucleotide
having the (Rp) configuration at each phosphorothioate
internucleoside linkage.
[0315] Embodiment 69: Certain embodiments provide the chirally
enriched population of embodiment 63 or 66, wherein wherein the
population is enriched for oligomeric compounds having a modified
oligonucleotide having at least 3 contiguous phosphorothioate
internucleoside linkages in the Sp-Sp-Rp configurations, in the 5'
to 3' direction.
[0316] Embodiment 70: Certain embodiments provide a population of
compounds having a modified oligonucleotide of any of embodiments
69, wherein all of the phosphorothioate internucleoside linkages of
the modified oligonucleotide are stereorandom.
[0317] Embodiment 71: Certain embodiments provide a composition
comprising the compound of any one of embodiments 1-70 and a
pharmaceutically acceptable carrier.
[0318] Embodiment 72: Certain embodiments provide a composition
comprising a compound of any preceding embodiment, for use in
therapy.
[0319] Embodiment 73: Certain embodiments provide a method of
treating, preventing, or ameliorating a disease associated with
HSD17B13 in an individual comprising administering to the
individual a compound complementary to HSD17B13, thereby treating,
preventing, or ameliorating the disease.
[0320] Embodiment 74: Certain embodiments provide a method of
administering the compound of embodiments 1-70 or composition of
embodiment 71 or embodiment 72 to an individual.
[0321] Embodiment 75: Certain embodiments provide the method of
embodiments 73 or 74, wherein the individual has a liver disease,
NAFLD, NASH, hepatic steatosis, hepatocellular carcinoma, alcoholic
liver disease, HCV hepatitis, chronic hepatitis, hereditary
hemochromatosis, or primary sclerosing cholangitis.
[0322] Embodiment 76: Certain embodiments provide the method of
embodiment 73 or embodiment 74, wherein the compound is an
antisense compound.
[0323] Embodiment 77: Certain embodiments provide the method of any
of embodiments 73-76, wherein administering the compound
ameliorates liver damage, steatosis, liver fibrosis, liver
inflammation, liver scarring or cirrhosis, liver failure, liver
enlargement, elevated transaminases, or hepatic fat accumulation in
the individual.
[0324] Embodiment 78: Certain embodiments provide a method of
inhibiting expression of HSD17B13 in a cell comprising contacting
the cell with a compound comprising a modified oligonucleotide
complementary to HSD17B13, thereby inhibiting expression of
HSD17B13 in the cell.
[0325] Embodiment 79: Certain embodiments provide the method of
embodiment 78, wherein the cell is in the liver of an
individual.
[0326] Embodiment 80: Certain embodiments provide the method of
embodiment 79, wherein the individual has, or is at risk of having,
liver disease, NAFLD, NASH, hepatic steatosis, hepatocellular
carcinoma, alcoholic liver disease, HCV hepatitis, chronic
hepatitis, hereditary hemochromatosis, or primary sclerosing
cholangitis.
[0327] Embodiment 81: Certain embodiments provide a method of
ameliorating, reducing or inhibiting liver damage, steatosis, liver
fibrosis, liver inflammation, liver scarring or cirrhosis, liver
failure, liver enlargement, elevated transaminases, or hepatic fat
accumulation in an individual, comprising administering a compound
comprising a modified oligonucleotide complementary to HSD17B13 to
the individual, thereby reducing or inhibiting liver damage,
steatosis, liver fibrosis, liver inflammation, liver scarring or
cirrhosis, liver failure, liver enlargement, elevated
transaminases, or hepatic fat accumulation in the individual.
[0328] Embodiment 82: Certain embodiments provide the method of
embodiment 81, wherein the individual has, or is at risk of having,
liver disease, NAFLD, NASH, hepatic steatosis, hepatocellular
carcinoma, alcoholic liver disease, HCV hepatitis, chronic
hepatitis, hereditary hemochromatosis, or primary sclerosing
cholangitis.
[0329] Embodiment 83: Certain embodiments provide the method of any
one of embodiments 78-82, wherein the compound is an antisense
compound.
[0330] Embodiment 84: Certain embodiments provide the method of any
one of embodiments 78-83, wherein the compound is the compound of
any one of embodiments 1-70 or composition of embodiment 71 or
embodiment 72.
[0331] Embodiment 85: Certain embodiments provide the method of
embodiment 83 or embodiment 84, wherein the compound or composition
is administered parenterally.
[0332] Embodiment 86: Certain embodiments provide the use of a
compound comprising a modified oligonucleotide complementary to
HSD17B13 for treating, preventing, or ameliorating a disease
associated with HSD17B13.
[0333] Embodiment 87: Certain embodiments provide the use of
embodiment 86, wherein the disease is liver disease, NAFLD, NASH,
hepatic steatosis, hepatocellular carcinoma, alcoholic liver
disease, HCV hepatitis, chronic hepatitis, hereditary
hemochromatosis, or primary sclerosing cholangitis.
[0334] Embodiment 88: Certain embodiments provide the use of
embodiments 86 or 87, wherein the compound is an antisense
compound.
[0335] Embodiment 89: Certain embodiments provide the use of any
one of embodiments 86-88, wherein the compound is the compound of
any one of embodiments 1-70 or composition of embodiment 71 or
embodiment 72.
[0336] Embodiment 90: Certain embodiments provide the use of a
compound comprising a modified oligonucleotide complementary to
HSD17B13 in the manufacture of a medicament for treating,
preventing, or ameliorating a disease associated with HSD17B13.
[0337] Embodiment 91: Certain embodiments provide the use of
embodiment 90, wherein the disease is liver disease, NAFLD, NASH,
hepatic steatosis, hepatocellular carcinoma, alcoholic liver
disease, HCV hepatitis, chronic hepatitis, hereditary
hemochromatosis, or primary sclerosing cholangitis.
[0338] Embodiment 92: Certain embodiments provide the use of
embodiments 90 or 91, wherein the compound is an antisense
compound.
[0339] Embodiment 93: Certain embodiments provide the use of any
one of embodiments 90-92, wherein the compound is the compound of
any one of embodiments 1-70 or composition of embodiment 71 or
embodiment 72.
Certain Indications
[0340] Certain embodiments provided herein relate to methods of
inhibiting HSD17B13 expression, which can be useful for treating,
preventing, or ameliorating a disease associated with HSD17B13 in
an individual, by administration of a compound that targets
HSD17B13. In certain embodiments, the compound can be a HSD17B13
specific inhibitor. In certain embodiments, the compound can be an
antisense compound, an oligomeric compound, or an oligonucleotide
targeted to HSD17B13.
[0341] Examples of diseases associated with HSD17B13 treatable,
preventable, and/or ameliorable with the methods provided herein
include liver disease, NAFLD, NASH, alcoholic steatohepatitis
(ASH), alcoholic liver disease, nonalcoholic liver disease,
alcoholic cirrhosis, nonalcoholic cirrhosis, steatohepatisis,
hepatic steatosis, hepatocellular carcinoma, alcoholic liver
disease, HCV hepatitis, chronic hepatitis, hereditary
hemochromatosis, or primary sclerosing cholangitis. Certain
compounds provided herein are directed to compounds and
compositions that reduce liver damage, steatosis, liver fibrosis,
liver inflammation, liver scarring or cirrhosis, liver failure,
liver enlargement, elevated transaminases, or hepatic fat
accumulation in an animal.
[0342] In certain embodiments, a method of treating, preventing, or
ameliorating a disease associated with HSD17B13 in an individual
comprises administering to the individual a compound comprising a
HSD17B13 specific inhibitor, thereby treating, preventing, or
ameliorating the disease. In certain embodiments, the individual is
identified as having, or at risk of having, a disease associated
with HSD17B13. In certain embodiments, the disease is a liver
disease. In certain embodiments, the compound comprises an
antisense compound targeted to HSD17B13. In certain embodiments,
the compound comprises an oligonucleotide targeted to HSD17B13. In
certain embodiments, a compound comprises a modified
oligonucleotide consisting of 8 to 80 linked nucleosides and having
a nucleobase sequence comprising at least 8 contiguous nucleobases
of any of the nucleobase sequences of SEQ ID NOs: 8-2896. In
certain embodiments, a compound comprises a modified
oligonucleotide consisting of 16 to 80 linked nucleosides and
having a nucleobase sequence comprising the nucleobase sequence of
any one of SEQ ID NOs: 8-2896. In certain embodiments, a compound
comprises a modified oligonucleotide consisting of the nucleobase
sequence of any one of SEQ ID NOs: 8-2896. In any of the foregoing
embodiments, the compound can be single-stranded or
double-stranded. In any of the foregoing embodiments, the compound
can be an antisense compound or oligomeric compound. In certain
embodiments, the compound is administered to the individual
parenterally. In certain embodiments, administering the compound
improves, preserves, or prevents liver damage, steatosis, liver
fibrosis, cirrhosis, elevated transaminases, or hepatic fat
accumulation in an animal.
[0343] In certain embodiments, a method of treating, preventing, or
ameliorating liver damage, steatosis, liver fibrosis, cirrhosis,
elevated transaminases, or hepatic fat accumulation in an animal
comprises administering to the individual a compound comprising a
HSD17B13 specific inhibitor, thereby treating, preventing, or
ameliorating liver damage, steatosis, liver fibrosis, cirrhosis,
elevated transaminases, or hepatic fat accumulation. In certain
embodiments, the compound comprises an antisense compound targeted
to HSD17B13. In certain embodiments, the compound comprises an
oligonucleotide targeted to HSD17B13. In certain embodiments, a
compound comprises consisting of 8 to 80 linked nucleosides and
having a nucleobase sequence comprising at least 8 contiguous
nucleobases of any of the nucleobase sequences of SEQ ID NOs:
8-2896. In certain embodiments, a compound comprises a modified
oligonucleotide consisting of 16 to 80 linked nucleosides and
having a nucleobase sequence comprising the nucleobase sequence of
any one of SEQ ID NOs: 8-2896. In certain embodiments, a compound
comprises a modified oligonucleotide consisting of the nucleobase
sequence of any one of SEQ ID NOs: 8-2896. In any of the foregoing
embodiments, the compound can be single-stranded or
double-stranded. In any of the foregoing embodiments, the compound
can be an antisense compound or oligomeric compound. In certain
embodiments, the compound is administered to the individual
parenterally. In certain embodiments, administering the compound
improves, preserves, or prevents liver damage, steatosis, liver
fibrosis, cirrhosis, elevated transaminases, or hepatic fat
accumulation. In certain embodiments, the individual is identified
as having, or at risk of having, a disease associated with
HSD17B13.
[0344] In certain embodiments, a method of inhibiting expression of
HSD17B13 in an individual having, or at risk of having, a disease
associated with HSD17B13 comprises administering to the individual
a compound comprising a HSD17B13 specific inhibitor, thereby
inhibiting expression of HSD17B13 in the individual. In certain
embodiments, administering the compound inhibits expression of
HSD17B13 in the liver. In certain embodiments, the disease is a
liver disease. In certain embodiments, the individual has, or is at
risk of having, liver disease, NAFLD, NASH, alcoholic
steatohepatitis (ASH), alcoholic liver disease, nonalcoholic liver
disease, alcoholic cirrhosis, nonalcoholic cirrhosis,
steatohepatisis, hepatic steatosis, hepatocellular carcinoma,
alcoholic liver disease, HCV hepatitis, chronic hepatitis,
hereditary hemochromatosis, or primary sclerosing cholangitis. In
certain embodiments, the individual has, or is at risk of having,
liver damage, steatosis, liver fibrosis, cirrhosis, elevated
transaminases, or hepatic fat accumulation. In certain embodiments,
the compound comprises an antisense compound targeted to HSD17B13.
In certain embodiments, the compound comprises an oligonucleotide
targeted to HSD17B13. In certain embodiments, a compound comprises
consisting of 8 to 80 linked nucleosides and having a nucleobase
sequence comprising at least 8 contiguous nucleobases of any of the
nucleobase sequences of SEQ ID NOs: 8-2896. In certain embodiments,
a compound comprises a modified oligonucleotide consisting of 16 to
80 linked nucleosides and having a nucleobase sequence comprising
the nucleobase sequence of any one of SEQ ID NOs: 8-2896. In
certain embodiments, a compound comprises a modified
oligonucleotide consisting of the nucleobase sequence of any one of
SEQ ID NOs: 8-2896. In any of the foregoing embodiments, the
compound can be single-stranded or double-stranded. In any of the
foregoing embodiments, the compound can be an antisense compound or
oligomeric compound. In certain embodiments, the compound is
administered to the individual parenterally. In certain
embodiments, administering the compound improves, preserves, or
prevents liver damage, steatosis, liver fibrosis, cirrhosis,
elevated transaminases, or hepatic fat accumulation.
[0345] In certain embodiments, a method of inhibiting expression of
HSD17B13 in a cell comprises contacting the cell with a compound
comprising a HSD17B13 specific inhibitor, thereby inhibiting
expression of HSD17B13 in the cell. In certain embodiments, the
cell is a hepatocyte. In certain embodiments, the cell is in the
liver. In certain embodiments, the cell is in the liver of an
individual who has, or is at risk of having, liver damage,
steatosis, liver fibrosis, cirrhosis, elevated transaminases, or
hepatic fat accumulation. In certain embodiments, the compound
comprises an antisense compound targeted to HSD17B13. In certain
embodiments, the compound comprises an oligonucleotide targeted to
HSD17B13. In certain embodiments, a compound comprises consisting
of 8 to 80 linked nucleosides and having a nucleobase sequence
comprising at least 8 contiguous nucleobases of any of the
nucleobase sequences of SEQ ID NOs: 8-2896. In certain embodiments,
a compound comprises a modified oligonucleotide consisting of 16 to
80 linked nucleosides and having a nucleobase sequence comprising
the nucleobase sequence of any one of SEQ ID NOs: 8-2896. In
certain embodiments, a compound comprises a modified
oligonucleotide consisting of the nucleobase sequence of any one of
SEQ ID NOs: 8-2896. In any of the foregoing embodiments, the
compound can be single-stranded or double-stranded. In any of the
foregoing embodiments, the compound can be an antisense compound or
oligomeric compound.
[0346] In certain embodiments, a method of reducing or inhibiting
liver damage, steatosis, liver fibrosis, cirrhosis, elevated
transaminases, or hepatic fat accumulation in an individual having,
or at risk of having, a disease associated with HSD17B13 comprises
administering to the individual a compound comprising a HSD17B13
specific inhibitor, thereby reducing or inhibiting liver damage,
steatosis, liver fibrosis, cirrhosis, elevated transaminases, or
hepatic fat accumulation in the individual. In certain embodiments,
the individual has, or is at risk of having, liver disease, NAFLD,
NASH, alcoholic steatohepatitis (ASH), alcoholic liver disease,
nonalcoholic liver disease, alcoholic cirrhosis, nonalcoholic
cirrhosis, steatohepatisis, hepatic steatosis, hepatocellular
carcinoma, alcoholic liver disease, HCV hepatitis, chronic
hepatitis, hereditary hemochromatosis, or primary sclerosing
cholangitis. In certain embodiments, the compound comprises an
antisense compound targeted to HSD17B13. In certain embodiments,
the compound comprises an oligonucleotide targeted to HSD17B13. In
certain embodiments, a compound comprises consisting of 8 to 80
linked nucleosides and having a nucleobase sequence comprising at
least 8 contiguous nucleobases of any of the nucleobase sequences
of SEQ ID NOs: 8-2896. In certain embodiments, a compound comprises
a modified oligonucleotide consisting of 16 to 80 linked
nucleosides and having a nucleobase sequence comprising the
nucleobase sequence of any one of SEQ ID NOs: 8-2896. In certain
embodiments, a compound comprises a modified oligonucleotide
consisting of the nucleobase sequence of any one of SEQ ID NOs:
8-2896. In any of the foregoing embodiments, the compound can be
single-stranded or double-stranded. In any of the foregoing
embodiments, the compound can be an antisense compound or
oligomeric compound. In certain embodiments, the compound is
administered to the individual parenterally. In certain
embodiments, the individual is identified as having, or at risk of
having, a disease associated with HSD17B13.
[0347] Certain embodiments are drawn to a compound comprising a
HSD17B13 specific inhibitor for use in treating a disease
associated with HSD17B13. In certain embodiments, the disease is
liver disease, NAFLD, NASH, alcoholic steatohepatitis (ASH),
alcoholic liver disease, nonalcoholic liver disease, alcoholic
cirrhosis, nonalcoholic cirrhosis, steatohepatisis, hepatic
steatosis, hepatocellular carcinoma, alcoholic liver disease, HCV
hepatitis, chronic hepatitis, hereditary hemochromatosis, or
primary sclerosing cholangitis. In certain embodiments, the
compound comprises an antisense compound targeted to HSD17B13. In
certain embodiments, the compound comprises an oligonucleotide
targeted to HSD17B13. In certain embodiments, a compound comprises
consisting of 8 to 80 linked nucleosides and having a nucleobase
sequence comprising at least 8 contiguous nucleobases of any of the
nucleobase sequences of SEQ ID NOs: 8-2896. In certain embodiments,
a compound comprises a modified oligonucleotide consisting of 16 to
80 linked nucleosides and having a nucleobase sequence comprising
the nucleobase sequence of any one of SEQ ID NOs: 8-2896. In
certain embodiments, a compound comprises a modified
oligonucleotide consisting of the nucleobase sequence of any one of
SEQ ID NOs: 8-2896. In any of the foregoing embodiments, the
compound can be single-stranded or double-stranded. In any of the
foregoing embodiments, the compound can be an antisense compound or
oligomeric compound. In certain embodiments, the compound is
administered to the individual parenterally.
[0348] Certain embodiments are drawn to a compound comprising a
HSD17B13 specific inhibitor for use in reducing or inhibiting liver
damage, steatosis, liver fibrosis, cirrhosis, elevated
transaminases, or hepatic fat accumulation in an individual having,
or at risk of having, liver disease, NAFLD, NASH, alcoholic
steatohepatitis (ASH), alcoholic liver disease, nonalcoholic liver
disease, alcoholic cirrhosis, nonalcoholic cirrhosis,
steatohepatisis, hepatic steatosis, hepatocellular carcinoma,
alcoholic liver disease, HCV hepatitis, chronic hepatitis,
hereditary hemochromatosis, or primary sclerosing cholangitis. In
certain embodiments, the compound comprises an antisense compound
targeted to HSD17B13. In certain embodiments, the compound
comprises an oligonucleotide targeted to HSD17B13. In certain
embodiments, a compound comprises consisting of 8 to 80 linked
nucleosides and having a nucleobase sequence comprising at least 8
contiguous nucleobases of any of the nucleobase sequences of SEQ ID
NOs: 8-2896. In certain embodiments, a compound comprises a
modified oligonucleotide consisting of 16 to 80 linked nucleosides
and having a nucleobase sequence comprising the nucleobase sequence
of any one of SEQ ID NOs: 8-2896. In certain embodiments, a
compound comprises a modified oligonucleotide consisting of the
nucleobase sequence of any one of SEQ ID NOs: 8-2896. In any of the
foregoing embodiments, the compound can be single-stranded or
double-stranded. In any of the foregoing embodiments, the compound
can be an antisense compound or oligomeric compound.
[0349] Certain embodiments are drawn to the use of a compound
comprising a HSD17B13 specific inhibitor for the manufacture or
preparation of a medicament for treating a disease associated with
HSD17B13. Certain embodiments are drawn to the use of a compound
comprising a HSD17B13 specific inhibitor for the preparation of a
medicament for treating a disease associated with HSD17B13. In
certain embodiments, the disease is a liver disease. In certain
embodiments, the disease is liver disease, NAFLD, NASH, alcoholic
steatohepatitis (ASH), alcoholic liver disease, nonalcoholic liver
disease, alcoholic cirrhosis, nonalcoholic cirrhosis,
steatohepatisis, hepatic steatosis, hepatocellular carcinoma,
alcoholic liver disease, HCV hepatitis, chronic hepatitis,
hereditary hemochromatosis, or primary sclerosing cholangitis. In
certain embodiments, the compound comprises an antisense compound
targeted to HSD17B13. In certain embodiments, the compound
comprises an oligonucleotide targeted to HSD17B13. In certain
embodiments, a compound comprises consisting of 8 to 80 linked
nucleosides and having a nucleobase sequence comprising at least 8
contiguous nucleobases of any of the nucleobase sequences of SEQ ID
NOs: 8-2896. In certain embodiments, a compound comprises a
modified oligonucleotide consisting of 16 to 80 linked nucleosides
and having a nucleobase sequence comprising the nucleobase sequence
of any one of SEQ ID NOs: 8-2896. In certain embodiments, a
compound comprises a modified oligonucleotide consisting of the
nucleobase sequence of any one of SEQ ID NOs: 8-2896. In any of the
foregoing embodiments, the compound can be single-stranded or
double-stranded. In any of the foregoing embodiments, the compound
can be an antisense compound or oligomeric compound.
[0350] Certain embodiments are drawn to the use of a compound
comprising a HSD17B13 specific inhibitor for the manufacture or
preparation of a medicament for reducing or inhibiting liver
damage, steatosis, liver fibrosis, cirrhosis, elevated
transaminases, or hepatic fat accumulation in an individual having,
or at risk of having, a disease associated with HSD17B13. In
certain embodiments, the disease is liver disease, NAFLD, NASH,
alcoholic steatohepatitis (ASH), alcoholic liver disease,
nonalcoholic liver disease, alcoholic cirrhosis, nonalcoholic
cirrhosis, steatohepatisis, hepatic steatosis, hepatocellular
carcinoma, alcoholic liver disease, HCV hepatitis, chronic
hepatitis, hereditary hemochromatosis, or primary sclerosing
cholangitis. Certain embodiments are drawn to use of a compound
comprising a HSD17B13 specific inhibitor for the preparation of a
medicament for treating a disease associated with HSD17B13. In
certain embodiments, the disease is liver disease, NAFLD, NASH,
alcoholic liver disease, nonalcoholic liver disease, alcoholic
cirrhosis, nonalcoholic cirrhosis, steatohepatisis, hepatic
steatosis, hepatocellular carcinoma, alcoholic liver disease, HCV
hepatitis, chronic hepatitis, hereditary hemochromatosis, or
primary sclerosing cholangitis. In certain embodiments, the
compound comprises an antisense compound targeted to HSD17B13. In
certain embodiments, the compound comprises an oligonucleotide
targeted to HSD17B13. In certain embodiments, a compound comprises
consisting of 8 to 80 linked nucleosides and having a nucleobase
sequence comprising at least 8 contiguous nucleobases of any of the
nucleobase sequences of SEQ ID NOs: 8-2896. In certain embodiments,
a compound comprises a modified oligonucleotide consisting of 16 to
80 linked nucleosides and having a nucleobase sequence comprising
the nucleobase sequence of any one of SEQ ID NOs: 8-2896. In
certain embodiments, a compound comprises a modified
oligonucleotide consisting of the nucleobase sequence of any one of
SEQ ID NOs: 8-2896. In any of the foregoing embodiments, the
compound can be single-stranded or double-stranded. In any of the
foregoing embodiments, the compound can be an antisense compound or
oligomeric compound.
[0351] In any of the foregoing methods or uses, the compound can be
targeted to HSD17B13. In certain embodiments, the compound
comprises or consists of a modified oligonucleotide, for example, a
modified oligonucleotide consisting of 8 to 80 linked nucleosides,
10 to 30 linked nucleosides, 12 to 30 linked nucleosides, or 20
linked nucleosides. In certain embodiments, the modified
oligonucleotide is at least 80%, at least 85%, at least 90%, at
least 95% or 100% complementary to any of the nucleobase sequences
recited in SEQ ID NOs: 1-4. In certain embodiments, the modified
oligonucleotide comprises at least one modified internucleoside
linkage, at least one modified sugar and/or at least one modified
nucleobase. In certain embodiments, the modified internucleoside
linkage is a phosphorothioate internucleoside linkage, the modified
sugar is a bicyclic sugar or a 2'-O-methoxyethyl modified sugar,
and the modified nucleobase is a 5-methylcytosine. In certain
embodiments, the modified oligonucleotide comprises a gap segment
consisting of linked deoxynucleosides; a 5' wing segment consisting
of linked nucleosides; and a 3' wing segment consisting of linked
nucleosides, wherein the gap segment is positioned immediately
adjacent to and between the 5' wing segment and the 3' wing segment
and wherein each nucleoside of each wing segment comprises a
modified sugar.
[0352] In any of the foregoing embodiments, the modified
oligonucleotide consists of 12 to 30, 15 to 30, 15 to 25, 15 to 24,
16 to 24, 17 to 24, 18 to 24, 19 to 24, 20 to 24, 19 to 22, 20 to
22, 16 to 20, or 16 or 20 linked nucleosides. In certain
embodiments, the modified oligonucleotide is at least 80%, at least
85%, at least 90%, at least 95% or 100% complementary to any of the
nucleobase sequences recited in SEQ ID NOs: 1-4.
[0353] In any of the foregoing methods or uses, the compound
comprises or consists of a modified oligonucleotide consisting of
16 to 30 linked nucleosides and having a nucleobase sequence
comprising any one of SEQ ID NOs: 8-2896, wherein the modified
oligonucleotide has: [0354] a gap segment consisting of linked
2'-deoxynucleosides; [0355] a 5' wing segment consisting of linked
nucleosides; and [0356] a 3' wing segment consisting of linked
nucleosides;
[0357] wherein the gap segment is positioned between the 5' wing
segment and the 3' wing segment and wherein each nucleoside of each
wing segment comprises a modified sugar. In certain embodiments,
the modified oligonucleotide is 16-30 linked nucleosides in length.
In certain embodiments, the modified oligonucleotide is 16 linked
nucleosides in length.
[0358] In any of the foregoing methods or uses, the compound can be
administered parenterally. For example, in certain embodiments the
compound can be administered through injection or infusion.
Parenteral administration includes subcutaneous administration,
intravenous administration, intramuscular administration,
intraarterial administration, intraperitoneal administration, or
intracranial administration, e.g. intrathecal or
intracerebroventricular administration.
Certain Compounds
[0359] In certain embodiments, compounds described herein can be
antisense compounds. In certain embodiments, the antisense compound
comprises or consists of an oligomeric compound. In certain
embodiments, the oligomeric compound comprises a modified
oligonucleotide. In certain embodiments, the modified
oligonucleotide has a nucleobase sequence complementary to that of
a target nucleic acid.
[0360] In certain embodiments, a compound described herein
comprises or consists of a modified oligonucleotide. In certain
embodiments, the modified oligonucleotide has a nucleobase sequence
complementary to that of a target nucleic acid.
[0361] In certain embodiments, a compound or antisense compound is
single-stranded. Such a single-stranded compound or antisense
compound comprises or consists of an oligomeric compound. In
certain embodiments, such an oligomeric compound comprises or
consists of an oligonucleotide and optionally a conjugate group. In
certain embodiments, the oligonucleotide is an antisense
oligonucleotide. In certain embodiments, the oligonucleotide is
modified. In certain embodiments, the oligonucleotide of a
single-stranded antisense compound or oligomeric compound comprises
a self-complementary nucleobase sequence.
[0362] In certain embodiments, compounds are double-stranded. Such
double-stranded compounds comprise a first modified oligonucleotide
having a region complementary to a target nucleic acid and a second
modified oligonucleotide having a region complementary to the first
modified oligonucleotide. In certain embodiments, the modified
oligonucleotide is an RNA oligonucleotide. In such embodiments, the
thymine nucleobase in the modified oligonucleotide is replaced by a
uracil nucleobase. In certain embodiments, compound comprises a
conjugate group. In certain embodiments, one of the modified
oligonucleotides is conjugated. In certain embodiments, both the
modified oligonucleotides are conjugated. In certain embodiments,
the first modified oligonucleotide is conjugated. In certain
embodiments, the second modified oligonucleotide is conjugated. In
certain embodiments, the first modified oligonucleotide is 16-30
linked nucleosides in length and the second modified
oligonucleotide is 16-30 linked nucleosides in length. In certain
embodiments, one of the modified oligonucleotides has a nucleobase
sequence comprising at least 8 contiguous nucleobases of any of SEQ
ID NOs: 8-2035.
[0363] In certain embodiments, antisense compounds are
double-stranded. Such double-stranded antisense compounds comprise
a first oligomeric compound having a region complementary to a
target nucleic acid and a second oligomeric compound having a
region complementary to the first oligomeric compound. The first
oligomeric compound of such double stranded antisense compounds
typically comprises or consists of a modified oligonucleotide and
optionally a conjugate group. The oligonucleotide of the second
oligomeric compound of such a double-stranded antisense compound
may be modified or unmodified. Either or both oligomeric compounds
of a double-stranded antisense compound may comprise a conjugate
group. The oligomeric compounds of double-stranded antisense
compounds may include non-complementary overhanging
nucleosides.
[0364] Examples of single-stranded and double-stranded compounds
include, but are not limited to, oligonucleotides, siRNAs, microRNA
targeting oligonucleotides, and single-stranded RNAi compounds,
such as small hairpin RNAs (shRNAs), single-stranded siRNAs
(ssRNAs), and microRNA mimics.
[0365] In certain embodiments, a compound described herein has a
nucleobase sequence that, when written in the 5' to 3' direction,
comprises the reverse complement of the target segment of a target
nucleic acid to which it is targeted.
[0366] In certain embodiments, a compound described herein
comprises an oligonucleotide 12 to 30 linked subunits in length. In
certain embodiments, a compound described herein comprises an
oligonucleotide 12 to 22 linked subunits in length. In certain
embodiments, compound described herein comprises an oligonucleotide
14 to 30 linked subunits in length. In certain embodiments,
compound described herein comprises an oligonucleotide 14 to 20
linked subunits in length. In certain embodiments, a compound
described herein comprises an oligonucleotide 15 to 30 linked
subunits in length. In certain embodiments, a compound described
herein comprises an oligonucleotide 15 to 20 linked subunits in
length. In certain embodiments, a compound described herein
comprises an oligonucleotide 16 to 30 linked subunits in length. In
certain embodiments, a compound described herein comprises an
oligonucleotide 16 to 20 linked subunits in length. In certain
embodiments, a compound described herein comprises an
oligonucleotide 17 to 30 linked subunits in length. In certain
embodiments, a compound described herein comprises an
oligonucleotide 17 to 20 linked subunits in length. In certain
embodiments, a compound described herein comprises an
oligonucleotide 18 to 30 linked subunits in length. In certain
embodiments, a compound described herein comprises an
oligonucleotide 18 to 20 linked subunits in length. In certain
embodiments, a compound described herein comprises an
oligonucleotide 20 to 30 linked subunits in length. In other words,
such oligonucleotides are 12 to 30 linked subunits, 14 to 30 linked
subunits, 14 to 20 subunits, 15 to 30 subunits, 15 to 20 subunits,
16 to 30 subunits, 16 to 20 subunits, 17 to 30 subunits, 17 to 20
subunits, 18 to 30 subunits, 18 to 20 subunits, or 20 to 30
subunits in length, respectively. In certain embodiments, a
compound described herein comprises an oligonucleotide 14 linked
subunits in length. In certain embodiments, a compound described
herein comprises an oligonucleotide 16 linked subunits in length.
In certain embodiments, a compound described herein comprises an
oligonucleotide 17 linked subunits in length. In certain
embodiments, compound described herein comprises an oligonucleotide
18 linked subunits in length. In certain embodiments, a compound
described herein comprises an oligonucleotide 19 linked subunits in
length. In certain embodiments, a compound described herein
comprises an oligonucleotide 20 linked subunits in length. In other
embodiments, a compound described herein comprises an
oligonucleotide 8 to 80, 12 to 50, 13 to 30, 13 to 50, 14 to 30, 14
to 50, 15 to 30, 15 to 50, 16 to 30, 16 to 50, 17 to 30, 17 to 50,
18 to 22, 18 to 24, 18 to 30, 18 to 50, 19 to 22, 19 to 30, 19 to
50, or 20 to 30 linked subunits. In certain such embodiments, the
compound described herein comprises an oligonucleotide 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,
28, 29, or 30 linked subunits in length, or a range defined by any
two of the above values. In some embodiments the linked subunits
are nucleotides, nucleosides, or nucleobases.
[0367] In certain embodiments, the compound may further comprise
additional features or elements, such as a conjugate group, that
are attached to the oligonucleotide. In certain embodiments, such
compounds are antisense compounds. In certain embodiments, such
compounds are oligomeric compounds. In embodiments where a
conjugate group comprises a nucleoside (i.e. a nucleoside that
links the conjugate group to the oligonucleotide), the nucleoside
of the conjugate group is not counted in the length of the
oligonucleotide.
[0368] In certain embodiments, compounds may be shortened or
truncated. For example, a single subunit may be deleted from the 5'
end (5' truncation), or alternatively from the 3' end (3'
truncation). A shortened or truncated compound targeted to a
HSD17B13 nucleic acid may have two subunits deleted from the 5'
end, or alternatively, may have two subunits deleted from the 3'
end of the compound. Alternatively, the deleted nucleosides may be
dispersed throughout the compound.
[0369] When a single additional subunit is present in a lengthened
compound, the additional subunit may be located at the 5' or 3' end
of the compound. When two or more additional subunits are present,
the added subunits may be adjacent to each other, for example, in a
compound having two subunits added to the 5' end (5' addition), or
alternatively, to the 3' end (3' addition) of the compound.
Alternatively, the added subunits may be dispersed throughout the
compound.
[0370] It is possible to increase or decrease the length of a
compound, such as an oligonucleotide, and/or introduce mismatch
bases without eliminating activity (Woolf et al. Proc. Natl. Acad.
Sci. USA 1992, 89:7305-7309; Gautschi et al. J. Natl. Cancer Inst.
March 2001, 93:463-471; Maher and Dolnick Nuc. Acid. Res. 1998,
16:3341-3358). However, seemingly small changes in oligonucleotide
sequence, chemistry and motif can make large differences in one or
more of the many properties required for clinical development (Seth
et al. J. Med. Chem. 2009, 52, 10; Egli et al. J. Am. Chem. Soc.
2011, 133, 16642).
[0371] In certain embodiments, compounds described herein are
interfering RNA compounds (RNAi), which include double-stranded RNA
compounds (also referred to as short-interfering RNA or siRNA) and
single-stranded RNAi compounds (or ssRNA). Such compounds work at
least in part through the RISC pathway to degrade and/or sequester
a target nucleic acid (thus, include microRNA/microRNA-mimic
compounds). As used herein, the term siRNA is meant to be
equivalent to other terms used to describe nucleic acid molecules
that are capable of mediating sequence-specific RNAi, for example,
short interfering RNA (siRNA), double-stranded RNA (dsRNA),
micro-RNA (miRNA), short hairpin RNA (shRNA), short interfering
oligonucleotide, short interfering nucleic acid, short interfering
modified oligonucleotide, chemically modified siRNA,
post-transcriptional gene silencing RNA (ptgsRNA), and others. In
addition, as used herein, the term "RNAi" is meant to be equivalent
to other terms used to describe sequence-specific RNA interference,
such as post transcriptional gene silencing, translational
inhibition, or epigenetics.
[0372] In certain embodiments, a compound described herein can
comprise any of the oligonucleotide sequences targeted to HSD17B13
described herein. In certain embodiments, the compound can be
double-stranded. In certain embodiments, the compound comprises a
first strand comprising at least an 8, 9, 10, 11, 12, 13, 14, 15,
or 16 contiguous nucleobase portion of any one of SEQ ID NOs:
8-2035 and a second strand. In certain embodiments, the compound
comprises a first strand comprising the nucleobase sequence of any
one of SEQ ID NOs: 8-2035 and a second strand. In certain
embodiments, the compound comprises ribonucleotides in which the
first strand has uracil (U) in place of thymine (T) in any one of
SEQ ID NOs: 8-2035. In certain embodiments, the compound comprises
(i) a first strand comprising a nucleobase sequence complementary
to the site on HSD17B13 to which any of SEQ ID NOs: 8-2035 is
targeted, and (ii) a second strand. In certain embodiments, the
compound comprises one or more modified nucleotides in which the 2'
position of the sugar contains a halogen (such as fluorine group;
2'-F) or contains an alkoxy group (such as a methoxy group;
2'-OMe). In certain embodiments, the compound comprises at least
one 2'-F sugar modification and at least one 2'-OMe sugar
modification. In certain embodiments, the at least one 2'-F sugar
modification and at least one 2'-OMe sugar modification are
arranged in an alternating pattern for at least 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous
nucleobases along a strand of the dsRNA compound. In certain
embodiments, the compound comprises one or more linkages between
adjacent nucleotides other than a naturally-occurring
phosphodiester linkage. Examples of such linkages include
phosphoramide, phosphorothioate, and phosphorodithioate linkages.
The compounds may also be chemically modified nucleic acid
molecules as taught in U.S. Pat. No. 6,673,661. In other
embodiments, the compound contains one or two capped strands, as
disclosed, for example, by WO 00/63364, filed Apr. 19, 2000.
[0373] In certain embodiments, the first strand of the compound is
an siRNA guide strand and the second strand of the compound is an
siRNA passenger strand. In certain embodiments, the second strand
of the compound is complementary to the first strand. In certain
embodiments, each strand of the compound is 16, 17, 18, 19, 20, 21,
22, or 23 linked nucleosides in length. In certain embodiments, the
first or second strand of the compound can comprise a conjugate
group.
[0374] In certain embodiments, a compound described herein can
comprise any of the oligonucleotide sequences targeted to HSD17B13
described herein. In certain embodiments, the compound is single
stranded. In certain embodiments, such a compound is a
single-stranded RNAi (ssRNAi) compound. In certain embodiments, the
compound comprises at least an 8, 9, 10, 11, 12, 13, 14, 15, or 16
contiguous nucleobase portion of any one of SEQ ID NOs: 8-2035. In
certain embodiments, the compound comprises the nucleobase sequence
of any one of SEQ ID NOs: 8-2035. In certain embodiments, the
compound comprises ribonucleotides in which uracil (U) is in place
of thymine (T) in any one of SEQ ID NOs: 8-2035. In certain
embodiments, the compound comprises a nucleobase sequence
complementary to the site on HSD17B13 to which any of SEQ ID NOs:
8-2035 is targeted. In certain embodiments, the compound comprises
one or more modified nucleotides in which the 2' position in the
sugar contains a halogen (such as fluorine group; 2'-F) or contains
an alkoxy group (such as a methoxy group; 2'-OMe). In certain
embodiments, the compound comprises at least one 2'-F sugar
modification and at least one 2'-OMe sugar modification. In certain
embodiments, the at least one 2'-F sugar modification and at least
one 2'-OMe sugar modification are arranged in an alternating
pattern for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,
15, 16, 17, 18, 19, or 20 contiguous nucleobases along a strand of
the compound. In certain embodiments, the compound comprises one or
more linkages between adjacent nucleotides other than a
naturally-occurring phosphodiester linkage. Examples of such
linkages include phosphoramide, phosphorothioate, and
phosphorodithioate linkages. The compounds may also be chemically
modified nucleic acid molecules as taught in U.S. Pat. No.
6,673,661. In other embodiments, the compound contains a capped
strand, as disclosed, for example, by WO 00/63364, filed Apr. 19,
2000. In certain embodiments, the compound consists of 16, 17, 18,
19, 20, 21, 22, or 23 linked nucleosides. In certain embodiments,
the compound can comprise a conjugate group.
Certain Mechanisms
[0375] In certain embodiments, compounds described herein comprise
or consist of modified oligonucleotides. In certain embodiments,
compounds described herein are antisense compounds. In certain
embodiments, compounds comprise oligomeric compounds. In certain
embodiments, compounds described herein are capable of hybridizing
to a target nucleic acid, resulting in at least one antisense
activity. In certain embodiments, compounds described herein
selectively affect one or more target nucleic acid. Such compounds
comprise a nucleobase sequence that hybridizes to one or more
target nucleic acid, resulting in one or more desired antisense
activity and does not hybridize to one or more non-target nucleic
acid or does not hybridize to one or more non-target nucleic acid
in such a way that results in a significant undesired antisense
activity.
[0376] In certain antisense activities, hybridization of a compound
described herein to a target nucleic acid results in recruitment of
a protein that cleaves the target nucleic acid. For example,
certain compounds described herein result in RNase H mediated
cleavage of the target nucleic acid. RNase H is a cellular
endonuclease that cleaves the RNA strand of an RNA:DNA duplex. The
DNA in such an RNA:DNA duplex need not be unmodified DNA. In
certain embodiments, compounds described herein are sufficiently
"DNA-like" to elicit RNase H activity. Further, in certain
embodiments, one or more non-DNA-like nucleoside in the gap of a
gapmer is tolerated.
[0377] In certain antisense activities, compounds described herein
or a portion of the compound is loaded into an RNA-induced
silencing complex (RISC), ultimately resulting in cleavage of the
target nucleic acid. For example, certain compounds described
herein result in cleavage of the target nucleic acid by Argonaute.
Compounds that are loaded into RISC are RNAi compounds. RNAi
compounds may be double-stranded (siRNA) or single-stranded
(ssRNA).
[0378] In certain embodiments, hybridization of compounds described
herein to a target nucleic acid does not result in recruitment of a
protein that cleaves that target nucleic acid. In certain such
embodiments, hybridization of the compound to the target nucleic
acid results in alteration of splicing of the target nucleic acid.
In certain embodiments, hybridization of the compound to a target
nucleic acid results in inhibition of a binding interaction between
the target nucleic acid and a protein or other nucleic acid. In
certain such embodiments, hybridization of the compound to a target
nucleic acid results in alteration of translation of the target
nucleic acid.
[0379] Antisense activities may be observed directly or indirectly.
In certain embodiments, observation or detection of an antisense
activity involves observation or detection of a change in an amount
of a target nucleic acid or protein encoded by such target nucleic
acid, a change in the ratio of splice variants of a nucleic acid or
protein, and/or a phenotypic change in a cell or animal.
Target Nucleic Acids, Target Regions and Nucleotide Sequences
[0380] In certain embodiments, compounds described herein comprise
or consist of an oligonucleotide comprising a region that is
complementary to a target nucleic acid. In certain embodiments, the
target nucleic acid is an endogenous RNA molecule. In certain
embodiments, the target nucleic acid encodes a protein. In certain
such embodiments, the target nucleic acid is selected from an mRNA
and a pre-mRNA, including intronic, exonic and untranslated
regions. In certain embodiments, the target RNA is an mRNA. In
certain embodiments, the target nucleic acid is a pre-mRNA. In
certain such embodiments, the target region is entirely within an
intron. In certain embodiments, the target region spans an
intron/exon junction. In certain embodiments, the target region is
at least 50% within an intron.
[0381] Nucleotide sequences that encode HSD17B13 include, without
limitation, the following: RefSeq or GENBANK Accession No.
NM_178135.4 (incorporated by reference, disclosed herein as SEQ ID
NO: 1), the complement of GENBANK Accession No. NC_000004.12
truncated from nucleotides 87301001 to U.S. Pat. No. 87,326,000
(incorporated by reference, disclosed herein as SEQ ID NO: 2), the
sequence listed as SEQ ID NO: 3, or GENBANK Accession No.
NM_001136230.2 (incorporated by reference, disclosed herein as SEQ
ID NO: 4).
Hybridization
[0382] In some embodiments, hybridization occurs between a compound
disclosed herein and a HSD17B13 nucleic acid. The most common
mechanism of hybridization involves hydrogen bonding (e.g.,
Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding)
between complementary nucleobases of the nucleic acid
molecules.
[0383] Hybridization can occur under varying conditions.
Hybridization conditions are sequence-dependent and are determined
by the nature and composition of the nucleic acid molecules to be
hybridized.
[0384] Methods of determining whether a sequence is specifically
hybridizable to a target nucleic acid are well known in the art. In
certain embodiments, the compounds provided herein are specifically
hybridizable with a HSD17B13 nucleic acid.
Complementarity
[0385] An oligonucleotide is said to be complementary to another
nucleic acid when the nucleobase sequence of such oligonucleotide
or one or more regions thereof matches the nucleobase sequence of
another oligonucleotide or nucleic acid or one or more regions
thereof when the two nucleobase sequences are aligned in opposing
directions. Nucleobase matches or complementary nucleobases, as
described herein, are limited to the following pairs: adenine (A)
and thymine (T), adenine (A) and uracil (U), cytosine (C) and
guanine (G), and 5-methyl cytosine (mC) and guanine (G), unless
otherwise specified. Complementary oligonucleotides and/or nucleic
acids need not have nucleobase complementarity at each nucleoside
and may include one or more nucleobase mismatches. An
oligonucleotide is fully complementary or 100% complementary when
such oligonucleotides have nucleobase matches at each nucleoside
without any nucleobase mismatches.
[0386] In certain embodiments, compounds described herein comprise
or consist of modified oligonucleotides. In certain embodiments,
compounds described herein are antisense compounds. In certain
embodiments, compounds comprise oligomeric compounds.
Non-complementary nucleobases between a compound and a HSD17B13
nucleic acid may be tolerated provided that the compound remains
able to specifically hybridize to a target nucleic acid. Moreover,
a compound may hybridize over one or more segments of a HSD17B13
nucleic acid such that intervening or adjacent segments are not
involved in the hybridization event (e.g., a loop structure,
mismatch or hairpin structure).
[0387] In certain embodiments, the compounds provided herein, or a
specified portion thereof are at least, or are up to 70%, 80%, 85%,
86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,
99%, or 100% complementary to a HSD17B13 nucleic acid, a target
region, target segment, or specified portion thereof. In certain
embodiments, the compounds provided herein, or a specified portion
thereof, are 70% to 75%, 75% to 80%, 80% to 85%, 85% to 90%, 90% to
95%, 95% to 100%, or any number in between these ranges,
complementary to a HSD17B13 nucleic acid, a target region, target
segment, or specified portion thereof. Percent complementarity of a
compound with a target nucleic acid can be determined using routine
methods.
[0388] For example, a compound in which 18 of 20 nucleobases of the
compound are complementary to a target region, and would therefore
specifically hybridize, would represent 90 percent complementarity.
In this example, the remaining non-complementary nucleobases may be
clustered or interspersed with complementary nucleobases and need
not be contiguous to each other or to complementary nucleobases. As
such, a compound which is 18 nucleobases in length having four
non-complementary nucleobases which are flanked by two regions of
complete complementarity with the target nucleic acid would have
77.8% overall complementarity with the target nucleic acid. Percent
complementarity of a compound with a region of a target nucleic
acid can be determined routinely using BLAST programs (basic local
alignment search tools) and PowerBLAST programs known in the art
(Altschul et al., J. Mol. Biol., 1990, 215, 403 410; Zhang and
Madden, Genome Res., 1997, 7, 649 656). Percent homology, sequence
identity or complementarity, can be determined by, for example, the
Gap program (Wisconsin Sequence Analysis Package, Version 8 for
Unix, Genetics Computer Group, University Research Park, Madison
Wis.), using default settings, which uses the algorithm of Smith
and Waterman (Adv. Appl. Math., 1981, 2, 482 489).
[0389] In certain embodiments, compounds described herein, or
specified portions thereof, are fully complementary (i.e. 100%
complementary) to a target nucleic acid, or specified portion
thereof. For example, a compound may be fully complementary to a
HSD17B13 nucleic acid, or a target region, or a target segment or
target sequence thereof. As used herein, "fully complementary"
means each nucleobase of a compound is complementary to the
corresponding nucleobase of a target nucleic acid. For example, a
20 nucleobase compound is fully complementary to a target sequence
that is 400 nucleobases long, so long as there is a corresponding
20 nucleobase portion of the target nucleic acid that is fully
complementary to the compound. "Fully complementary" can also be
used in reference to a specified portion of the first and/or the
second nucleic acid. For example, a 20 nucleobase portion of a 30
nucleobase compound can be "fully complementary" to a target
sequence that is 400 nucleobases long. The 20 nucleobase portion of
the 30 nucleobase compound is fully complementary to the target
sequence if the target sequence has a corresponding 20 nucleobase
portion wherein each nucleobase is complementary to the 20
nucleobase portion of the compound. At the same time, the entire 30
nucleobase compound may or may not be fully complementary to the
target sequence, depending on whether the remaining 10 nucleobases
of the compound are also complementary to the target sequence.
[0390] In certain embodiments, compounds described herein comprise
one or more mismatched nucleobases relative to the target nucleic
acid. In certain such embodiments, antisense activity against the
target is reduced by such mismatch, but activity against a
non-target is reduced by a greater amount. Thus, in certain such
embodiments, selectivity of the compound is improved. In certain
embodiments, the mismatch is specifically positioned within an
oligonucleotide having a gapmer motif. In certain such embodiments,
the mismatch is at position 1, 2, 3, 4, 5, 6, 7, or 8 from the
5'-end of the gap region. In certain such embodiments, the mismatch
is at position 9, 8, 7, 6, 5, 4, 3, 2, 1 from the 3'-end of the gap
region. In certain such embodiments, the mismatch is at position 1,
2, 3, or 4 from the 5'-end of the wing region. In certain such
embodiments, the mismatch is at position 4, 3, 2, or 1 from the
3'-end of the wing region. In certain embodiments, the mismatch is
specifically positioned within an oligonucleotide not having a
gapmer motif. In certain such embodiments, the mismatch is at
position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 from the 5'-end
of the oligonucleotide. In certain such embodiments, the mismatch
is at position, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 from the
3'-end of the oligonucleotide.
[0391] The location of a non-complementary nucleobase may be at the
5' end or 3' end of the compound. Alternatively, the
non-complementary nucleobase or nucleobases may be at an internal
position of the compound. When two or more non-complementary
nucleobases are present, they may be contiguous (i.e. linked) or
non-contiguous. In one embodiment, a non-complementary nucleobase
is located in the wing segment of a gapmer oligonucleotide.
[0392] In certain embodiments, compounds described herein that are,
or are up to 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleobases
in length comprise no more than 4, no more than 3, no more than 2,
or no more than 1 non-complementary nucleobase(s) relative to a
target nucleic acid, such as a HSD17B13 nucleic acid, or specified
portion thereof.
[0393] In certain embodiments, compounds described herein that are,
or are up to 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,
24, 25, 26, 27, 28, 29, or 30 nucleobases in length comprise no
more than 6, no more than 5, no more than 4, no more than 3, no
more than 2, or no more than 1 non-complementary nucleobase(s)
relative to a target nucleic acid, such as a HSD17B13 nucleic acid,
or specified portion thereof.
[0394] In certain embodiments, compounds described herein also
include those which are complementary to a portion of a target
nucleic acid. As used herein, "portion" refers to a defined number
of contiguous (i.e. linked) nucleobases within a region or segment
of a target nucleic acid. A "portion" can also refer to a defined
number of contiguous nucleobases of a compound. In certain
embodiments, the compounds, are complementary to at least an 8
nucleobase portion of a target segment. In certain embodiments, the
compounds are complementary to at least a 9 nucleobase portion of a
target segment. In certain embodiments, the compounds are
complementary to at least a 10 nucleobase portion of a target
segment. In certain embodiments, the compounds are complementary to
at least an 11 nucleobase portion of a target segment. In certain
embodiments, the compounds are complementary to at least a 12
nucleobase portion of a target segment. In certain embodiments, the
compounds are complementary to at least a 13 nucleobase portion of
a target segment. In certain embodiments, the compounds are
complementary to at least a 14 nucleobase portion of a target
segment. In certain embodiments, the compounds are complementary to
at least a 15 nucleobase portion of a target segment. In certain
embodiments, the compounds are complementary to at least a 16
nucleobase portion of a target segment. Also contemplated are
compounds that are complementary to at least a 9, 10, 17, 18, 19,
20, or more nucleobase portion of a target segment, or a range
defined by any two of these values.
Identity
[0395] The compounds provided herein may also have a defined
percent identity to a particular nucleotide sequence, SEQ ID NO, or
compound represented by a specific ION number, or portion thereof.
In certain embodiments, compounds described herein are antisense
compounds or oligomeric compounds. In certain embodiments,
compounds described herein are modified oligonucleotides. As used
herein, a compound is identical to the sequence disclosed herein if
it has the same nucleobase pairing ability. For example, a RNA
which contains uracil in place of thymidine in a disclosed DNA
sequence would be considered identical to the DNA sequence since
both uracil and thymidine pair with adenine. Shortened and
lengthened versions of the compounds described herein as well as
compounds having non-identical bases relative to the compounds
provided herein also are contemplated. The non-identical bases may
be adjacent to each other or dispersed throughout the compound.
Percent identity of an compound is calculated according to the
number of bases that have identical base pairing relative to the
sequence to which it is being compared.
[0396] In certain embodiments, compounds described herein, or
portions thereof, are, or are at least, 70%, 75%, 80%, 85%, 90%,
91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to
one or more of the compounds or SEQ ID NOs, or a portion thereof,
disclosed herein. In certain embodiments, compounds described
herein are about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%,
96%, 97%, 98%, or 99% identical, or any percentage between such
values, to a particular nucleotide sequence, SEQ ID NO, or compound
represented by a specific ION number, or portion thereof, in which
the compounds comprise an oligonucleotide having one or more
mismatched nucleobases. In certain such embodiments, the mismatch
is at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 from the
5'-end of the oligonucleotide. In certain such embodiments, the
mismatch is at position, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 from
the 3'-end of the oligonucleotide.
[0397] In certain embodiments, compounds described herein comprise
or consist of antisense compounds. In certain embodiments, a
portion of the antisense compound is compared to an equal length
portion of the target nucleic acid. In certain embodiments, an 8,
9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or
25 nucleobase portion is compared to an equal length portion of the
target nucleic acid.
[0398] In certain embodiments, compounds described herein comprise
or consist of oligonucleotides. In certain embodiments, a portion
of the oligonucleotide is compared to an equal length portion of
the target nucleic acid. In certain embodiments, an 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25
nucleobase portion is compared to an equal length portion of the
target nucleic acid.
Certain Modified Compounds
[0399] In certain embodiments, compounds described herein comprise
or consist of oligonucleotides consisting of linked nucleosides.
Oligonucleotides may be unmodified oligonucleotides (RNA or DNA) or
may be modified oligonucleotides. Modified oligonucleotides
comprise at least one modification relative to unmodified RNA or
DNA (i.e., comprise at least one modified nucleoside (comprising a
modified sugar moiety and/or a modified nucleobase) and/or at least
one modified internucleoside linkage).
A. Modified Nucleosides
[0400] Modified nucleosides comprise a modified sugar moiety or a
modified nucleobase or both a modified sugar moiety and a modified
nucleobase.
[0401] 1. Modified Sugar Moieties
[0402] In certain embodiments, sugar moieties are non-bicyclic
modified sugar moieties. In certain embodiments, modified sugar
moieties are bicyclic or tricyclic sugar moieties. In certain
embodiments, modified sugar moieties are sugar surrogates. Such
sugar surrogates may comprise one or more substitutions
corresponding to those of other types of modified sugar
moieties.
[0403] In certain embodiments, modified sugar moieties are
non-bicyclic modified furanosyl sugar moieties comprising one or
more acyclic substituent, including, but not limited, to
substituents at the 2', 4', and/or 5' positions. In certain
embodiments, the furanosyl sugar moiety is a ribosyl sugar moiety.
In certain embodiments, one or more acyclic substituent of
non-bicyclic modified sugar moieties is branched. Examples of
2'-substituent groups suitable for non-bicyclic modified sugar
moieties include but are not limited to: 2'-F, 2'-OCH.sub.3 ("OMe"
or "O-methyl"), and 2'-O(CH.sub.2).sub.2OCH.sub.3 ("MOE"). In
certain embodiments, 2'-substituent groups are selected from among:
halo, allyl, amino, azido, SH, CN, OCN, CF.sub.3, OCF.sub.3,
O--C.sub.1-C.sub.10 alkoxy, O--C.sub.1-C.sub.10 substituted alkoxy,
O--C.sub.1-C.sub.10 alkyl, O--C.sub.1-C.sub.10 substituted alkyl,
S-alkyl, N(R.sub.m)-alkyl, O-alkenyl, S-alkenyl,
N(R.sub.m)-alkenyl, O-alkynyl, S-alkynyl, N(R.sub.m)-alkynyl,
O-alkylenyl-O-alkyl, alkynyl, alkaryl, aralkyl, O-alkaryl,
O-aralkyl, O(CH.sub.2).sub.2SCH.sub.3,
O(CH.sub.2).sub.2ON(R.sub.m)(R.sub.n) or
OCH.sub.2C(.dbd.O)--N(R.sub.m)(R.sub.n), where each R.sub.m and
R.sub.n is, independently, H, an amino protecting group, or
substituted or unsubstituted C.sub.1-C.sub.10 alkyl, and the
2'-substituent groups described in Cook et al., U.S. Pat. No.
6,531,584; Cook et al., U.S. Pat. No. 5,859,221; and Cook et al.,
U.S. Pat. No. 6,005,087. Certain embodiments of these
2'-substituent groups can be further substituted with one or more
substituent groups independently selected from among: hydroxyl,
amino, alkoxy, carboxy, benzyl, phenyl, nitro (NO.sub.2), thiol,
thioalkoxy, thioalkyl, halogen, alkyl, aryl, alkenyl and alkynyl.
Examples of 4'-substituent groups suitable for linearly
non-bicyclic modified sugar moieties include, but are not limited
to, alkoxy (e.g., methoxy), alkyl, and those described in Manoharan
et al., WO 2015/106128. Examples of 5'-substituent groups suitable
for non-bicyclic modified sugar moieties include, but are not
limited to: 5'-methyl (R or S), 5'-vinyl, and 5'-methoxy. In
certain embodiments, non-bicyclic modified sugars comprise more
than one non-bridging sugar substituent, for example,
2'-F-5'-methyl sugar moieties and the modified sugar moieties and
modified nucleosides described in Migawa et al., WO 2008/101157 and
Rajeev et al., US2013/0203836.
[0404] In certain embodiments, a 2'-substituted nucleoside or
2'-non-bicyclic modified nucleoside comprises a sugar moiety
comprising a linear 2'-substituent group selected from: F,
NH.sub.2, N.sub.3, OCF.sub.3, OCH.sub.3, O(CH.sub.2).sub.3NH.sub.2,
CH.sub.2CH.dbd.CH.sub.2, OCH.sub.2CH.dbd.CH.sub.2,
OCH.sub.2CH.sub.2OCH.sub.3, O(CH.sub.2).sub.2SCH.sub.3,
O(CH.sub.2).sub.2ON(R.sub.m)(R.sub.n),
O(CH.sub.2).sub.2O(CH.sub.2).sub.2N(CH.sub.3).sub.2, and
N-substituted acetamide (OCH.sub.2C(.dbd.O)--N(R.sub.m)(R.sub.n),
where each R.sub.m and R.sub.n is, independently, H, an amino
protecting group, or substituted or unsubstituted C.sub.1-C.sub.10
alkyl.
[0405] In certain embodiments, a 2'-substituted nucleoside or
2'-non-bicyclic modified nucleoside comprises a sugar moiety
comprising a linear 2'-substituent group selected from: F,
OCF.sub.3, OCH.sub.3, OCH.sub.2CH.sub.2OCH.sub.3,
O(CH.sub.2).sub.2SCH.sub.3, O(CH.sub.2).sub.2ON(CH.sub.3).sub.2,
O(CH.sub.2).sub.2O(CH.sub.2).sub.2N(CH.sub.3).sub.2, and
OCH.sub.2C(.dbd.O)--N(H)CH.sub.3 ("NMA").
[0406] In certain embodiments, a 2'-substituted nucleoside or
2'-non-bicyclic modified nucleoside comprises a sugar moiety
comprising a linear 2'-substituent group selected from: F,
OCH.sub.3, and OCH.sub.2CH.sub.2OCH.sub.3.
[0407] Nucleosides comprising modified sugar moieties, such as
non-bicyclic modified sugar moieties, are referred to by the
position(s) of the substitution(s) on the sugar moiety of the
nucleoside. For example, nucleosides comprising 2'-substituted or
2'-modified sugar moieties are referred to as 2'-substituted
nucleosides or 2'-modified nucleosides.
[0408] Certain modified sugar moieties comprise a bridging sugar
substituent that forms a second ring resulting in a bicyclic sugar
moiety. In certain such embodiments, the bicyclic sugar moiety
comprises a bridge between the 4' and the 2' furanose ring atoms.
In certain such embodiments, the furanose ring is a ribose ring.
Examples of such 4' to 2' bridging sugar substituents include, but
are not limited to: 4'-CH.sub.2-2', 4'-(CH.sub.2).sub.2-2',
4'-(CH.sub.2).sub.3-2', 4'-CH.sub.2--O-2' ("LNA"),
4'-CH.sub.2--S-2', 4'-(CH.sub.2).sub.2--O-2' ("ENA"),
4'-CH(CH.sub.3)--O-2' (referred to as "constrained ethyl" or "cEt"
when in the S configuration), 4'-CH.sub.2--O--CH.sub.2-2',
4'-CH.sub.2--N(R)-2', 4'-CH(CH.sub.2OCH.sub.3)--O-2' ("constrained
MOE" or "cMOE") and analogs thereof (see, e.g., Seth et al., U.S.
Pat. No. 7,399,845, Bhat et al., U.S. Pat. No. 7,569,686, Swayze et
al., U.S. Pat. No. 7,741,457, and Swayze et al., U.S. Pat. No.
8,022,193), 4'-C(CH.sub.3)(CH.sub.3)--O-2' and analogs thereof
(see, e.g., Seth et al., U.S. Pat. No. 8,278,283),
4'-CH.sub.2--N(OCH.sub.3)-2' and analogs thereof (see, e.g.,
Prakash et al., U.S. Pat. No. 8,278,425),
4'-CH.sub.2--O--N(CH.sub.3)-2' (see, e.g., Allerson et al., U.S.
Pat. No. 7,696,345 and Allerson et al., U.S. Pat. No. 8,124,745),
4'-CH.sub.2--C(H)(CH.sub.3)-2' (see, e.g., Zhou, et al., J. Org.
Chem., 2009, 74, 118-134), 4'-CH.sub.2--C(.dbd.CH.sub.2)-2' and
analogs thereof (see e.g., Seth et al., U.S. Pat. No. 8,278,426),
4'-C(R.sub.aR.sub.b)--N(R)--O-2', 4'-C(R.sub.aR.sub.b)--O--N(R)-2',
4'-CH.sub.2--O--N(R)-2', and 4'-CH.sub.2--N(R)--O-2', wherein each
R, R.sub.a, and R.sub.b is, independently, H, a protecting group,
or C.sub.1-C.sub.12 alkyl (see, e.g. Imanishi et al., U.S. Pat. No.
7,427,672).
[0409] In certain embodiments, such 4' to 2' bridges independently
comprise from 1 to 4 linked groups independently selected from:
--[C(R.sub.a)(R.sub.b)].sub.n--,
--[C(R.sub.a)(R.sub.b)].sub.n--O--, --C(R.sub.n).dbd.C(R.sub.b)--,
--C(R.sub.a).dbd.N--, --C(.dbd.NR.sub.a)--, --C(.dbd.O)--,
--C(.dbd.S)--, --O--, --Si(R.sub.a).sub.2--, --S(.dbd.O).sub.x--,
and --N(R.sub.a)--;
[0410] wherein:
[0411] x is 0, 1, or 2;
[0412] n is 1, 2, 3, or 4;
[0413] each R.sub.a and R.sub.b is, independently, H, a protecting
group, hydroxyl, C.sub.1-C.sub.12 alkyl, substituted
C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.12 alkenyl, substituted
C.sub.2-C.sub.12 alkenyl, C.sub.2-C.sub.12 alkynyl, substituted
C.sub.2-C.sub.12 alkynyl, C.sub.5-C.sub.20 aryl, substituted
C.sub.5-C.sub.20 aryl, heterocycle radical, substituted heterocycle
radical, heteroaryl, substituted heteroaryl, C.sub.5-C.sub.7
alicyclic radical, substituted C.sub.5-C.sub.7 alicyclic radical,
halogen, OJ.sub.1, NJ.sub.1J.sub.2, SJ.sub.1, N.sub.3, COOJ.sub.1,
acyl (C(.dbd.O)--H), substituted acyl, CN, sulfonyl
(S(.dbd.O).sub.2-J.sub.1), or sulfoxyl (S(.dbd.O)-J.sub.1); and
each J.sub.1 and J.sub.2 is, independently, H, C.sub.1-C.sub.12
alkyl, substituted C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.12
alkenyl, substituted C.sub.2-C.sub.12 alkenyl, C.sub.2-C.sub.12
alkynyl, substituted C.sub.2-C.sub.12 alkynyl, C.sub.5-C.sub.20
aryl, substituted C.sub.5-C.sub.20 aryl, acyl (C(.dbd.O)--H),
substituted acyl, a heterocycle radical, a substituted heterocycle
radical, C.sub.1-C.sub.12 aminoalkyl, substituted C.sub.1-C.sub.12
aminoalkyl, or a protecting group.
[0414] Additional bicyclic sugar moieties are known in the art,
see, for example: Freier et al., Nucleic Acids Research, 1997,
25(22), 4429-4443, Albaek et al., J. Org. Chem., 2006, 71,
7731-7740, Singh et al., Chem. Commun., 1998, 4, 455-456; Koshkin
et al., Tetrahedron, 1998, 54, 3607-3630; Wahlestedt et al., Proc.
Natl. Acad. Sci. U S. A., 2000, 97, 5633-5638; Kumar et al.,
Bioorg. Med. Chem. Lett., 1998, 8, 2219-2222; Singh et al., J. Org.
Chem., 1998, 63, 10035-10039; Srivastava et al., J. Am. Chem. Soc.,
2007, 129, 8362-8379; Elayadi et al., Curr. Opinion Invens. Drugs,
2001, 2, 558-561; Braasch et al., Chem. Biol., 2001, 8, 1-7; Orum
et al., Curr. Opinion Mol. Ther., 2001, 3, 239-243; Wengel et al.,
U.S. Pat. No. 7,053,207, Imanishi et al., U.S. Pat. No. 6,268,490,
Imanishi et al. U.S. Pat. No. 6,770,748, Imanishi et al., U.S.
RE44,779; Wengel et al., U.S. Pat. No. 6,794,499, Wengel et al.,
U.S. Pat. No. 6,670,461; Wengel et al., U.S. Pat. No. 7,034,133,
Wengel et al., U.S. Pat. No. 8,080,644; Wengel et al., U.S. Pat.
No. 8,034,909; Wengel et al., U.S. Pat. No. 8,153,365; Wengel et
al., U.S. Pat. No. 7,572,582; and Ramasamy et al., U.S. Pat. No.
6,525,191, Torsten et al., WO 2004/106356, Wengel et al., WO
1999/014226; Seth et al., WO 2007/134181; Seth et al., U.S. Pat.
No. 7,547,684; Seth et al., U.S. Pat. No. 7,666,854; Seth et al.,
U.S. Pat. No. 8,088,746; Seth et al., U.S. Pat. No. 7,750,131; Seth
et al., U.S. Pat. No. 8,030,467; Seth et al., U.S. Pat. No.
8,268,980; Seth et al., U.S. Pat. No. 8,546,556; Seth et al., U.S.
Pat. No. 8,530,640; Migawa et al., U.S. Pat. No. 9,012,421; Seth et
al., U.S. Pat. No. 8,501,805; Allerson et al., US2008/0039618; and
Migawa et al., US2015/0191727.
[0415] In certain embodiments, bicyclic sugar moieties and
nucleosides incorporating such bicyclic sugar moieties are further
defined by isomeric configuration. For example, an LNA nucleoside
(described herein) may be in the .alpha.-L configuration or in the
.beta.-D configuration.
##STR00055##
.alpha.-L-methyleneoxy (4'-CH.sub.2--O-2') or .alpha.-L-LNA
bicyclic nucleosides have been incorporated into oligonucleotides
that showed antisense activity (Frieden et al., Nucleic Acids
Research, 2003, 21, 6365-6372). Herein, general descriptions of
bicyclic nucleosides include both isomeric configurations. When the
positions of specific bicyclic nucleosides (e.g., LNA or cEt) are
identified in exemplified embodiments herein, they are in the
.beta.-D configuration, unless otherwise specified.
[0416] In certain embodiments, modified sugar moieties comprise one
or more non-bridging sugar substituent and one or more bridging
sugar substituent (e.g., 5'-substituted and 4'-2' bridged
sugars).
[0417] In certain embodiments, modified sugar moieties are sugar
surrogates. In certain such embodiments, the oxygen atom of the
sugar moiety is replaced, e.g., with a sulfur, carbon or nitrogen
atom. In certain such embodiments, such modified sugar moieties
also comprise bridging and/or non-bridging substituents as
described herein. For example, certain sugar surrogates comprise a
4'-sulfur atom and a substitution at the 2'-position (see, e.g.,
Bhat et al., U.S. Pat. No. 7,875,733 and Bhat et al., U.S. Pat. No.
7,939,677) and/or the 5' position.
[0418] In certain embodiments, sugar surrogates comprise rings
having other than 5 atoms. For example, in certain embodiments, a
sugar surrogate comprises a six-membered tetrahydropyran ("THP").
Such tetrahydropyrans may be further modified or substituted.
Nucleosides comprising such modified tetrahydropyrans include, but
are not limited to, hexitol nucleic acid ("HNA"), anitol nucleic
acid ("ANA"), manitol nucleic acid ("MNA") (see e.g., Leumann, C J.
Bioorg. & Med. Chem. 2002, 10, 841-854), fluoro HNA:
##STR00056##
("F-HNA", see e.g., Swayze et al., U.S. Pat. No. 8,088,904; Swayze
et al., U.S. Pat. No. 8,440,803; and Swayze et al., U.S. 9,005,906)
F-HNA can also be referred to as a F-THP or 3'-fluoro
tetrahydropyran, and nucleosides comprising additional modified THP
compounds having the formula:
##STR00057##
wherein, independently, for each of said modified THP
nucleoside:
[0419] Bx is a nucleobase moiety;
[0420] T.sub.3 and T.sub.4 are each, independently, an
internucleoside linking group linking the modified THP nucleoside
to the remainder of an oligonucleotide or one of T.sub.3 and
T.sub.4 is an internucleoside linking group linking the modified
THP nucleoside to the remainder of an oligonucleotide and the other
of T.sub.3 and T.sub.4 is H, a hydroxyl protecting group, a linked
conjugate group, or a 5' or 3'-terminal group; q.sub.1, q.sub.2,
q.sub.3, q.sub.4, q.sub.5, q.sub.6 and q.sub.7 are each,
independently, H, C.sub.1-C.sub.6 alkyl, substituted
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, substituted
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, or substituted
C.sub.2-C.sub.6 alkynyl; and each of R.sub.1 and R.sub.2 is
independently selected from among: hydrogen, halogen, substituted
or unsubstituted alkoxy, NJ.sub.1J.sub.2, SJ.sub.1, N.sub.3,
OC(.dbd.X)J.sub.1, OC(.dbd.X)NJ.sub.1J.sub.2,
NJ.sub.3C(.dbd.X)NJ.sub.1J.sub.2, and CN, wherein X is O, S or
NJ.sub.1, and each J.sub.1, J.sub.2, and J.sub.3 is, independently,
H or C.sub.1-C.sub.6 alkyl.
[0421] In certain embodiments, modified THP nucleosides are
provided wherein q.sub.1, q.sub.2, q.sub.3, q.sub.4, q.sub.5,
q.sub.6 and q.sub.7 are each H. In certain embodiments, at least
one of q.sub.1, q.sub.2, q.sub.3, q.sub.4, q.sub.5, q.sub.6 and
q.sub.7 is other than H. In certain embodiments, at least one of
q.sub.1, q.sub.2, q.sub.3, q.sub.4, q.sub.5, q.sub.6 and q.sub.7 is
methyl. In certain embodiments, modified THP nucleosides are
provided wherein one of R.sub.1 and R.sub.2 is F. In certain
embodiments, R.sub.1 is F and R.sub.2 is H, in certain embodiments,
R.sub.1 is methoxy and R.sub.2 is H, and in certain embodiments,
R.sub.1 is methoxyethoxy and R.sub.2 is H.
[0422] In certain embodiments, sugar surrogates comprise rings
having more than 5 atoms and more than one heteroatom. For example,
nucleosides comprising morpholino sugar moieties and their use in
oligonucleotides have been reported (see, e.g., Braasch et al.,
Biochemistry, 2002, 41, 4503-4510 and Summerton et al., U.S. Pat.
No. 5,698,685; Summerton et al., U.S. Pat. No. 5,166,315; Summerton
et al., U.S. Pat. No. 5,185,444; and Summerton et al., U.S. Pat.
No. 5,034,506). As used here, the term "morpholino" means a sugar
surrogate having the following structure:
##STR00058##
In certain embodiments, morpholinos may be modified, for example,
by adding or altering various substituent groups from the above
morpholino structure. Such sugar surrogates are referred to herein
as "modified morpholinos."
[0423] In certain embodiments, sugar surrogates comprise acyclic
moieties. Examples of nucleosides and oligonucleotides comprising
such acyclic sugar surrogates include, but are not limited to:
peptide nucleic acid ("PNA"), acyclic butyl nucleic acid (see,
e.g., Kumar et al., Org. Biomol. Chem., 2013, 11, 5853-5865), and
nucleosides and oligonucleotides described in Manoharan et al.,
US2013/130378.
[0424] Many other bicyclic and tricyclic sugar and sugar surrogate
ring systems are known in the art that can be used in modified
nucleosides.
[0425] In certain embodiments, modified oligonucleotides comprise a
2'-OMe modified nucleoside in the gap of a cEt gapmer. In certain
embodiments, the 2'-OMe modified nucleoside is at position 2 or 3
of the gap. In certain embodiments, the 2'-OMe modified nucleoside
is at position 2 of the gap. In certain embodiments, modified
oligonucleotides have a sugar motif kkkdmddddddddkkk, wherein each
k represents a cEt nucleoside, each d represents a
2'-.beta.-D-deoxyribosyl mucleoside, and each m represents a
nucleoside comprising a 2'-OMe sugar moiety ("2'-OMe
nucleoside").
[0426] In certain embodiments, modified oligonucleotides have a
formula A-B-C, wherein A is a 5'-region, B is a central region, and
C is a 3'-region. In certain embodiments, A and C each consist of
1-5 linked nucleosides and B consists of 7-11 linked nucleosides.
In certain embodiments, A and C consist of 3 linked cEt
nucleosides. In certain embodiments, the second nucleoside of the
central region comprises a 2'-OMe modified sugar moiety, and each
of the remaining central region nucleosides comprises a
2'-.beta.-D-deoxyribosyl sugar moiety.
[0427] In certain embodiments, modified oligonucleotides comprise a
neutral phosphonate linkage at one or more positions. In certain
embodiments, modified oligonucleotides comprise a methoxypropyl
phosphonate linkage at one or more positions. In certain
embodiments, the sugar motif of a modified oligonucleotide is a
gapmer, and the internucleoside linkage motif comprises at least
one methoxypropyl phosphonate linkage in the gap. In certain
embodiments, the methoxypropyl phosphonate linkage is between the
second and third nucleosides in the gap. In certain embodiments,
the methoxypropyl phosphonate linkage is between the third and
fourth nucleosides in the gap.
[0428] 2. Modified Nucleobases
[0429] Nucleobase (or base) modifications or substitutions are
structurally distinguishable from, yet functionally interchangeable
with, naturally occurring or synthetic unmodified nucleobases. Both
natural and modified nucleobases are capable of participating in
hydrogen bonding. Such nucleobase modifications can impart nuclease
stability, binding affinity or some other beneficial biological
property to antisense compounds.
[0430] In certain embodiments, compounds described herein comprise
modified oligonucleotides. In certain embodiments, modified
oligonucleotides comprise one or more nucleoside comprising an
unmodified nucleobase. In certain embodiments, modified
oligonucleotides comprise one or more nucleoside comprising a
modified nucleobase. In certain embodiments, modified
oligonucleotides comprise one or more nucleosides that does not
comprise a nucleobase, referred to as an abasic nucleoside.
[0431] In certain embodiments, modified nucleobases are selected
from: 5-substituted pyrimidines, 6-azapyrimidines, alkyl or alkynyl
substituted pyrimidines, alkyl substituted purines, and N-2, N-6
and 0-6 substituted purines. In certain embodiments, modified
nucleobases are selected from: 2-aminopropyladenine,
5-hydroxymethyl cytosine, 5-methylcytosine, xanthine, hypoxanthine,
2-aminoadenine, 6-N-methylguanine, 6-N-methyladenine,
2-propyladenine, 2-thiouracil, 2-thiothymine and 2-thiocytosine,
5-propynyl (C.ident.C--CH.sub.3) uracil, 5-propynylcytosine,
6-azouracil, 6-azocytosine, 6-azothymine, 5-ribosyluracil
(pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol,
8-thioalkyl, 8-hydroxyl, 8-aza and other 8-substituted purines,
5-halo, particularly, 5-bromo, 5-trifluoromethyl, 5-halouracil, and
5-halocytosine, 7-methylguanine, 7-methyladenine, 2-F-adenine,
2-aminoadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine,
3-deazaadenine, 6-N-benzoyladenine, 2-N-isobutyrylguanine,
4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl
4-N-benzoylcytosine, 5-methyl 4-N-benzoyluracil, universal bases,
hydrophobic bases, promiscuous bases, size-expanded bases, and
fluorinated bases. Further modified nucleobases include tricyclic
pyrimidines, such as 1,3-diazaphenoxazine-2-one,
1,3-diazaphenothiazine-2-one, and
9-(2-aminoethoxy)-1,3-diazaphenoxazine-2-one (G-clamp). Modified
nucleobases may also include those in which the purine or
pyrimidine base is replaced with other heterocycles, for example,
7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone.
Further nucleobases include those disclosed in Merigan et al., U.S.
Pat. No. 3,687,808, those disclosed in The Concise Encyclopedia Of
Polymer Science And Engineering, Kroschwitz, J. I., Ed., John Wiley
& Sons, 1990, 858-859; Englisch et al., Angewandte Chemie,
International Edition, 1991, 30, 613; Sanghvi, Y. S., Chapter 15,
Antisense Research and Applications, Crooke, S. T. and Lebleu, B.,
Eds., CRC Press, 1993, 273-288; and those disclosed in Chapters 6
and 15, Antisense Drug Technology, Crooke S. T., Ed., CRC Press,
2008, 163-166 and 442-443.
[0432] Publications that teach the preparation of certain of the
above noted modified nucleobases, as well as other modified
nucleobases include without limitation, Manoharan et al.,
US2003/0158403, Manoharan et al., US2003/0175906; Dinh et al., U.S.
Pat. No. 4,845,205; Spielvogel et al., U.S. Pat. No. 5,130,302;
Rogers et al., U.S. Pat. No. 5,134,066; Bischofberger et al., U.S.
Pat. No. 5,175,273; Urdea et al., U.S. Pat. No. 5,367,066; Benner
et al., U.S. Pat. No. 5,432,272; Matteucci et al., U.S. Pat. No.
5,434,257; Gmeiner et al., U.S. Pat. No. 5,457,187; Cook et al.,
U.S. Pat. No. 5,459,255; Froehler et al., U.S. Pat. No. 5,484,908;
Matteucci et al., U.S. Pat. No. 5,502,177; Hawkins et al., U.S.
Pat. No. 5,525,711; Haralambidis et al., U.S. Pat. No. 5,552,540;
Cook et al., U.S. Pat. No. 5,587,469; Froehler et al., U.S. Pat.
No. 5,594,121; Switzer et al., U.S. Pat. No. 5,596,091; Cook et
al., U.S. Pat. No. 5,614,617; Froehler et al., U.S. Pat. No.
5,645,985; Cook et al., U.S. Pat. No. 5,681,941; Cook et al., U.S.
Pat. No. 5,811,534; Cook et al., U.S. Pat. No. 5,750,692; Cook et
al., U.S. Pat. No. 5,948,903; Cook et al., U.S. Pat. No. 5,587,470;
Cook et al., U.S. Pat. No. 5,457,191; Matteucci et al., U.S. Pat.
No. 5,763,588; Froehler et al., U.S. Pat. No. 5,830,653; Cook et
al., U.S. Pat. No. 5,808,027; Cook et al., U.S. Pat. No. 6,166,199;
and Matteucci et al., U.S. Pat. No. 6,005,096.
[0433] In certain embodiments, compounds targeted to a HSD17B13
nucleic acid comprise one or more modified nucleobases. In certain
embodiments, the modified nucleobase is 5-methylcytosine. In
certain embodiments, each cytosine is a 5-methylcytosine.
[0434] Modified Internucleoside Linkages
[0435] The naturally occurring internucleoside linkage of RNA and
DNA is a 3' to 5' phosphodiester linkage. In certain embodiments,
compounds described herein having one or more modified, i.e.
non-naturally occurring, internucleoside linkages are often
selected over compounds having naturally occurring internucleoside
linkages because of desirable properties such as, for example,
enhanced cellular uptake, enhanced affinity for target nucleic
acids, and increased stability in the presence of nucleases.
[0436] Representative internucleoside linkages having a chiral
center include but are not limited to alkylphosphonates and
phosphorothioates. Modified oligonucleotides comprising
internucleoside linkages having a chiral center can be prepared as
populations of modified oligonucleotides comprising stereorandom
internucleoside linkages, or as populations of modified
oligonucleotides comprising phosphorothioate linkages in particular
stereochemical configurations. In certain embodiments, populations
of modified oligonucleotides comprise phosphorothioate
internucleoside linkages wherein all of the phosphorothioate
internucleoside linkages are stereorandom. Such modified
oligonucleotides can be generated using synthetic methods that
result in random selection of the stereochemical configuration of
each phosphorothioate linkage. Nonetheless, as is well understood
by those of skill in the art, each individual phosphorothioate of
each individual oligonucleotide molecule has a defined
stereoconfiguration. In certain embodiments, populations of
modified oligonucleotides are enriched for modified
oligonucleotides comprising one or more particular phosphorothioate
internucleoside linkages in a particular, independently selected
stereochemical configuration. In certain embodiments, the
particular configuration of the particular phosphorothioate linkage
is present in at least 65% of the molecules in the population. In
certain embodiments, the particular configuration of the particular
phosphorothioate linkage is present in at least 70% of the
molecules in the population. In certain embodiments, the particular
configuration of the particular phosphorothioate linkage is present
in at least 80% of the molecules in the population. In certain
embodiments, the particular configuration of the particular
phosphorothioate linkage is present in at least 90% of the
molecules in the population. In certain embodiments, the particular
configuration of the particular phosphorothioate linkage is present
in at least 99% of the molecules in the population. Such chirally
enriched populations of modified oligonucleotides can be generated
using synthetic methods known in the art, e.g., methods described
in Oka et al., JACS 125, 8307 (2003), Wan et al. Nuc. Acid. Res.
42, 13456 (2014), and WO 2017/015555. In certain embodiments, a
population of modified oligonucleotides is enriched for modified
oligonucleotides having at least one indicated phosphorothioate in
the (Sp) configuration. In certain embodiments, a population of
modified oligonucleotides is enriched for modified oligonucleotides
having at least one phosphorothioate in the (Rp) configuration. In
certain embodiments, modified oligonucleotides comprising (Rp)
and/or (Sp) phosphorothioates comprise one or more of the following
formulas, respectively, wherein "B" indicates a nucleobase:
##STR00059##
Unless otherwise indicated, chiral internucleoside linkages of
modified oligonucleotides described herein can be stereorandom or
in a particular stereochemical configuration.
[0437] In certain embodiments, compounds targeted to a HSD17B13
nucleic acid comprise one or more modified internucleoside
linkages. In certain embodiments, the modified internucleoside
linkages are phosphorothioate linkages. In certain embodiments,
each internucleoside linkage of an antisense compound is a
phosphorothioate internucleoside linkage.
[0438] In certain embodiments, compounds described herein comprise
oligonucleotides. Oligonucleotides having modified internucleoside
linkages include internucleoside linkages that retain a phosphorus
atom as well as internucleoside linkages that do not have a
phosphorus atom. Representative phosphorus containing
internucleoside linkages include, but are not limited to,
phosphodiesters, phosphotriesters, methylphosphonates,
phosphoramidate, and phosphorothioates. Methods of preparation of
phosphorous-containing and non-phosphorous-containing linkages are
well known.
[0439] In certain embodiments, nucleosides of modified
oligonucleotides may be linked together using any internucleoside
linkage. The two main classes of internucleoside linking groups are
defined by the presence or absence of a phosphorus atom.
Representative phosphorus-containing internucleoside linkages
include, but are not limited to, phosphates, which contain a
phosphodiester bond ("P.dbd.O") (also referred to as unmodified or
naturally occurring linkages), phosphotriesters,
methylphosphonates, phosphoramidates, and phosphorothioates
("P.dbd.S"), and phosphorodithioates ("HS--P.dbd.S").
Representative non-phosphorus containing internucleoside linking
groups include, but are not limited to, methylenemethylimino
(--CH.sub.2--N(CH.sub.3)--O--CH.sub.2), thiodiester,
thionocarbamate (--O--C(.dbd.O)(NH)--S--); siloxane
(--O--SiH.sub.2--O--); and N,N'-dimethylhydrazine
(--CH.sub.2--N(CH.sub.3)--N(CH.sub.3)--). Modified internucleoside
linkages, compared to naturally occurring phosphate linkages, can
be used to alter, typically increase, nuclease resistance of the
oligonucleotide. In certain embodiments, internucleoside linkages
having a chiral atom can be prepared as a racemic mixture, or as
separate enantiomers. Representative chiral internucleoside
linkages include, but are not limited to, alkylphosphonates and
phosphorothioates. Methods of preparation of phosphorous-containing
and non-phosphorous-containing internucleoside linkages are well
known to those skilled in the art.
[0440] Neutral internucleoside linkages include, without
limitation, phosphotriesters, methylphosphonates, MMI
(3'-CH.sub.2--N(CH.sub.3)--O-5'), amide-3
(3'-CH.sub.2--C(.dbd.O)--N(H)-5'), amide-4
(3'-CH.sub.2--N(H)--C(.dbd.O)-5'), formacetal
(3'-O--CH.sub.2--O-5'), methoxypropyl, and thioformacetal
(3'-S--CH.sub.2--O-5'). Further neutral internucleoside linkages
include nonionic linkages comprising siloxane (dialkylsiloxane),
carboxylate ester, carboxamide, sulfide, sulfonate ester and amides
(See, for example: Carbohydrate Modifications in Antisense
Research; Y. S. Sanghvi and P. D. Cook, Eds., ACS Symposium Series
580; Chapters 3 and 4, 40-65). Further neutral internucleoside
linkages include nonionic linkages comprising mixed N, O, S and
CH.sub.2 component parts.
[0441] In certain embodiments, oligonucleotides comprise modified
internucleoside linkages arranged along the oligonucleotide or
region thereof in a defined pattern or modified internucleoside
linkage motif. In certain embodiments, internucleoside linkages are
arranged in a gapped motif. In such embodiments, the
internucleoside linkages in each of two wing regions are different
from the internucleoside linkages in the gap region. In certain
embodiments, the internucleoside linkages in the wings are
phosphodiester and the internucleoside linkages in the gap are
phosphorothioate. The nucleoside motif is independently selected,
so such oligonucleotides having a gapped internucleoside linkage
motif may or may not have a gapped nucleoside motif and, if it does
have a gapped nucleoside motif, the wing and gap lengths may or may
not be the same.
[0442] In certain embodiments, oligonucleotides comprise a region
having an alternating internucleoside linkage motif. In certain
embodiments, oligonucleotides comprise a region of uniformly
modified internucleoside linkages. In certain such embodiments, the
oligonucleotide comprises a region that is uniformly linked by
phosphorothioate internucleoside linkages. In certain embodiments,
the oligonucleotide is uniformly linked by phosphorothioate. In
certain embodiments, each internucleoside linkage of the
oligonucleotide is selected from phosphodiester and
phosphorothioate. In certain embodiments, each internucleoside
linkage of the oligonucleotide is selected from phosphodiester and
phosphorothioate and at least one internucleoside linkage is
phosphorothioate.
[0443] In certain embodiments, the oligonucleotide comprises at
least 6 phosphorothioate internucleoside linkages. In certain
embodiments, the oligonucleotide comprises at least 8
phosphorothioate internucleoside linkages. In certain embodiments,
the oligonucleotide comprises at least 10 phosphorothioate
internucleoside linkages. In certain embodiments, the
oligonucleotide comprises at least one block of at least 6
consecutive phosphorothioate internucleoside linkages. In certain
embodiments, the oligonucleotide comprises at least one block of at
least 8 consecutive phosphorothioate internucleoside linkages. In
certain embodiments, the oligonucleotide comprises at least one
block of at least 10 consecutive phosphorothioate internucleoside
linkages. In certain embodiments, the oligonucleotide comprises at
least block of at least one 12 consecutive phosphorothioate
internucleoside linkages. In certain such embodiments, at least one
such block is located at the 3' end of the oligonucleotide. In
certain such embodiments, at least one such block is located within
3 nucleosides of the 3' end of the oligonucleotide.
[0444] In certain embodiments, oligonucleotides comprise one or
more methylphosphonate linkages. In certain embodiments,
oligonucleotides having a gapmer nucleoside motif comprise a
linkage motif comprising all phosphorothioate linkages except for
one or two methylphosphonate linkages. In certain embodiments, one
methylphosphonate linkage is in the central gap of an
oligonucleotide having a gapmer nucleoside motif.
[0445] In certain embodiments, it is desirable to arrange the
number of phosphorothioate internucleoside linkages and
phosphodiester internucleoside linkages to maintain nuclease
resistance. In certain embodiments, it is desirable to arrange the
number and position of phosphorothioate internucleoside linkages
and the number and position of phosphodiester internucleoside
linkages to maintain nuclease resistance. In certain embodiments,
the number of phosphorothioate internucleoside linkages may be
decreased and the number of phosphodiester internucleoside linkages
may be increased. In certain embodiments, the number of
phosphorothioate internucleoside linkages may be decreased and the
number of phosphodiester internucleoside linkages may be increased
while still maintaining nuclease resistance. In certain
embodiments, it is desirable to decrease the number of
phosphorothioate internucleoside linkages while retaining nuclease
resistance. In certain embodiments, it is desirable to increase the
number of phosphodiester internucleoside linkages while retaining
nuclease resistance.
[0446] 3. Certain Motifs
[0447] In certain embodiments, compounds described herein comprise
oligonucleotides. Oligonucleotides can have a motif, e.g. a pattern
of unmodified and/or modified sugar moieties, nucleobases, and/or
internucleoside linkages. In certain embodiments, modified
oligonucleotides comprise one or more modified nucleosides
comprising a modified sugar. In certain embodiments, modified
oligonucleotides comprise one or more modified nucleosides
comprising a modified nucleobase. In certain embodiments, modified
oligonucleotides comprise one or more modified internucleoside
linkage. In such embodiments, the modified, unmodified, and
differently modified sugar moieties, nucleobases, and/or
internucleoside linkages of a modified oligonucleotide define a
pattern or motif. In certain embodiments, the patterns of sugar
moieties, nucleobases, and internucleoside linkages are each
independent of one another. Thus, a modified oligonucleotide may be
described by its sugar motif, nucleobase motif and/or
internucleoside linkage motif (as used herein, nucleobase motif
describes the modifications to the nucleobases independent of the
sequence of nucleobases).
[0448] a. Certain Sugar Motifs
[0449] In certain embodiments, compounds described herein comprise
oligonucleotides. In certain embodiments, oligonucleotides comprise
one or more type of modified sugar and/or unmodified sugar moiety
arranged along the oligonucleotide or region thereof in a defined
pattern or sugar motif. In certain instances, such sugar motifs
include, but are not limited to, any of the sugar modifications
discussed herein.
[0450] In certain embodiments, modified oligonucleotides comprise
or consist of a region having a gapmer motif, which comprises two
external regions or "wings" and a central or internal region or
"gap". The three regions of a gapmer motif (the 5'-wing, the gap,
and the 3'-wing) form a contiguous sequence of nucleosides, wherein
at least some of the sugar moieties of the nucleosides of each of
the wings differ from at least some of the sugar moieties of the
nucleosides of the gap. Specifically, at least the sugar moieties
of the nucleosides of each wing that are closest to the gap (the
3'-most nucleoside of the 5'-wing and the 5'-most nucleoside of the
3'-wing) differ from the sugar moiety of the neighboring gap
nucleosides, thus defining the boundary between the wings and the
gap (i.e., the wing/gap junction). In certain embodiments, the
sugar moieties within the gap are the same as one another. In
certain embodiments, the gap includes one or more nucleosides
having a sugar moiety that differs from the sugar moiety of one or
more other nucleosides of the gap. In certain embodiments, the
sugar motifs of the two wings are the same as one another
(symmetric gapmer). In certain embodiments, the sugar motif of the
5'-wing differs from the sugar motif of the 3'-wing (asymmetric
gapmer).
[0451] In certain embodiments, the wings of a gapmer comprise 1-5
nucleosides. In certain embodiments, the wings of a gapmer comprise
2-5 nucleosides. In certain embodiments, the wings of a gapmer
comprise 3-5 nucleosides. In certain embodiments, the nucleosides
of a gapmer are all modified nucleosides.
[0452] In certain embodiments, the gap of a gapmer comprises 7-12
nucleosides. In certain embodiments, the gap of a gapmer comprises
7-10 nucleosides. In certain embodiments, the gap of a gapmer
comprises 8-10 nucleosides. In certain embodiments, the gap of a
gapmer comprises 10 nucleosides. In certain embodiments, each
nucleoside of the gap of a gapmer is an unmodified 2'-deoxy
nucleoside.
[0453] In certain embodiments, the gapmer is a deoxy gapmer. In
such embodiments, the nucleosides on the gap side of each wing/gap
junction are unmodified 2'-deoxy nucleosides and the nucleosides on
the wing sides of each wing/gap junction are modified nucleosides.
In certain such embodiments, each nucleoside of the gap is an
unmodified 2'-deoxy nucleoside. In certain such embodiments, each
nucleoside of each wing is a modified nucleoside.
[0454] In certain embodiments, a modified oligonucleotide has a
fully modified sugar motif wherein each nucleoside of the modified
oligonucleotide comprises a modified sugar moiety. In certain
embodiments, modified oligonucleotides comprise or consist of a
region having a fully modified sugar motif wherein each nucleoside
of the region comprises a modified sugar moiety. In certain
embodiments, modified oligonucleotides comprise or consist of a
region having a fully modified sugar motif, wherein each nucleoside
within the fully modified region comprises the same modified sugar
moiety, referred to herein as a uniformly modified sugar motif. In
certain embodiments, a fully modified oligonucleotide is a
uniformly modified oligonucleotide. In certain embodiments, each
nucleoside of a uniformly modified comprises the same
2'-modification.
[0455] b. Certain Nucleobase Motifs
[0456] In certain embodiments, compounds described herein comprise
oligonucleotides. In certain embodiments, oligonucleotides comprise
modified and/or unmodified nucleobases arranged along the
oligonucleotide or region thereof in a defined pattern or motif. In
certain embodiments, each nucleobase is modified. In certain
embodiments, none of the nucleobases are modified. In certain
embodiments, each purine or each pyrimidine is modified. In certain
embodiments, each adenine is modified. In certain embodiments, each
guanine is modified. In certain embodiments, each thymine is
modified. In certain embodiments, each uracil is modified. In
certain embodiments, each cytosine is modified. In certain
embodiments, some or all of the cytosine nucleobases in a modified
oligonucleotide are 5-methylcytosines.
[0457] In certain embodiments, modified oligonucleotides comprise a
block of modified nucleobases. In certain such embodiments, the
block is at the 3'-end of the oligonucleotide. In certain
embodiments, the block is within 3 nucleosides of the 3'-end of the
oligonucleotide. In certain embodiments, the block is at the 5'-end
of the oligonucleotide. In certain embodiments, the block is within
3 nucleosides of the 5'-end of the oligonucleotide.
[0458] In certain embodiments, oligonucleotides having a gapmer
motif comprise a nucleoside comprising a modified nucleobase. In
certain such embodiments, one nucleoside comprising a modified
nucleobase is in the central gap of an oligonucleotide having a
gapmer motif. In certain such embodiments, the sugar moiety of said
nucleoside is a 2'-deoxyribosyl moiety. In certain embodiments, the
modified nucleobase is selected from: a 2-thiopyrimidine and a
5-propynepyrimidine.
[0459] c. Certain Internucleoside Linkage Motifs
[0460] In certain embodiments, compounds described herein comprise
oligonucleotides. In certain embodiments, oligonucleotides comprise
modified and/or unmodified internucleoside linkages arranged along
the oligonucleotide or region thereof in a defined pattern or
motif. In certain embodiments, essentially each internucleoside
linking group is a phosphate internucleoside linkage (P.dbd.O). In
certain embodiments, each internucleoside linking group of a
modified oligonucleotide is a phosphorothioate (P.dbd.S). In
certain embodiments, each internucleoside linking group of a
modified oligonucleotide is independently selected from a
phosphorothioate and phosphate internucleoside linkage. In certain
embodiments, the sugar motif of a modified oligonucleotide is a
gapmer and the internucleoside linkages within the gap are all
modified. In certain such embodiments, some or all of the
internucleoside linkages in the wings are unmodified phosphate
linkages. In certain embodiments, the terminal internucleoside
linkages are modified. In certain embodiments, the sugar motif of a
modified oligonucleotide is a gapmer, and the internucleoside
linkage motif comprises at least one phosphodiester internucleoside
linkage in at least one wing, wherein the at least one
phosphodiester linkage is not a terminal internucleoside linkage,
and the remaining internucleoside linkages are phosphorothioate
internucleoside linkages. In certain such embodiments, all of the
phosphorothioate linkages are stereorandom. In certain embodiments,
all of the phosphorothioate linkages in the wings are (Sp)
phosphorothioates, and the gap comprises at least one Sp, Sp, Rp
motif. In certain embodiments, populations of modified
oligonucleotides are enriched for modified oligonucleotides
comprising such internucleoside linkage motifs.
[0461] 4. Certain Modified Oligonucleotides
[0462] In certain embodiments, compounds described herein comprise
modified oligonucleotides. In certain embodiments, the above
modifications (sugar, nucleobase, internucleoside linkage) are
incorporated into a modified oligonucleotide. In certain
embodiments, modified oligonucleotides are characterized by their
modification, motifs, and overall lengths. In certain embodiments,
such parameters are each independent of one another. Thus, unless
otherwise indicated, each internucleoside linkage of an
oligonucleotide having a gapmer sugar motif may be modified or
unmodified and may or may not follow the gapmer modification
pattern of the sugar modifications. For example, the
internucleoside linkages within the wing regions of a sugar gapmer
may be the same or different from one another and may be the same
or different from the internucleoside linkages of the gap region of
the sugar motif. Likewise, such gapmer oligonucleotides may
comprise one or more modified nucleobases independent of the gapmer
pattern of the sugar modifications. Furthermore, in certain
instances, an oligonucleotide is described by an overall length or
range and by lengths or length ranges of two or more regions (e.g.,
a regions of nucleosides having specified sugar modifications). In
such circumstances, it may be possible to select numbers for each
range that result in an oligonucleotide having an overall length
falling outside the specified range. In such circumstances, both
elements must be satisfied. For example, in certain embodiments, a
modified oligonucleotide consists of 15-20 linked nucleosides and
has a sugar motif consisting of three regions, A, B, and C, wherein
region A consists of 2-6 linked nucleosides having a specified
sugar motif, region B consists of 6-10 linked nucleosides having a
specified sugar motif, and region C consists of 2-6 linked
nucleosides having a specified sugar motif. Such embodiments do not
include modified oligonucleotides where A and C each consist of 6
linked nucleosides and B consists of 10 linked nucleosides (even
though those numbers of nucleosides are permitted within the
requirements for A, B, and C) because the overall length of such
oligonucleotide will be 22, which exceeds the upper limit of the
overall length of the modified oligonucleotide (20). Herein, if a
description of an oligonucleotide is silent with respect to one or
more parameters, such parameter is not limited. Thus, a modified
oligonucleotide described only as having a gapmer sugar motif
without further description may have any length, internucleoside
linkage motif, and nucleobase motif. Unless otherwise indicated,
all modifications are independent of nucleobase sequence.
Certain Conjugated Compounds
[0463] In certain embodiments, the compounds described herein
comprise or consist of an oligonucleotide (modified or unmodified)
and, optionally, one or more conjugate groups and/or terminal
groups. Conjugate groups consist of one or more conjugate moiety
and a conjugate linker which links the conjugate moiety to the
oligonucleotide. Conjugate groups may be attached to either or both
ends of an oligonucleotide and/or at any internal position. In
certain embodiments, conjugate groups are attached to the
2'-position of a nucleoside of a modified oligonucleotide. In
certain embodiments, conjugate groups that are attached to either
or both ends of an oligonucleotide are terminal groups. In certain
such embodiments, conjugate groups or terminal groups are attached
at the 3' and/or 5'-end of oligonucleotides. In certain such
embodiments, conjugate groups (or terminal groups) are attached at
the 3'-end of oligonucleotides. In certain embodiments, conjugate
groups are attached near the 3'-end of oligonucleotides. In certain
embodiments, conjugate groups (or terminal groups) are attached at
the 5'-end of oligonucleotides. In certain embodiments, conjugate
groups are attached near the 5'-end of oligonucleotides.
[0464] In certain embodiments, the oligonucleotide is modified. In
certain embodiments, the oligonucleotide of a compound has a
nucleobase sequence that is complementary to a target nucleic acid.
In certain embodiments, oligonucleotides are complementary to a
messenger RNA (mRNA). In certain embodiments, oligonucleotides are
complementary to a pre-mRNA. In certain embodiments,
oligonucleotides are complementary to a sense transcript.
[0465] Examples of terminal groups include but are not limited to
conjugate groups, capping groups, phosphate moieties, protecting
groups, modified or unmodified nucleosides, and two or more
nucleosides that are independently modified or unmodified.
[0466] In certain embodiments, oligonucleotides are covalently
attached to one or more conjugate groups. In certain embodiments,
conjugate groups modify one or more properties of the attached
oligonucleotide, including but not limited to pharmacodynamics,
pharmacokinetics, stability, binding, absorption, tissue
distribution, cellular distribution, cellular uptake, charge and
clearance. In certain embodiments, conjugate groups impart a new
property on the attached oligonucleotide, e.g., fluorophores or
reporter groups that enable detection of the oligonucleotide.
Certain conjugate groups and conjugate moieties have been described
previously, for example: cholesterol moiety (Letsinger et al.,
Proc. Natl. Acad. Sci. USA, 1989, 86, 6553-6556), cholic acid
(Manoharan et al., Bioorg. Med. Chem. Lett., 1994, 4, 1053-1060), a
thioether, e.g., hexyl-S-tritylthiol (Manoharan et al., Ann. N.Y.
Acad. Sci., 1992, 660, 306-309; Manoharan et al., Bioorg. Med.
Chem. Lett., 1993, 3, 2765-2770), a thiocholesterol (Oberhauser et
al., Nucl. Acids Res., 1992, 20, 533-538), an aliphatic chain,
e.g., do-decan-diol or undecyl residues (Saison-Behmoaras et al.,
EMBO J., 1991, 10, 1111-1118; Kabanov et al., FEBS Lett., 1990,
259, 327-330; Svinarchuk et al., Biochimie, 1993, 75, 49-54), a
phospholipid, e.g., di-hexadecyl-rac-glycerol or triethyl-ammonium
1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate (Manoharan et al.,
Tetrahedron Lett., 1995, 36, 3651-3654; Shea et al., Nucl. Acids
Res., 1990, 18, 3777-3783), a polyamine or a polyethylene glycol
chain (Manoharan et al., Nucleosides & Nucleotides, 1995, 14,
969-973), or adamantane acetic acid a palmityl moiety (Mishra et
al., Biochim. Biophys. Acta, 1995, 1264, 229-237), an
octadecylamine or hexylamino-carbonyl-oxycholesterol moiety (Crooke
et al., J. Pharmacol. Exp. Ther., 1996, 277, 923-937), a tocopherol
group (Nishina et al., Molecular Therapy Nucleic Acids, 2015, 4,
e220; and Nishina et al., Molecular Therapy, 2008, 16, 734-740), or
a GalNAc cluster (e.g., WO2014/179620).
[0467] 1. Conjugate Moieties
[0468] Conjugate moieties include, without limitation,
intercalators, reporter molecules, polyamines, polyamides,
peptides, carbohydrates (e.g., GalNAc), vitamin moieties,
polyethylene glycols, thioethers, polyethers, cholesterols,
thiocholesterols, cholic acid moieties, folate, lipids,
phospholipids, biotin, phenazine, phenanthridine, anthraquinone,
adamantane, acridine, fluoresceins, rhodamines, coumarins,
fluorophores, and dyes.
[0469] In certain embodiments, a conjugate moiety comprises an
active drug substance, for example, aspirin, warfarin,
phenylbutazone, ibuprofen, suprofen, fen-bufen, ketoprofen,
(S)-(+)-pranoprofen, carprofen, dansylsarcosine,
2,3,5-triiodobenzoic acid, fingolimod, flufenamic acid, folinic
acid, a benzothiadiazide, chlorothiazide, a diazepine,
indo-methicin, a barbiturate, a cephalosporin, a sulfa drug, an
antidiabetic, an antibacterial or an antibiotic.
[0470] 2. Conjugate Linkers
[0471] Conjugate moieties are attached to oligonucleotides through
conjugate linkers. In certain compounds, the conjugate linker is a
single chemical bond (i.e., the conjugate moiety is attached
directly to an oligonucleotide through a single bond). In certain
compounds, a conjugate moiety is attached to an oligonucleotide via
a more complex conjugate linker comprising one or more conjugate
linker moieities, which are sub-units making up a conjugate linker.
In certain embodiments, the conjugate linker comprises a chain
structure, such as a hydrocarbyl chain, or an oligomer of repeating
units such as ethylene glycol, nucleosides, or amino acid
units.
[0472] In certain embodiments, a conjugate linker comprises one or
more groups selected from alkyl, amino, oxo, amide, disulfide,
polyethylene glycol, ether, thioether, and hydroxylamino. In
certain such embodiments, the conjugate linker comprises groups
selected from alkyl, amino, oxo, amide and ether groups. In certain
embodiments, the conjugate linker comprises groups selected from
alkyl and amide groups. In certain embodiments, the conjugate
linker comprises groups selected from alkyl and ether groups. In
certain embodiments, the conjugate linker comprises at least one
phosphorus moiety. In certain embodiments, the conjugate linker
comprises at least one phosphate group. In certain embodiments, the
conjugate linker includes at least one neutral linking group.
[0473] In certain embodiments, conjugate linkers, including the
conjugate linkers described above, are bifunctional linking
moieties, e.g., those known in the art to be useful for attaching
conjugate groups to parent compounds, such as the oligonucleotides
provided herein. In general, a bifunctional linking moiety
comprises at least two functional groups. One of the functional
groups is selected to bind to a particular site on a parent
compound and the other is selected to bind to a conjugate group.
Examples of functional groups used in a bifunctional linking moiety
include but are not limited to electrophiles for reacting with
nucleophilic groups and nucleophiles for reacting with
electrophilic groups. In certain embodiments, bifunctional linking
moieties comprise one or more groups selected from amino, hydroxyl,
carboxylic acid, thiol, alkyl, alkenyl, and alkynyl.
[0474] Examples of conjugate linkers include but are not limited to
pyrrolidine, 8-amino-3,6-dioxaoctanoic acid (ADO), succinimidyl
4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) and
6-aminohexanoic acid (AHEX or AHA). Other conjugate linkers include
but are not limited to substituted or unsubstituted
C.sub.1-C.sub.10 alkyl, substituted or unsubstituted
C.sub.2-C.sub.10 alkenyl or substituted or unsubstituted
C.sub.2-C.sub.10 alkynyl, wherein a nonlimiting list of preferred
substituent groups includes hydroxyl, amino, alkoxy, carboxy,
benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl,
alkenyl and alkynyl.
[0475] In certain embodiments, conjugate linkers comprise 1-10
linker-nucleosides. In certain embodiments, such linker-nucleosides
are modified nucleosides. In certain embodiments such
linker-nucleosides comprise a modified sugar moiety. In certain
embodiments, linker-nucleosides are unmodified. In certain
embodiments, linker-nucleosides comprise an optionally protected
heterocyclic base selected from a purine, substituted purine,
pyrimidine or substituted pyrimidine. In certain embodiments, a
cleavable moiety is a nucleoside selected from uracil, thymine,
cytosine, 4-N-benzoylcytosine, 5-methylcytosine,
4-N-benzoyl-5-methylcytosine, adenine, 6-N-benzoyladenine, guanine
and 2-N-isobutyrylguanine. It is typically desirable for
linker-nucleosides to be cleaved from the compound after it reaches
a target tissue. Accordingly, linker-nucleosides are typically
linked to one another and to the remainder of the compound through
cleavable bonds. In certain embodiments, such cleavable bonds are
phosphodiester bonds.
[0476] Herein, linker-nucleosides are not considered to be part of
the oligonucleotide. Accordingly, in embodiments in which an
compound comprises an oligonucleotide consisting of a specified
number or range of linked nucleosides and/or a specified percent
complementarity to a reference nucleic acid and the compound also
comprises a conjugate group comprising a conjugate linker
comprising linker-nucleosides, those linker-nucleosides are not
counted toward the length of the oligonucleotide and are not used
in determining the percent complementarity of the oligonucleotide
for the reference nucleic acid. For example, a compound may
comprise (1) a modified oligonucleotide consisting of 8-30
nucleosides and (2) a conjugate group comprising 1-10
linker-nucleosides that are contiguous with the nucleosides of the
modified oligonucleotide. The total number of contiguous linked
nucleosides in such a compound is more than 30. Alternatively, a
compound may comprise a modified oligonucleotide consisting of 8-30
nucleosides and no conjugate group. The total number of contiguous
linked nucleosides in such a compound is no more than 30. Unless
otherwise indicated conjugate linkers comprise no more than 10
linker-nucleosides. In certain embodiments, conjugate linkers
comprise no more than 5 linker-nucleosides. In certain embodiments,
conjugate linkers comprise no more than 3 linker-nucleosides. In
certain embodiments, conjugate linkers comprise no more than 2
linker-nucleosides. In certain embodiments, conjugate linkers
comprise no more than 1 linker-nucleoside.
[0477] In certain embodiments, it is desirable for a conjugate
group to be cleaved from the oligonucleotide. For example, in
certain circumstances compounds comprising a particular conjugate
moiety are better taken up by a particular cell type, but once the
compound has been taken up, it is desirable that the conjugate
group be cleaved to release the unconjugated or parent
oligonucleotide. Thus, certain conjugate linkers may comprise one
or more cleavable moieties. In certain embodiments, a cleavable
moiety is a cleavable bond. In certain embodiments, a cleavable
moiety is a group of atoms comprising at least one cleavable bond.
In certain embodiments, a cleavable moiety comprises a group of
atoms having one, two, three, four, or more than four cleavable
bonds. In certain embodiments, a cleavable moiety is selectively
cleaved inside a cell or subcellular compartment, such as a
lysosome. In certain embodiments, a cleavable moiety is selectively
cleaved by endogenous enzymes, such as nucleases.
[0478] In certain embodiments, a cleavable bond is selected from
among: an amide, an ester, an ether, one or both esters of a
phosphodiester, a phosphate ester, a carbamate, or a disulfide. In
certain embodiments, a cleavable bond is one or both of the esters
of a phosphodiester. In certain embodiments, a cleavable moiety
comprises a phosphate or phosphodiester. In certain embodiments,
the cleavable moiety is a phosphate linkage between an
oligonucleotide and a conjugate moiety or conjugate group.
[0479] In certain embodiments, a cleavable moiety comprises or
consists of one or more linker-nucleosides. In certain such
embodiments, the one or more linker-nucleosides are linked to one
another and/or to the remainder of the compound through cleavable
bonds. In certain embodiments, such cleavable bonds are unmodified
phosphodiester bonds. In certain embodiments, a cleavable moiety is
2'-deoxy nucleoside that is attached to either the 3' or
5'-terminal nucleoside of an oligonucleotide by a phosphate
internucleoside linkage and covalently attached to the remainder of
the conjugate linker or conjugate moiety by a phosphate or
phosphorothioate linkage. In certain such embodiments, the
cleavable moiety is 2'-deoxyadenosine.
[0480] 3. Certain Cell-Targeting Conjugate Moietiess
[0481] In certain embodiments, a conjugate group comprises a
cell-targeting conjugate moiety. In certain embodiments, a
conjugate group has the general formula:
##STR00060##
[0482] wherein n is from 1 to about 3, m is 0 when n is 1, m is 1
when n is 2 or greater, j is 1 or 0, and k is 1 or 0.
[0483] In certain embodiments, n is 1, j is 1 and k is 0. In
certain embodiments, n is 1, j is 0 and k is 1. In certain
embodiments, n is 1, j is 1 and k is 1. In certain embodiments, n
is 2, j is 1 and k is 0. In certain embodiments, n is 2, j is 0 and
k is 1. In certain embodiments, n is 2, j is 1 and k is 1. In
certain embodiments, n is 3, j is 1 and k is 0. In certain
embodiments, n is 3, j is 0 and k is 1. In certain embodiments, n
is 3, j is 1 and k is 1.
[0484] In certain embodiments, conjugate groups comprise
cell-targeting moieties that have at least one tethered ligand. In
certain embodiments, cell-targeting moieties comprise two tethered
ligands covalently attached to a branching group. In certain
embodiments, cell-targeting moieties comprise three tethered
ligands covalently attached to a branching group.
[0485] In certain embodiments, the cell-targeting moiety comprises
a branching group comprising one or more groups selected from
alkyl, amino, oxo, amide, disulfide, polyethylene glycol, ether,
thioether and hydroxylamino groups. In certain embodiments, the
branching group comprises a branched aliphatic group comprising
groups selected from alkyl, amino, oxo, amide, disulfide,
polyethylene glycol, ether, thioether and hydroxylamino groups. In
certain such embodiments, the branched aliphatic group comprises
groups selected from alkyl, amino, oxo, amide and ether groups. In
certain such embodiments, the branched aliphatic group comprises
groups selected from alkyl, amino and ether groups. In certain such
embodiments, the branched aliphatic group comprises groups selected
from alkyl and ether groups. In certain embodiments, the branching
group comprises a mono or polycyclic ring system.
[0486] In certain embodiments, each tether of a cell-targeting
moiety comprises one or more groups selected from alkyl,
substituted alkyl, ether, thioether, disulfide, amino, oxo, amide,
phosphodiester, and polyethylene glycol, in any combination. In
certain embodiments, each tether is a linear aliphatic group
comprising one or more groups selected from alkyl, ether,
thioether, disulfide, amino, oxo, amide, and polyethylene glycol,
in any combination. In certain embodiments, each tether is a linear
aliphatic group comprising one or more groups selected from alkyl,
phosphodiester, ether, amino, oxo, and amide, in any combination.
In certain embodiments, each tether is a linear aliphatic group
comprising one or more groups selected from alkyl, ether, amino,
oxo, and amid, in any combination. In certain embodiments, each
tether is a linear aliphatic group comprising one or more groups
selected from alkyl, amino, and oxo, in any combination. In certain
embodiments, each tether is a linear aliphatic group comprising one
or more groups selected from alkyl and oxo, in any combination. In
certain embodiments, each tether is a linear aliphatic group
comprising one or more groups selected from alkyl and
phosphodiester, in any combination. In certain embodiments, each
tether comprises at least one phosphorus linking group or neutral
linking group. In certain embodiments, each tether comprises a
chain from about 6 to about 20 atoms in length. In certain
embodiments, each tether comprises a chain from about 10 to about
18 atoms in length. In certain embodiments, each tether comprises
about 10 atoms in chain length.
[0487] In certain embodiments, each ligand of a cell-targeting
moiety has an affinity for at least one type of receptor on a
target cell. In certain embodiments, each ligand has an affinity
for at least one type of receptor on the surface of a mammalian
liver cell. In certain embodiments, each ligand has an affinity for
the hepatic asialoglycoprotein receptor (ASGP-R). In certain
embodiments, each ligand is a carbohydrate. In certain embodiments,
each ligand is, independently selected from galactose, N-acetyl
galactoseamine (GalNAc), mannose, glucose, glucoseamine and fucose.
In certain embodiments, each ligand is N-acetyl galactoseamine
(GalNAc). In certain embodiments, the cell-targeting moiety
comprises 3 GalNAc ligands. In certain embodiments, the
cell-targeting moiety comprises 2 GalNAc ligands. In certain
embodiments, the cell-targeting moiety comprises 1 GalNAc
ligand.
[0488] In certain embodiments, each ligand of a cell-targeting
moiety is a carbohydrate, carbohydrate derivative, modified
carbohydrate, polysaccharide, modified polysaccharide, or
polysaccharide derivative. In certain such embodiments, the
conjugate group comprises a carbohydrate cluster (see, e.g., Maier
et al., "Synthesis of Antisense Oligonucleotides Conjugated to a
Multivalent Carbohydrate Cluster for Cellular Targeting,"
Bioconjugate Chemistry, 2003, 14, 18-29 or Rensen et al., "Design
and Synthesis of Novel N-Acetylgalactosamine-Terminated Glycolipids
for Targeting of Lipoproteins to the Hepatic Asiaglycoprotein
Receptor," J. Med. Chem. 2004, 47, 5798-5808). In certain such
embodiments, each ligand is an amino sugar or a thio sugar. For
example, amino sugars may be selected from any number of compounds
known in the art, such as sialic acid, .alpha.-D-galactosamine,
.beta.-muramic acid, 2-deoxy-2-methylamino-L-glucopyranose,
4,6-dideoxy-4-formamido-2,3-di-O-methyl-D-mannopyranose,
2-deoxy-2-sulfoamino-D-glucopyranose and N-sulfo-D-glucosamine, and
N-glycoloyl-.alpha.-neuraminic acid. For example, thio sugars may
be selected from 5-Thio-.beta.-D-glucopyranose, methyl
2,3,4-tri-O-acetyl-1-thio-6-O-trityl-.alpha.-D-glucopyranoside,
galactopyranose, and ethyl
3,4,6,7-tetra-O-acetyl-2-deoxy-1,5-dithio-.alpha.-D-gLuco-heptopyranoside-
.
[0489] In certain embodiments, conjugate groups comprise a
cell-targeting moiety having the formula:
##STR00061##
[0490] In certain embodiments, conjugate groups comprise a
cell-targeting moiety having the formula:
##STR00062##
[0491] In certain embodiments, conjugate groups comprise a
cell-targeting moiety having the formula:
##STR00063##
[0492] In certain embodiments, conjugate groups comprise a
cell-targeting moiety having the formula:
##STR00064##
[0493] In certain embodiments, conjugate groups comprise a
cell-targeting moiety having the formula:
##STR00065##
[0494] In certain embodiments, compounds comprise a conjugate group
described herein as "LICA-1". LICA-1 has the formula:
##STR00066##
[0495] In certain embodiments, compounds described herein comprise
LICA-1 and a cleavable moiety within the conjugate linker have the
formula:
##STR00067##
[0496] wherein oligo is an oligonucleotide.
[0497] Representative United States patents, United States patent
application publications, international patent application
publications, and other publications that teach the preparation of
certain of the above noted conjugate groups, compounds comprising
conjugate groups, tethers, conjugate linkers, branching groups,
ligands, cleavable moieties as well as other modifications include
without limitation, U.S. Pat. Nos. 5,994,517, 6,300,319, 6,660,720,
6,906,182, 7,262,177, 7,491,805, 8,106,022, 7,723,509, US
2006/0148740, US 2011/0123520, WO 2013/033230 and WO 2012/037254,
Biessen et al., J. Med. Chem. 1995, 38, 1846-1852, Lee et al.,
Bioorganic & Medicinal Chemistry 2011, 19, 2494-2500, Rensen et
al., J. Biol. Chem. 2001, 276, 37577-37584, Rensen et al., J. Med.
Chem. 2004, 47, 5798-5808, Sliedregt et al., J. Med. Chem. 1999,
42, 609-618, and Valentijn et al., Tetrahedron, 1997, 53,
759-770.
[0498] In certain embodiments, modified oligonucleotides comprise a
gapmer or fully modified sugar motif and a conjugate group
comprising at least one, two, or three GalNAc ligands. In certain
embodiments, compounds comprise a conjugate group found in any of
the following references: Lee, Carbohydr Res, 1978, 67, 509-514;
Connolly et al., J Biol Chem, 1982, 257, 939-945; Pavia et al., Int
J Pep Protein Res, 1983, 22, 539-548; Lee et al., Biochem, 1984,
23, 4255-4261; Lee et al., Glycoconjugate J, 1987, 4, 317-328;
Toyokuni et al., Tetrahedron Lett, 1990, 31, 2673-2676; Biessen et
al., J Med Chem, 1995, 38, 1538-1546; Valentijn et al.,
Tetrahedron, 1997, 53, 759-770; Kim et al., Tetrahedron Lett, 1997,
38, 3487-3490; Lee et al., Bioconjug Chem, 1997, 8, 762-765; Kato
et al., Glycobiol, 2001, 11, 821-829; Rensen et al., J Biol Chem,
2001, 276, 37577-37584; Lee et al., Methods Enzymol, 2003, 362,
38-43; Westerlind et al., Glycoconj J, 2004, 21, 227-241; Lee et
al., Bioorg Med Chem Lett, 2006, 16(19), 5132-5135; Maierhofer et
al., Bioorg Med Chem, 2007, 15, 7661-7676; Khorev et al., Bioorg
Med Chem, 2008, 16, 5216-5231; Lee et al., Bioorg Med Chem, 2011,
19, 2494-2500; Kornilova et al., Analyt Biochem, 2012, 425, 43-46;
Pujol et al., Angew Chemie Int Ed Engl, 2012, 51, 7445-7448;
Biessen et al., J Med Chem, 1995, 38, 1846-1852; Sliedregt et al.,
J Med Chem, 1999, 42, 609-618; Rensen et al., J Med Chem, 2004, 47,
5798-5808; Rensen et al., Arterioscler Thromb Vasc Biol, 2006, 26,
169-175; van Rossenberg et al., Gene Ther, 2004, 11, 457-464; Sato
et al., J Am Chem Soc, 2004, 126, 14013-14022; Lee et al., J Org
Chem, 2012, 77, 7564-7571; Biessen et al., FASEB J, 2000, 14,
1784-1792; Rajur et al., Bioconjug Chem, 1997, 8, 935-940; Duff et
al., Methods Enzymol, 2000, 313, 297-321; Maier et al., Bioconjug
Chem, 2003, 14, 18-29; Jayaprakash et al., Org Lett, 2010, 12,
5410-5413; Manoharan, Antisense Nucleic Acid Drug Dev, 2002, 12,
103-128; Merwin et al., Bioconjug Chem, 1994, 5, 612-620; Tomiya et
al., Bioorg Med Chem, 2013, 21, 5275-5281; International
applications WO1998/013381; WO2011/038356; WO1997/046098;
WO2008/098788; WO2004/101619; WO2012/037254; WO2011/120053;
WO2011/100131; WO2011/163121; WO2012/177947; WO2013/033230;
WO2013/075035; WO2012/083185; WO2012/083046; WO2009/082607;
WO2009/134487; WO2010/144740; WO2010/148013; WO1997/020563;
WO2010/088537; WO2002/043771; WO2010/129709; WO2012/068187;
WO2009/126933; WO2004/024757; WO2010/054406; WO2012/089352;
WO2012/089602; WO2013/166121; WO2013/165816; U.S. Pat. Nos.
4,751,219; 8,552,163; 6,908,903; 7,262,177; 5,994,517; 6,300,319;
8,106,022; 7,491,805; 7,491,805; 7,582,744; 8,137,695; 6,383,812;
6,525,031; 6,660,720; 7,723,509; 8,541,548; 8,344,125; 8,313,772;
8,349,308; 8,450,467; 8,501,930; 8,158,601; 7,262,177; 6,906,182;
6,620,916; 8,435,491; 8,404,862; 7,851,615; Published U.S. Patent
Application Publications US2011/0097264; US2011/0097265;
US2013/0004427; US2005/0164235; US2006/0148740; US2008/0281044;
U52010/0240730; U52003/0119724; US2006/0183886; US2008/0206869;
U52011/0269814; US2009/0286973; US2011/0207799; US2012/0136042;
US2012/0165393; US2008/0281041; US2009/0203135; US2012/0035115;
US2012/0095075; US2012/0101148; US2012/0128760; US2012/0157509;
US2012/0230938; US2013/0109817; US2013/0121954; US2013/0178512;
US2013/0236968; US2011/0123520; US2003/0077829; US2008/0108801; and
US2009/0203132.
[0499] In certain embodiments, compounds are single-stranded. In
certain embodiments, compounds are double-stranded.
Compositions and Methods for Formulating Pharmaceutical
Compositions
[0500] Compounds described herein may be admixed with
pharmaceutically acceptable active or inert substances for the
preparation of pharmaceutical compositions or formulations.
Compositions and methods for the formulation of pharmaceutical
compositions are dependent upon a number of criteria, including,
but not limited to, route of administration, extent of disease, or
dose to be administered.
[0501] Certain embodiments provide pharmaceutical compositions
comprising one or more compounds or a salt thereof. In certain
embodiments, the compounds are antisense compounds or oligomeric
compounds. In certain embodiments, the compounds comprise or
consist of a modified oligonucleotide. In certain such embodiments,
the pharmaceutical composition comprises a suitable
pharmaceutically acceptable diluent or carrier. In certain
embodiments, a pharmaceutical composition comprises a sterile
saline solution and one or more compound. In certain embodiments,
such pharmaceutical composition consists of a sterile saline
solution and one or more compound. In certain embodiments, the
sterile saline is pharmaceutical grade saline. In certain
embodiments, a pharmaceutical composition comprises one or more
compound and sterile water. In certain embodiments, a
pharmaceutical composition consists of one compound and sterile
water. In certain embodiments, the sterile water is pharmaceutical
grade water. In certain embodiments, a pharmaceutical composition
comprises one or more compounds and phosphate-buffered saline
(PBS). In certain embodiments, a pharmaceutical composition
consists of one or more compound and sterile PBS. In certain
embodiments, the sterile PBS is pharmaceutical grade PBS.
Compositions and methods for the formulation of pharmaceutical
compositions are dependent upon a number of criteria, including,
but not limited to, route of administration, extent of disease, or
dose to be administered.
[0502] A compound described herein targeted to HSD17B13 nucleic
acid can be utilized in pharmaceutical compositions by combining
the compound with a suitable pharmaceutically acceptable diluent or
carrier. In certain embodiments, a pharmaceutically acceptable
diluent is water, such as sterile water suitable for injection.
Accordingly, in one embodiment, employed in the methods described
herein is a pharmaceutical composition comprising a compound
targeted to HSD17B13 nucleic acid and a pharmaceutically acceptable
diluent. In certain embodiments, the pharmaceutically acceptable
diluent is water. In certain embodiments, the compound comprises or
consists of a modified oligonucleotide provided herein.
[0503] Pharmaceutical compositions comprising compounds provided
herein encompass any pharmaceutically acceptable salts, esters, or
salts of such esters, or any other oligonucleotide which, upon
administration to an animal, including a human, is capable of
providing (directly or indirectly) the biologically active
metabolite or residue thereof. In certain embodiments, the
compounds are antisense compounds or oligomeric compounds. In
certain embodiments, the compound comprises or consists of a
modified oligonucleotide. Accordingly, for example, the disclosure
is also drawn to pharmaceutically acceptable salts of compounds,
prodrugs, pharmaceutically acceptable salts of such prodrugs, and
other bioequivalents. Suitable pharmaceutically acceptable salts
include, but are not limited to, sodium and potassium salts.
[0504] A prodrug can include the incorporation of additional
nucleosides at one or both ends of a compound which are cleaved by
endogenous nucleases within the body, to form the active
compound.
[0505] In certain embodiments, the compounds or compositions
further comprise a pharmaceutically acceptable carrier or
diluent.
Examples
[0506] The Examples below describe the screening process to
identify compounds targeted to HSD17B13.
Non-Limiting Disclosure and Incorporation by Reference
[0507] Although the sequence listing accompanying this filing
identifies each sequence as either "RNA" or "DNA" as required, in
reality, those sequences may be modified with any combination of
chemical modifications. One of skill in the art will readily
appreciate that such designation as "RNA" or "DNA" to describe
modified oligonucleotides is, in certain instances, arbitrary. For
example, an oligonucleotide comprising a nucleoside comprising a
2'-OH sugar moiety and a thymine base could be described as a DNA
having a modified sugar (2'-OH for the natural 2'-H of DNA) or as
an RNA having a modified base (thymine (methylated uracil) for
natural uracil of RNA).
[0508] Accordingly, nucleic acid sequences provided herein,
including, but not limited to, those in the sequence listing, are
intended to encompass nucleic acids containing any combination of
natural or modified RNA and/or DNA, including, but not limited to,
such nucleic acids having modified nucleobases. By way of further
example and without limitation, an oligonucleotide having the
nucleobase sequence "ATCGATCG" encompasses any oligonucleotides
having such nucleobase sequence, whether modified or unmodified,
including, but not limited to, such compounds comprising RNA bases,
such as those having sequence "AUCGAUCG" and those having some DNA
bases and some RNA bases such as "AUCGATCG" and compounds having
other modified nucleobases, such as "ATmCGAUCG," wherein mC
indicates a cytosine base comprising a methyl group at the
5-position.
[0509] Certain compounds described herein (e.g. modified
oligonucleotides) have one or more asymmetric centers and thus give
rise to enantiomers, diastereomers, and other stereoisomeric
configurations that may be defined, in terms of absolute
stereochemistry, as (R) or (S), as .alpha. or .beta., such as for
sugar anomers, or as (D) or (L), such as for amino acids, etc.
Compounds provided herein that are drawn or described as having
certain stereoisomeric configurations include only the indicated
compounds. Compounds provided herein that are drawn or described
with undefined stereochemistry include all such possible isomers,
including their stereorandom and optically pure forms. Likewise,
all tautomeric forms of the compounds provided herein are included
unless otherwise indicated. Unless otherwise indicated, oligomeric
compounds and modified oligonucleotides described herein are
intended to include corresponding salt forms.
[0510] Compounds described herein include variations in which one
or more atoms are replaced with a non-radioactive isotope or
radioactive isotope of the indicated element. For example,
compounds herein that comprise hydrogen atoms encompass all
possible deuterium substitutions for each of the .sup.1H hydrogen
atoms. Isotopic substitutions encompassed by the compounds herein
include, but are not limited to: .sup.2H or .sup.3H in place of
.sup.1H, .sup.13C or .sup.14C in place of .sup.12C, .sup.15N in
place of .sup.14N, .sup.17O or .sup.18O in place of .sup.16O, and
.sup.33S, .sup.34S, .sup.35S, or .sup.36S in place of .sup.32S.
[0511] While certain compounds, compositions and methods described
herein have been described with specificity in accordance with
certain embodiments, the following examples serve only to
illustrate the compounds described herein and are not intended to
limit the same. Each of the references recited in the present
application is incorporated herein by reference in its
entirety.
Example 1: Antisense Inhibition of Human HSD17B13 in HepaRG Cells
by cEt Gapmers
[0512] Modified oligonucleotides complementary to an HSD17B13
nucleic acid were synthesized and tested for their effect on
HSD17B13 RNA levels in vitro. The modified oligonucleotides were
tested in a series of experiments using the same culture
conditions. The results for each separate experiment are presented
in tables below.
[0513] The modified oligonucleotides were all 3-10-3 cEt gapmers
(i.e. had a central gap segment of ten 2'-deoxynucleosides flanked
on each side by wing segments each comprising three cEt modified
nucleosides). The internucleoside linkages throughout each modified
oligonucleotide were phosphorothioate (P.dbd.S) linkages. All
cytosine nucleobases throughout each modified oligonucleotide were
5-methylcytosines.
[0514] "Start site" indicates the 5'-most nucleoside of the target
sequence to which the modified oligonucleotide is complementary.
"Stop site" indicates the 3'-most nucleoside of the target sequence
to which the modified oligonucleotide is complementary. As shown in
the Tables below, the modified oligonucleotide are complementary to
either the human HSD17B13 mRNA, designated herein as SEQ ID NO: 1
(GENBANK Accession No. NM_178135.4) or to the human HSD17B13
genomic sequence, designated herein as SEQ ID NO: 2 (the complement
of GENBANK Accession No. NC_000004.12 truncated from nucleotides
87301001 to 87326000) or to both. `N/A` indicates that the modified
oligonucleotide is not complementary to that particular target
sequence with 100% complementarity.
[0515] Cultured HepaRG cells at a density of 20,000 cells per well
were transfected using electroporation with 1,000 nM of modified
oligonucleotide. After a treatment period of approximately 24
hours, RNA was isolated from the cells and HSD17B13 RNA levels were
measured by quantitative real-time RTPCR. Human primer probe set
RTS43553 (forward sequence AGACTACAGAAGTTTCTTCCTGAAC, designated
herein as SEQ ID NO: 5; reverse sequence CATCTCTGGCTGGAGCTTATTT,
designated herein as SEQ ID NO: 6; probe sequence
TTTGAAGCAGTGGTTGGCCACAAA, designated herein as SEQ ID NO: 7) was
used to measure RNA levels. HSD17B13 RNA levels were normalized to
total RNA content, as measured by RIBOGREEN.RTM.. Results are
presented as percent inhibition of HSD17B13 relative to untreated
control cells. As used herein, a value of `0` indicates that
treatment with the modified oligonucleotide did not inhibit
HSD17B13 mRNA levels. An asterisk (*) indicates that the modified
oligonucleotide is complementary to the target transcript within
the amplicon region of the primer probe set and so, the associated
data is not reliable. In such instances, additional using alternate
primer probe sets must be performed to accurately assess the
potency and efficacy of such modified oligonucleotides.
TABLE-US-00001 TABLE 1 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO: 1 and 2 SEQ SEQ ID SEQ ID SEQ NO: 1 ID
NO: NO: 2 ID NO: HSD17B13 SEQ Compound Start 1 Stop Start 2 Stop
Sequence (% ID Number Site Site Site Site (5' to 3') Inhibition) NO
1245068 1 16 3095 3110 GGAGGAGGTACTGTCT 44 8 1245094 59 74 3153
3168 GATGTTCATGGCTTTG 81 9 1245120 111 126 3205 3220
ACTCCAAGTAGGAGTA 0 10 1245146 181 196 3275 3290 GCTCCAGTAATGAGAA 34
11 1245172 251 266 3345 3360 ATCCCACAGAACCAAT 34 12 1245198 299 314
7588 7603 TAGTTTTCGGCACTCA 35 13 1245224 359 374 7648 7663
AGAGCGATAGATCTCT 8 14 1245250 402 417 8796 8811 CCACGATTGTTACATC 42
15 1245276 432 447 8826 8841 CGGCTGGATATACTGT 35 16 1245302 473 488
8867 8882 AAATGTCTTGGTAATC 30 17 1245328 515 530 10401 10416
AAGTGCTTTTGTGATC 41 18 1245354 561 576 10447 10462 CCACTGTGACGATGTG
0 19 1245380 614 629 N/A N/A GCTGGAACAATATGGG 36 20 1245406 670 685
12088 12103 CCCAAGGCCTGAAGTT 61 21 1245432 759 774 15640 15655
ATACAGGCCATAATCT 0 22 1245458 790 805 15671 15686 ATCAGACTTCTTACGA
45 23 1245484 842 857 15723 15738 ATTGATATACGATGGA 31 24 1245510*
907 922 20722 20737 TTCTGCATACGATTTA 83 25 1245536* 973 988 20788
20803 TCTGGCTGGAGCTTAT 85 26 1245562 1014 1029 20829 20844
CATTGATTCGAAACTA 40 27 1245588 1088 1103 20903 20918
TTGACTGCTGCTAGTG 30 28 1245614 1260 1275 21075 21090
GGTAGCTTTTGTCCAC 66 29 1245640 1314 1329 21129 21144
CAGTCTTAAACCTTCC 70 30 1245666 1341 1356 21156 21171
TGGCTACAGATTGGAA 55 31 1245692 1385 1400 21200 21215
TTAGCTGTGCACTCAT 61 32 1245718 1423 1438 21238 21253
CCAGGTTGAGATAAAG 49 33 1245744 1499 1514 21314 21329
AGAGTTGCACCGTTTT 76 34 1245770 1558 1573 21373 21388
CACTTTTGGTGGACTT 21 35 1245796 1617 1632 21432 21447
CGGTCACCTTTCATAA 69 36 1245822 1710 1725 21525 21540
ATCTCTGGGACCAAGG 72 37 1245841 1765 1780 21580 21595
GTACAGTTCCTTTTCC 55 38 1245848 1772 1787 21587 21602
ATAGCCAGTACAGTTC 65 39 1245874 2177 2192 21992 22007
GGAGTCGGATTATTTT 41 40 1245900 2244 2259 22059 22074
GTCCATGCAAAAGCAT 62 41 1245926 N/A N/A 3405 3420 AATACATATCTTACTC
37 42 1245952 N/A N/A 3552 3567 GTCATAAAAATCGCTG 72 43 1245978 N/A
N/A 3948 3963 GAAAAGCCTGACTCAC 48 44 1246004 N/A N/A 4517 4532
CATCAAGCCCTTTTCA 23 45 1246030 N/A N/A 5078 5093 CTAAAGGAGATCTGAG
47 46 1246056 N/A N/A 5222 5237 TAGCTTAAACTCCAAT 60 47 1246065 N/A
N/A 5659 5674 ATAAGTTACCAGAGCA 87 48 1246082 N/A N/A 5817 5832
CTCAAAGTCAGTATCC 70 49 1246108 N/A N/A 5989 6004 GGCAAGGATACCTGAA
67 50 1246134 N/A N/A 6233 6248 CTCATTTATGTACCAA 87 51 1246160 N/A
N/A 6474 6489 TATGTAATAGGCAGTA 62 52 1246186 N/A N/A 7482 7497
GACAATTAACATTCGG 69 53 1246212 N/A N/A 7951 7966 CTAGGAAGTGATCCAT
66 54 1246238 N/A N/A 8243 8258 CTAATAACTACATGAC 18 55 1246264 N/A
N/A 8694 8709 TCCAAAGATGAGAGTC 17 56 1246290 N/A N/A 9002 9017
GCAAAGATCTGGCCAG 22 57 1246316 N/A N/A 9348 9363 TCCAAAAGTGTCCTCG
31 58 1246342 N/A N/A 9518 9533 CTACACTAATATTGAG 20 59 1246368 N/A
N/A 9715 9730 AGTGAACATACATTGT 48 60 1246394 N/A N/A 9981 9996
ATTAAGACAGTTGAGT 34 61 1246420 N/A N/A 10211 10226 ATTTATTGGTATGGTA
46 62 1246446 N/A N/A 10730 10745 CTGTAATTGGCTCTTG 28 63 1246472
N/A N/A 11261 11276 TCTTATCTTGGGCACC 44 64 1246498 N/A N/A 11742
11757 TCCATTGAATCTTCAA 57 65 1246524 N/A N/A 11985 12000
GAAACCAATCCTCAGC 3 66 1246550 N/A N/A 12421 12436 TGGTAACGGTGATCAA
74 67 1246576 N/A N/A 12624 12639 TTAAGCAGATGGCTTA 0 68 1246602 N/A
N/A 12761 12776 ACAGAGAATTGTTTAG 39 69 1246628 N/A N/A 13605 13620
AGACAATACAGGATAG 15 70 1246654 N/A N/A 13862 13877 CCTTAGGAAAGCTCAT
29 71 1246680 N/A N/A 14041 14056 ATCAATGCCTTAGCCC 38 72 1246706
N/A N/A 14199 14214 TATTATGTGATTGAGT 86 73 1246732 N/A N/A 14399
14414 ATTCATAAACATAGGC 36 74 1246758 N/A N/A 14730 14745
ACTCTAAATACCCTTG 16 75 1246784 N/A N/A 15316 15331 GGATTAATCATGGGAC
44 76 1246810 N/A N/A 15405 15420 TCATAGCTCACTTAGT 0 77 1246836 N/A
N/A 15775 15790 TTTAGTATTTGGGTGT 21 78 1246862 N/A N/A 16407 16422
CAATTGCTCTATAGAT 15 79 1246888 N/A N/A 17767 17782 AGCATATTCATTTGGC
61 80 1246914 N/A N/A 18033 18048 AGTTTATATGGATTTG 67 81 1246940
N/A N/A 18816 18831 CTAGTAATTGCATCTG 57 82 1246966 N/A N/A 19445
19460 CTGGGATAGTGGAGGA 21 83 1246992 N/A N/A 19686 19701
GCTAAAAGCTCACCAA 26 84 1247018 N/A N/A 19902 19917 GATACCCAGGTTGCTT
53 85 1247044 N/A N/A 20186 20201 ATTAGAAGTCAGCCCA 42 86 1247070
N/A N/A 20401 20416 GCTATAGTAATTGCTA 33 87
TABLE-US-00002 TABLE 2 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO: 1 and 2 SEQ SEQ ID SEQ ID SEQ NO: 1 ID
NO: NO: 2 ID NO: HSD17B13 SEQ Compound Start 1 Stop Start 2 Stop
Sequence (% ID Number Site Site Site Site (5' to 3') Inhibition) NO
1245069 2 17 3096 3111 GGGAGGAGGTACTGTC 35 88 1245095 61 76 3155
3170 ATGATGTTCATGGCTT 72 89 1245121 112 127 3206 3221
GACTCCAAGTAGGAGT 0 90 1245147 182 197 3276 3291 AGCTCCAGTAATGAGA 26
91 1245173 263 278 N/A N/A GCGCTTATTAATATCC 3 92 1245199 300 315
7589 7604 CTAGTTTTCGGCACTC 33 93 1245225 360 375 7649 7664
GAGAGCGATAGATCTC 1 94 1245251 403 418 8797 8812 ACCACGATTGTTACAT 34
95 1245277 433 448 8827 8842 TCGGCTGGATATACTG 23 96 1245303 476 491
8870 8885 CTCAAATGTCTTGGTA 29 97 1245329 516 531 10402 10417
GAAGTGCTTTTGTGAT 34 98 1245355 562 577 10448 10463 GCCACTGTGACGATGT
9 99 1245381 615 630 N/A N/A TGCTGGAACAATATGG 36 100 1245407 671
686 12089 12104 TCCCAAGGCCTGAAGT 43 101 1245433 760 775 15641 15656
AATACAGGCCATAATC 16 102 1245459 791 806 15672 15687
TATCAGACTTCTTACG 59 103 1245485 843 858 15724 15739
TATTGATATACGATGG 16 104 1245511* 908 923 20723 20738
ATTCTGCATACGATTT 89 105 1245537* 974 989 20789 20804
CTCTGGCTGGAGCTTA 86 106 1245563 1015 1030 20830 20845
GCATTGATTCGAAACT 66 107 1245589 1089 1104 20904 20919
TTTGACTGCTGCTAGT 21 108 1245615 1261 1276 21076 21091
AGGTAGCTTTTGTCCA 56 109 1245641 1315 1330 21130 21145
ACAGTCTTAAACCTTC 76 110 1245667 1342 1357 21157 21172
ATGGCTACAGATTGGA 72 111 1245693 1386 1401 21201 21216
CTTAGCTGTGCACTCA 60 112 1245719 1425 1440 21240 21255
GTCCAGGTTGAGATAA 60 113 1245745 1500 1515 21315 21330
TAGAGTTGCACCGTTT 58 114 1245771 1559 1574 21374 21389
CCACTTTTGGTGGACT 17 115 1245797 1618 1633 21433 21448
TCGGTCACCTTTCATA 64 116 1245823 1711 1726 21526 21541
CATCTCTGGGACCAAG 51 117 1245841 1765 1780 21580 21595
GTACAGTTCCTTTTCC 46 38 1245849 1773 1788 21588 21603
AATAGCCAGTACAGTT 46 118 1245875 2178 2193 21993 22008
GGGAGTCGGATTATTT 33 119 1245901 2245 2260 22060 22075
AGTCCATGCAAAAGCA 77 120 1245927 N/A N/A 3433 3448 AGTAGATGGTAAGTCA
90 121 1245953 N/A N/A 3553 3568 TGTCATAAAAATCGCT 57 122 1245979
N/A N/A 3962 3977 TACTAATGTCCAAGGA 77 123 1246005 N/A N/A 4529 4544
AAGGTTAGATTTCATC 80 124 1246031 N/A N/A 5079 5094 CCTAAAGGAGATCTGA
48 125 1246057 N/A N/A 5225 5240 CTTTAGCTTAAACTCC 69 126 1246065
N/A N/A 5659 5674 ATAAGTTACCAGAGCA 84 48 1246083 N/A N/A 5833 5848
GATGTTAGGACCCAGT 64 127 1246109 N/A N/A 5990 6005 AGGCAAGGATACCTGA
42 128 1246135 N/A N/A 6298 6313 GGAGATATAACATTAC 70 129 1246161
N/A N/A 6475 6490 CTATGTAATAGGCAGT 73 130 1246187 N/A N/A 7483 7498
AGACAATTAACATTCG 62 131 1246213 N/A N/A 7952 7967 ACTAGGAAGTGATCCA
58 132 1246239 N/A N/A 8244 8259 CCTAATAACTACATGA 3 133 1246265 N/A
N/A 8695 8710 ATCCAAAGATGAGAGT 5 134 1246291 N/A N/A 9003 9018
GGCAAAGATCTGGCCA 10 135 1246317 N/A N/A 9349 9364 GTCCAAAAGTGTCCTC
35 136 1246343 N/A N/A 9526 9541 CCTAGATTCTACACTA 14 137 1246369
N/A N/A 9718 9733 GATAGTGAACATACAT 54 138 1246395 N/A N/A 9983 9998
GTATTAAGACAGTTGA 45 139 1246421 N/A N/A 10212 10227
AATTTATTGGTATGGT 30 140 1246447 N/A N/A 10831 10846
GTAAACGACTCTGTAA 8 141 1246473 N/A N/A 11308 11323 GCACAAGCACACTGTA
7 142 1246499 N/A N/A 11758 11773 CTACATGTAAGGTTTT 11 143 1246525
N/A N/A 12000 12015 TAGCTAAGGGAGAGTG 9 144 1246551 N/A N/A 12429
12444 AGACAGGGTGGTAACG 51 145 1246577 N/A N/A 12625 12640
GTTAAGCAGATGGCTT 41 146 1246603 N/A N/A 12765 12780
CTCAACAGAGAATTGT 29 147 1246629 N/A N/A 13612 13627
GCTTTGAAGACAATAC 42 148 1246655 N/A N/A 13863 13878
CCCTTAGGAAAGCTCA 37 149 1246681 N/A N/A 14042 14057
TATCAATGCCTTAGCC 15 150 1246707 N/A N/A 14200 14215
TTATTATGTGATTGAG 23 151 1246733 N/A N/A 14432 14447
ACTGAAGGCTGTGTAC 14 152 1246759 N/A N/A 14731 14746
AACTCTAAATACCCTT 28 153 1246785 N/A N/A 15317 15332
AGGATTAATCATGGGA 37 154 1246811 N/A N/A 15407 15422
TTTCATAGCTCACTTA 16 155 1246837 N/A N/A 15787 15802
CTCTATTGGTGTTTTA 32 156 1246863 N/A N/A 16416 16431
AATACTCCCCAATTGC 0 157 1246889 N/A N/A 17780 17795 AGAAGATATTATCAGC
64 158 1246915 N/A N/A 18087 18102 CACCAATGCAGTTTGT 42 159 1246941
N/A N/A 18817 18832 GCTAGTAATTGCATCT 47 160 1246967 N/A N/A 19474
19489 GCTATAACTGGAAGGA 58 161 1246993 N/A N/A 19687 19702
TGCTAAAAGCTCACCA 49 162 1247019 N/A N/A 19906 19921
TTAAGATACCCAGGTT 37 163 1247045 N/A N/A 20187 20202
TATTAGAAGTCAGCCC 27 164 1247071 N/A N/A 20402 20417
GGCTATAGTAATTGCT 13 165
TABLE-US-00003 TABLE 3 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO: 1 and 2 SEQ SEQ ID SEQ ID SEQ NO: 1 ID
NO: NO: 2 ID NO: HSD17B13 SEQ Compound Start 1 Stop Start 2 Stop
Sequence (% ID Number Site Site Site Site (5' to 3') Inhibition) NO
1245070 5 20 3099 3114 CTAGGGAGGAGGTACT 29 166 1245096 62 77 3156
3171 GATGATGTTCATGGCT 86 167 1245122 113 128 3207 3222
CGACTCCAAGTAGGAG 10 168 1245148 200 215 3294 3309 CCTGCCTATTCCATGC
24 169 1245174 264 279 N/A N/A CGCGCTTATTAATATC 6 170 1245200 301
316 7590 7605 CCTAGTTTTCGGCACT 62 171 1245226 361 376 7650 7665
AGAGAGCGATAGATCT 15 172 1245252 404 419 8798 8813 CACCACGATTGTTACA
36 173 1245278 434 449 8828 8843 ATCGGCTGGATATACT 10 174 1245304
477 492 8871 8886 CCTCAAATGTCTTGGT 6 175 1245330 524 539 10410
10425 CGATGGAAGAAGTGCT 3 176 1245356 563 578 10449 10464
AGCCACTGTGACGATG 10 177 1245382 616 631 N/A N/A TTGCTGGAACAATATG 20
178 1245408 688 703 12106 12121 GTTTTGATACCAGTTT 67 179 1245434 761
776 15642 15657 CAATACAGGCCATAAT 0 180 1245460 792 807 15673 15688
CTATCAGACTTCTTAC 39 181 1245486 844 859 15725 15740
ATATTGATATACGATG 0 182 1245512* 909 924 20724 20739
TATTCTGCATACGATT 81 183 1245538* 975 990 20790 20805
TCTCTGGCTGGAGCTT 90 184 1245564 1016 1031 20831 20846
AGCATTGATTCGAAAC 70 185 1245590 1090 1105 20905 20920
GTTTGACTGCTGCTAG 58 186 1245616 1262 1277 21077 21092
GAGGTAGCTTTTGTCC 59 187 1245642 1316 1331 21131 21146
AACAGTCTTAAACCTT 82 188 1245668 1343 1358 21158 21173
CATGGCTACAGATTGG 54 189 1245694 1387 1402 21202 21217
TCTTAGCTGTGCACTC 69 190 1245720 1426 1441 21241 21256
TGTCCAGGTTGAGATA 48 191 1245746 1501 1516 21316 21331
ATAGAGTTGCACCGTT 57 192 1245772 1560 1575 21375 21390
TCCACTTTTGGTGGAC 16 193 1245798 1619 1634 21434 21449
GTCGGTCACCTTTCAT 85 194 1245824 1712 1727 21527 21542
ACATCTCTGGGACCAA 78 195 1245841 1765 1780 21580 21595
GTACAGTTCCTTTTCC 64 38 1245850 1774 1789 21589 21604
TAATAGCCAGTACAGT 64 196 1245876 2179 2194 21994 22009
TGGGAGTCGGATTATT 44 197 1245902 2246 2261 22061 22076
TAGTCCATGCAAAAGC 66 198 1245928 N/A N/A 3434 3449 AAGTAGATGGTAAGTC
85 199 1245954 N/A N/A 3554 3569 ATGTCATAAAAATCGC 53 200 1245980
N/A N/A 3963 3978 ATACTAATGTCCAAGG 89 201 1246006 N/A N/A 4535 4550
GATTTGAAGGTTAGAT 47 202 1246032 N/A N/A 5080 5095 GCCTAAAGGAGATCTG
67 203 1246058 N/A N/A 5239 5254 TAGCAAAACACTTGCT 21 204 1246065
N/A N/A 5659 5674 ATAAGTTACCAGAGCA 87 48 1246084 N/A N/A 5834 5849
GGATGTTAGGACCCAG 81 205 1246110 N/A N/A 6035 6050 ATACTTTTCCGTCTCA
90 206 1246136 N/A N/A 6303 6318 CTCTAGGAGATATAAC 49 207 1246162
N/A N/A 6476 6491 ACTATGTAATAGGCAG 85 208 1246188 N/A N/A 7681 7696
AAATTTGTGAACCTGC 26 209 1246214 N/A N/A 7953 7968 AACTAGGAAGTGATCC
58 210 1246240 N/A N/A 8245 8260 ACCTAATAACTACATG 0 211 1246266 N/A
N/A 8703 8718 CCAATATAATCCAAAG 28 212 1246292 N/A N/A 9006 9021
TAAGGCAAAGATCTGG 46 213 1246318 N/A N/A 9350 9365 CGTCCAAAAGTGTCCT
53 214 1246344 N/A N/A 9527 9542 CCCTAGATTCTACACT 22 215 1246370
N/A N/A 9719 9734 GGATAGTGAACATACA 62 216 1246396 N/A N/A 9984 9999
TGTATTAAGACAGTTG 34 217 1246422 N/A N/A 10335 10350
CCAAATCAGGTAGTTT 13 218 1246448 N/A N/A 10832 10847
AGTAAACGACTCTGTA 33 219 1246474 N/A N/A 11385 11400
TTTTAGTCAGGTAGAG 3 220 1246500 N/A N/A 11761 11776 ATCCTACATGTAAGGT
24 221 1246526 N/A N/A 12002 12017 GTTAGCTAAGGGAGAG 18 222 1246552
N/A N/A 12433 12448 TTAAAGACAGGGTGGT 21 223 1246578 N/A N/A 12626
12641 TGTTAAGCAGATGGCT 39 224 1246604 N/A N/A 12777 12792
AATGAGGCGGCACTCA 20 225 1246630 N/A N/A 13639 13654
TGACAATGTGCAGCTC 64 226 1246656 N/A N/A 13864 13879
ACCCTTAGGAAAGCTC 52 227 1246682 N/A N/A 14043 14058
ATATCAATGCCTTAGC 32 228 1246708 N/A N/A 14202 14217
GATTATTATGTGATTG 39 229 1246734 N/A N/A 14435 14450
TATACTGAAGGCTGTG 44 230 1246760 N/A N/A 14800 14815
GAATTGCTCACCCTTT 24 231 1246786 N/A N/A 15318 15333
TAGGATTAATCATGGG 47 232 1246812 N/A N/A 15418 15433
CAGTAGGTGTGTTTCA 47 233 1246838 N/A N/A 15793 15808
AAAAAGCTCTATTGGT 0 234 1246864 N/A N/A 16424 16439 GATATGTCAATACTCC
59 235 1246890 N/A N/A 17857 17872 CATTTGAAGTCTATAC 21 236 1246916
N/A N/A 18091 18106 GATACACCAATGCAGT 73 237 1246942 N/A N/A 18818
18833 TGCTAGTAATTGCATC 17 238 1246968 N/A N/A 19475 19490
GGCTATAACTGGAAGG 52 239 1246994 N/A N/A 19688 19703
ATGCTAAAAGCTCACC 50 240 1247020 N/A N/A 19907 19922
CTTAAGATACCCAGGT 36 241 1247046 N/A N/A 20188 20203
TTATTAGAAGTCAGCC 36 242 1247072 N/A N/A 20403 20418
TGGCTATAGTAATTGC 34 243
TABLE-US-00004 TABLE 4 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO: 1, and 2 SEQ SEQ ID SEQ ID SEQ NO: 1
ID NO: NO: 2 ID NO: HSD17B13 SEQ Compound Start 1 Stop Start 2 Stop
Sequence (% ID Number Site Site Site Site (5' to 3') Inhibition) NO
1245071 6 21 3100 3115 CCTAGGGAGGAGGTAC 34 244 1245097 63 78 3157
3172 GGATGATGTTCATGGC 82 245 1245123 114 129 3208 3223
ACGACTCCAAGTAGGA 24 246 1245149 202 217 3296 3311 TGCCTGCCTATTCCAT
40 247 1245175 265 280 N/A N/A CCGCGCTTATTAATAT 21 248 1245201 302
317 7591 7606 GCCTAGTTTTCGGCAC 12 249 1245227 362 377 7651 7666
TAGAGAGCGATAGATC 22 250 1245253 405 420 8799 8814 TCACCACGATTGTTAC
34 251 1245279 435 450 8829 8844 GATCGGCTGGATATAC 7 252 1245305 478
493 8872 8887 ACCTCAAATGTCTTGG 17 253 1245331 525 540 10411 10426
TCGATGGAAGAAGTGC 34 254 1245357 566 581 10452 10467
TGAAGCCACTGTGACG 49 255 1245383 623 638 12041 12056
GGCAAATTTGCTGGAA 54 256 1245409 689 704 12107 12122
GGTTTTGATACCAGTT 58 257 1245435 762 777 15643 15658
CCAATACAGGCCATAA 38 258 1245461 793 808 15674 15689
TCTATCAGACTTCTTA 49 259 1245487 845 860 15726 15741
GATATTGATATACGAT 2 260 1245513* 910 925 20725 20740
ATATTCTGCATACGAT 36 261 1245539* 977 992 20792 20807
CATCTCTGGCTGGAGC 79 262 1245565 1017 1032 20832 20847
CAGCATTGATTCGAAA 69 263 1245591 1091 1106 20906 20921
CGTTTGACTGCTGCTA 58 264 1245617 1263 1278 21078 21093
GGAGGTAGCTTTTGTC 43 265 1245643 1317 1332 21132 21147
GAACAGTCTTAAACCT 64 266 1245669 1344 1359 21159 21174
GCATGGCTACAGATTG 56 267 1245695 1388 1403 21203 21218
CTCTTAGCTGTGCACT 53 268 1245721 1427 1442 21242 21257
ATGTCCAGGTTGAGAT 55 269 1245747 1502 1517 21317 21332
AATAGAGTTGCACCGT 48 270 1245773 1561 1576 21376 21391
GTCCACTTTTGGTGGA 14 271 1245799 1620 1635 21435 21450
AGTCGGTCACCTTTCA 66 272 1245825 1713 1728 21528 21543
AACATCTCTGGGACCA 74 273 1245851 1775 1790 21590 21605
GTAATAGCCAGTACAG 77 274 1245877 2180 2195 21995 22010
GTGGGAGTCGGATTAT 37 275 1245903 2251 2266 22066 22081
GAGGATAGTCCATGCA 59 276 1245929 N/A N/A 3437 3452 GATAAGTAGATGGTAA
59 277 1245955 N/A N/A 3573 3588 TTCTATCAACCTGCAC 62 278 1245981
N/A N/A 3964 3979 AATACTAATGTCCAAG 65 279 1246007 N/A N/A 4572 4587
ATATAGCCCTTTCCCC 26 280 1246033 N/A N/A 5081 5096 CGCCTAAAGGAGATCT
59 281 1246059 N/A N/A 5241 5256 GTTAGCAAAACACTTG 71 282 1246085
N/A N/A 5840 5855 AAACATGGATGTTAGG 56 283 1246111 N/A N/A 6036 6051
TATACTTTTCCGTCTC 71 284 1246137 N/A N/A 6305 6320 TACTCTAGGAGATATA
33 285 1246163 N/A N/A 6478 6493 CAACTATGTAATAGGC 79 286 1246189
N/A N/A 7684 7699 AAGAAATTTGTGAACC 21 287 1246215 N/A N/A 7973 7988
AGTTAATAGGACTAAA 13 288 1246241 N/A N/A 8246 8261 AACCTAATAACTACAT
0 289 1246267 N/A N/A 8705 8720 GACCAATATAATCCAA 34 290 1246293 N/A
N/A 9009 9024 GATTAAGGCAAAGATC 25 291 1246319 N/A N/A 9373 9388
CTAGAACACTTGCCTC 25 292 1246345 N/A N/A 9540 9555 GAATCCAGATCTGCCC
29 293 1246371 N/A N/A 9721 9736 GAGGATAGTGAACATA 50 294 1246397
N/A N/A 9985 10000 CTGTATTAAGACAGTT 41 295 1246423 N/A N/A 10336
10351 TCCAAATCAGGTAGTT 22 296 1246449 N/A N/A 10833 10848
GAGTAAACGACTCTGT 43 297 1246475 N/A N/A 11386 11401
CTTTTAGTCAGGTAGA 33 298 1246501 N/A N/A 11780 11795
GCTTAATGTTCAGTTT 50 299 1246527 N/A N/A 12009 12024
AAGCATTGTTAGCTAA 11 300 1246553 N/A N/A 12465 12480
ATTTATTTGCTGGTCC 47 301 1246579 N/A N/A 12647 12662
TATACTAGGATTAGAA 2 302 1246605 N/A N/A 12778 12793 AAATGAGGCGGCACTC
20 303 1246631 N/A N/A 13704 13719 AATGTAAGAAGCCACG 26 304 1246657
N/A N/A 13881 13896 CCCAAGAGTGGCAGGA 29 305 1246683 N/A N/A 14044
14059 CATATCAATGCCTTAG 29 306 1246709 N/A N/A 14205 14220
GCAGATTATTATGTGA 59 307 1246735 N/A N/A 14436 14451
TTATACTGAAGGCTGT 23 308 1246761 N/A N/A 14916 14931
ATACATTAGCAAGCTA 69 309 1246787 N/A N/A 15319 15334
CTAGGATTAATCATGG 65 310 1246813 N/A N/A 15420 15435
TCCAGTAGGTGTGTTT 47 311 1246839 N/A N/A 16116 16131
CTCTATTGGGCCAGGC 46 312 1246865 N/A N/A 16461 16476
GATATTATGTTCTTGG 59 313 1246891 N/A N/A 17909 17924
GGAAATTGTTGCTGTT 46 314 1246917 N/A N/A 18097 18112
GAAATTGATACACCAA 67 315 1246943 N/A N/A 18819 18834
ATGCTAGTAATTGCAT 16 316 1246969 N/A N/A 19484 19499
AGAATTAAGGGCTATA 45 317 1246995 N/A N/A 19689 19704
GATGCTAAAAGCTCAC 46 318 1247021 N/A N/A 19908 19923
TCTTAAGATACCCAGG 58 319 1247047 N/A N/A 20189 20204
GTTATTAGAAGTCAGC 56 320 1247073 N/A N/A 20415 20430
AATTATGCCTTGTGGC 19 321
TABLE-US-00005 TABLE 5 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO: 1, and 2 SEQ SEQ ID SEQ ID SEQ NO: 1
ID NO: NO: 2 ID NO: HSD17B13 SEQ Compound Start 1 Stop Start 2 Stop
Sequence (% ID Number Site Site Site Site (5' to 3') Inhibition) NO
1245072 7 22 3101 3116 TCCTAGGGAGGAGGTA 33 322 1245098 64 79 3158
3173 AGGATGATGTTCATGG 88 323 1245124 115 130 3209 3224
AACGACTCCAAGTAGG 27 324 1245150 205 220 3299 3314 GTCTGCCTGCCTATTC
53 325 1245176 266 281 N/A N/A ACCGCGCTTATTAATA 4 326 1245202 303
318 7592 7607 CGCCTAGTTTTCGGCA 23 327 1245228 363 378 7652 7667
TTAGAGAGCGATAGAT 23 328 1245254 406 421 8800 8815 TTCACCACGATTGTTA
40 329 1245280 436 451 8830 8845 AGATCGGCTGGATATA 27 330 1245306
479 494 8873 8888 GACCTCAAATGTCTTG 12 331 1245332 526 541 10412
10427 ATCGATGGAAGAAGTG 39 332 1245358 573 588 10459 10474
CGCACACTGAAGCCAC 56 333 1245384 624 639 12042 12057
CGGCAAATTTGCTGGA 29 334 1245410 690 705 12108 12123
AGGTTTTGATACCAGT 60 335 1245436 763 778 15644 15659
TCCAATACAGGCCATA 62 336 1245462 795 810 15676 15691
CATCTATCAGACTTCT 38 337 1245488 846 861 15727 15742
AGATATTGATATACGA 20 338 1245514* 911 926 20726 20741
AATATTCTGCATACGA 70 339 1245540* 978 993 20793 20808
ACATCTCTGGCTGGAG 85 340 1245566 1018 1033 20833 20848
GCAGCATTGATTCGAA 63 341 1245592 1105 1120 20920 20935
TAATTAATCTTGTTCG 63 342 1245618 1264 1279 21079 21094
GGGAGGTAGCTTTTGT 10 343 1245644 1318 1333 21133 21148
TGAACAGTCTTAAACC 56 344 1245670 1345 1360 21160 21175
GGCATGGCTACAGATT 69 345 1245696 1389 1404 21204 21219
TCTCTTAGCTGTGCAC 79 346 1245722 1428 1443 21243 21258
TATGTCCAGGTTGAGA 64 347 1245748 1503 1518 21318 21333
GAATAGAGTTGCACCG 55 348 1245774 1562 1577 21377 21392
GGTCCACTTTTGGTGG 13 349 1245800 1621 1636 21436 21451
GAGTCGGTCACCTTTC 82 350 1245826 1715 1730 21530 21545
TAAACATCTCTGGGAC 51 351 1245841 1765 1780 21580 21595
GTACAGTTCCTTTTCC 58 38 1245852 1776 1791 21591 21606
TGTAATAGCCAGTACA 46 352 1245878 2181 2196 21996 22011
AGTGGGAGTCGGATTA 50 353 1245904 2252 2267 22067 22082
AGAGGATAGTCCATGC 74 354 1245930 N/A N/A 3439 3454 AAGATAAGTAGATGGT
79 355 1245956 N/A N/A 3602 3617 AGCTTGGAAGGAGACT 69 356 1245982
N/A N/A 3999 4014 GTTAATGTAGTGTTTA 77 357 1246008 N/A N/A 4573 4588
AATATAGCCCTTTCCC 44 358 1246034 N/A N/A 5082 5097 TCGCCTAAAGGAGATC
70 359 1246060 N/A N/A 5267 5282 TGCAAAATGTGATGCC 69 360 1246065
N/A N/A 5659 5674 ATAAGTTACCAGAGCA 90 48 1246086 N/A N/A 5841 5856
CAAACATGGATGTTAG 49 361 1246112 N/A N/A 6037 6052 TTATACTTTTCCGTCT
61 362 1246138 N/A N/A 6323 6338 ATAGGGAGACCATGCT 64 363 1246164
N/A N/A 6567 6582 AAAACATTGCTCTTCG 59 364 1246190 N/A N/A 7751 7766
TAAATCAGGCAGTCAT 35 365 1246216 N/A N/A 7974 7989 AAGTTAATAGGACTAA
17 366 1246242 N/A N/A 8248 8263 ATAACCTAATAACTAC 26 367 1246268
N/A N/A 8714 8729 AAGTTTTGGGACCAAT 11 368 1246294 N/A N/A 9012 9027
CTTGATTAAGGCAAAG 38 369 1246320 N/A N/A 9375 9390 ATCTAGAACACTTGCC
27 370 1246346 N/A N/A 9588 9603 CTGGTAAAGGTAAGGG 58 371 1246372
N/A N/A 9722 9737 AGAGGATAGTGAACAT 59 372 1246398 N/A N/A 9986
10001 ACTGTATTAAGACAGT 20 373 1246424 N/A N/A 10337 10352
TTCCAAATCAGGTAGT 12 374 1246450 N/A N/A 10834 10849
TGAGTAAACGACTCTG 23 375 1246476 N/A N/A 11387 11402
ACTTTTAGTCAGGTAG 26 376 1246502 N/A N/A 11781 11796
GGCTTAATGTTCAGTT 54 377 1246528 N/A N/A 12011 12026
TTAAGCATTGTTAGCT 16 378 1246554 N/A N/A 12466 12481
AATTTATTTGCTGGTC 27 379 1246580 N/A N/A 12648 12663
ATATACTAGGATTAGA 33 380 1246606 N/A N/A 12779 12794
CAAATGAGGCGGCACT 32 381 1246632 N/A N/A 13707 13722
GCAAATGTAAGAAGCC 4 382 1246658 N/A N/A 13894 13909 CTATCATGCCTTCCCC
1 383 1246684 N/A N/A 14046 14061 TACATATCAATGCCTT 38 384 1246710
N/A N/A 14206 14221 TGCAGATTATTATGTG 38 385 1246736 N/A N/A 14437
14452 CTTATACTGAAGGCTG 48 386 1246762 N/A N/A 14934 14949
CATTATAAGCTAACTA 39 387 1246788 N/A N/A 15321 15336
GGCTAGGATTAATCAT 44 388 1246814 N/A N/A 15421 15436
ATCCAGTAGGTGTGTT 41 389 1246840 N/A N/A 16123 16138
ATAATAGCTCTATTGG 46 390 1246866 N/A N/A 16533 16548
CAAGACTTAAACACCA 55 391 1246892 N/A N/A 17910 17925
GGGAAATTGTTGCTGT 42 392 1246918 N/A N/A 18099 18114
CTGAAATTGATACACC 67 393 1246944 N/A N/A 18827 18842
AAACCTTCATGCTAGT 27 394 1246970 N/A N/A 19485 19500
TAGAATTAAGGGCTAT 31 395 1246996 N/A N/A 19699 19714
GATTAATCTTGATGCT 26 396 1247022 N/A N/A 19909 19924
ATCTTAAGATACCCAG 70 397 1247048 N/A N/A 20192 20207
GCAGTTATTAGAAGTC 76 398 1247074 N/A N/A 20419 20434
GTAAAATTATGCCTTG 50 399
TABLE-US-00006 TABLE 6 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO: 1, and 2 SEQ SEQ ID SEQ ID SEQ NO: 1
ID NO: NO: 2 ID NO: HSD17B13 SEQ Compound Start 1 Stop Start 2 Stop
Sequence (% ID Number Site Site Site Site (5' to 3') Inhibition) NO
1245073 8 23 3102 3117 GTCCTAGGGAGGAGGT 36 400 1245099 65 80 3159
3174 TAGGATGATGTTCATG 72 401 1245125 116 131 3210 3225
CAACGACTCCAAGTAG 0 402 1245151 206 221 3300 3315 AGTCTGCCTGCCTATT
47 403 1245177 267 282 N/A N/A CACCGCGCTTATTAAT 7 404 1245203 304
319 7593 7608 ACGCCTAGTTTTCGGC 7 405 1245229 364 379 7653 7668
TTTAGAGAGCGATAGA 13 406 1245255 407 422 8801 8816 ATTCACCACGATTGTT
0 407 1245281 437 452 8831 8846 AAGATCGGCTGGATAT 1 408 1245307 481
496 8875 8890 TTGACCTCAAATGTCT 0 409 1245333 527 542 10413 10428
CATCGATGGAAGAAGT 16 410 1245359 574 589 10460 10475
CCGCACACTGAAGCCA 34 411 1245385 625 640 12043 12058
GCGGCAAATTTGCTGG 0 412 1245411 691 706 12109 12124 GAGGTTTTGATACCAG
59 413 1245437 764 779 15645 15660 CTCCAATACAGGCCAT 20 414 1245463
796 811 15677 15692 CCATCTATCAGACTTC 78 415 1245489 847 862 15728
15743 AAGATATTGATATACG 45 416 1245515* 912 927 20727 20742
GAATATTCTGCATACG 68 417 1245541* 979 994 20794 20809
TACATCTCTGGCTGGA 86 418 1245567 1019 1034 20834 20849
TGCAGCATTGATTCGA 47 419 1245593 1106 1121 20921 20936
GTAATTAATCTTGTTC 52 420 1245619 1265 1280 21080 21095
AGGGAGGTAGCTTTTG 46 421 1245645 1319 1334 21134 21149
TTGAACAGTCTTAAAC 33 422 1245671 1346 1361 21161 21176
TGGCATGGCTACAGAT 57 423 1245697 1390 1405 21205 21220
ATCTCTTAGCTGTGCA 63 424 1245723 1429 1444 21244 21259
ATATGTCCAGGTTGAG 61 425 1245749 1504 1519 21319 21334
AGAATAGAGTTGCACC 70 426 1245775 1563 1578 21378 21393
GGGTCCACTTTTGGTG 13 427 1245801 1622 1637 21437 21452
AGAGTCGGTCACCTTT 71 428 1245827 1718 1733 21533 21548
GTCTAAACATCTCTGG 58 429 1245841 1765 1780 21580 21595
GTACAGTTCCTTTTCC 57 38 1245853 1777 1792 21592 21607
ATGTAATAGCCAGTAC 52 430 1245879 2182 2197 21997 22012
TAGTGGGAGTCGGATT 54 431 1245905 2253 2268 22068 22083
AAGAGGATAGTCCATG 65 432 1245931 N/A N/A 3474 3489 AGGGAATTTATCAAAC
47 433 1245957 N/A N/A 3610 3625 CATTTAGCAGCTTGGA 88 434 1245983
N/A N/A 4002 4017 GTTGTTAATGTAGTGT 77 435 1246009 N/A N/A 4641 4656
ATACGACTTCCTTCTA 44 436 1246035 N/A N/A 5104 5119 GAAAACTCAGCCAGCA
78 437 1246061 N/A N/A 5278 5293 AGCTAGACAATTGCAA 30 438 1246065
N/A N/A 5659 5674 ATAAGTTACCAGAGCA 87 48 1246087 N/A N/A 5842 5857
CCAAACATGGATGTTA 43 439 1246113 N/A N/A 6038 6053 ATTATACTTTTCCGTC
75 440 1246139 N/A N/A 6327 6342 TTTCATAGGGAGACCA 71 441 1246165
N/A N/A 6607 6622 CTAAAGCAGGCTACTT 32 442 1246191 N/A N/A 7752 7767
TTAAATCAGGCAGTCA 45 443 1246217 N/A N/A 7975 7990 AAAGTTAATAGGACTA
12 444 1246243 N/A N/A 8249 8264 CATAACCTAATAACTA 10 445 1246269
N/A N/A 8717 8732 TCAAAGTTTTGGGACC 42 446 1246295 N/A N/A 9080 9095
TCCACTTGAATTCTGT 32 447 1246321 N/A N/A 9376 9391 GATCTAGAACACTTGC
27 448 1246347 N/A N/A 9589 9604 GCTGGTAAAGGTAAGG 65 449 1246373
N/A N/A 9751 9766 CTCCAAATTCCCAACC 31 450 1246399 N/A N/A 9998
10013 AAATCTTGTGTAACTG 41 451 1246425 N/A N/A 10359 10374
GACAATGACATAGACG 0 452 1246451 N/A N/A 10835 10850 CTGAGTAAACGACTCT
33 453 1246477 N/A N/A 11389 11404 CAACTTTTAGTCAGGT 66 454 1246503
N/A N/A 11782 11797 TGGCTTAATGTTCAGT 50 455 1246529 N/A N/A 12012
12027 ATTAAGCATTGTTAGC 0 456 1246555 N/A N/A 12467 12482
CAATTTATTTGCTGGT 31 457 1246581 N/A N/A 12649 12664
TATATACTAGGATTAG 10 458 1246607 N/A N/A 12781 12796
CTCAAATGAGGCGGCA 56 459 1246633 N/A N/A 13711 13726
CGTAGCAAATGTAAGA 0 460 1246659 N/A N/A 13896 13911 ATCTATCATGCCTTCC
6 461 1246685 N/A N/A 14047 14062 TTACATATCAATGCCT 12 462 1246711
N/A N/A 14243 14258 GTTAAAACTTCATTCC 5 463 1246737 N/A N/A 14438
14453 CCTTATACTGAAGGCT 41 464 1246763 N/A N/A 14935 14950
TCATTATAAGCTAACT 0 465 1246789 N/A N/A 15328 15343 GAGGAATGGCTAGGAT
47 466 1246815 N/A N/A 15424 15439 CATATCCAGTAGGTGT 37 467 1246841
N/A N/A 16128 16143 CCATAATAATAGCTCT 48 468 1246867 N/A N/A 16755
16770 AAAGTTAGTTGGGCGA 26 469 1246893 N/A N/A 17911 17926
TGGGAAATTGTTGCTG 38 470 1246919 N/A N/A 18100 18115
ACTGAAATTGATACAC 49 471 1246945 N/A N/A 18828 18843
GAAACCTTCATGCTAG 31 472 1246971 N/A N/A 19486 19501
CTAGAATTAAGGGCTA 42 473 1246997 N/A N/A 19700 19715
TGATTAATCTTGATGC 15 474 1247023 N/A N/A 19910 19925
CATCTTAAGATACCCA 76 475 1247049 N/A N/A 20248 20263
CCTAAACAAACACTAT 8 476 1247075 N/A N/A 20422 20437 ACAGTAAAATTATGCC
73 477
TABLE-US-00007 TABLE 7 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO: 1, and 2 SEQ SEQ ID SEQ ID SEQ NO: 1
ID NO: NO: 2 ID NO: HSD17B13 SEQ Compound Start 1 Stop Start 2 Stop
(% ID Number Site Site Site Site Sequence (5' to 3') Inhibition) NO
1245074 10 25 3104 3119 TAGTCCTAGGGAGGAG 68 478 1245100 66 81 3160
3175 CTAGGATGATGTTCAT 47 479 1245126 117 132 3211 3226
CCAACGACTCCAAGTA 20 480 1245152 207 222 3301 3316 TAGTCTGCCTGCCTAT
44 481 1245178 268 283 N/A N/A ACACCGCGCTTATTAA 7 482 1245204 316
331 7605 7620 GCATGCGCAGTGACGC 36 483 1245230 365 380 7654 7669
ATTTAGAGAGCGATAG 14 484 1245256 408 423 8802 8817 TATTCACCACGATTGT
2 485 1245282 438 453 8832 8847 GAAGATCGGCTGGATA 16 486 1245308 482
497 8876 8891 GTTGACCTCAAATGTC 0 487 1245334 528 543 10414 10429
TCATCGATGGAAGAAG 24 488 1245360 575 590 10461 10476
GCCGCACACTGAAGCC 25 489 1245386 626 641 12044 12059
AGCGGCAAATTTGCTG 5 490 1245412 692 707 12110 12125 TGAGGTTTTGATACCA
63 491 1245438 765 780 15646 15661 TCTCCAATACAGGCCA 21 492 1245464
797 812 15678 15693 TCCATCTATCAGACTT 42 493 1245490* 858 873 15739
15754 GTAGTCTCAGAAAGAT 45 494 1245516* 926 941 20741 20756
CACTGCTTCAAATTGA 64 495 1245542* 980 995 20795 20810
ATACATCTCTGGCTGG 88 496 1245568 1020 1035 20835 20850
TTGCAGCATTGATTCG 59 497 1245594 1107 1122 20922 20937
GGTAATTAATCTTGTT 58 498 1245620 1266 1281 21081 21096
TAGGGAGGTAGCTTTT 46 499 1245646 1320 1335 21135 21150
CTTGAACAGTCTTAAA 39 500 1245672 1347 1362 21162 21177
GTGGCATGGCTACAGA 56 501 1245698 1391 1406 21206 21221
GATCTCTTAGCTGTGC 64 502 1245724 1430 1445 21245 21260
AATATGTCCAGGTTGA 64 503 1245750 1505 1520 21320 21335
CAGAATAGAGTTGCAC 50 504 1245776 1564 1579 21379 21394
AGGGTCCACTTTTGGT 11 505 1245802 1623 1638 21438 21453
TAGAGTCGGTCACCTT 65 506 1245828 1719 1734 21534 21549
TGTCTAAACATCTCTG 58 507 1245841 1765 1780 21580 21595
GTACAGTTCCTTTTCC 51 38 1245854 1778 1793 21593 21608
TATGTAATAGCCAGTA 50 508 1245880 2183 2198 21998 22013
GTAGTGGGAGTCGGAT 48 509 1245906 2254 2269 22069 22084
CAAGAGGATAGTCCAT 58 510 1245932 N/A N/A 3487 3502 AGACTAAGGGACCAGG
80 511 1245958 N/A N/A 3611 3626 TCATTTAGCAGCTTGG 79 512 1245984
N/A N/A 4123 4138 ACAATTTTTCCAATCC 86 513 1246010 N/A N/A 4642 4657
AATACGACTTCCTTCT 26 514 1246036 N/A N/A 5105 5120 TGAAAACTCAGCCAGC
77 515 1246062 N/A N/A 5287 5302 TTATAACTGAGCTAGA 8 516 1246065 N/A
N/A 5659 5674 ATAAGTTACCAGAGCA 89 48 1246088 N/A N/A 5843 5858
CCCAAACATGGATGTT 72 517 1246114 N/A N/A 6039 6054 AATTATACTTTTCCGT
66 518 1246140 N/A N/A 6328 6343 CTTTCATAGGGAGACC 73 519 1246166
N/A N/A 6608 6623 TCTAAAGCAGGCTACT 32 520 1246192 N/A N/A 7757 7772
CCAATTTAAATCAGGC 73 521 1246218 N/A N/A 7976 7991 CAAAGTTAATAGGACT
50 522 1246244 N/A N/A 8280 8295 GTCTAAAGTGCTGGTT 39 523 1246270
N/A N/A 8747 8762 GAACACTTTCACTGGG 0 524 1246296 N/A N/A 9110 9125
ACCAAGTAGCTTACAT 2 525 1246322 N/A N/A 9377 9392 GGATCTAGAACACTTG
32 526 1246348 N/A N/A 9598 9613 ATGTGAAGAGCTGGTA 42 527 1246374
N/A N/A 9761 9776 CCCAAGCTACCTCCAA 15 528 1246400 N/A N/A 10001
10016 GTGAAATCTTGTGTAA 44 529 1246426 N/A N/A 10360 10375
AGACAATGACATAGAC 14 530 1246452 N/A N/A 10836 10851
ACTGAGTAAACGACTC 45 531 1246478 N/A N/A 11428 11443
CCCTTTATGTCTTTGG 35 532 1246504 N/A N/A 11790 11805
CTATTGATTGGCTTAA 31 533 1246530 N/A N/A 12038 12053
AAATTTGCTGGAACTG 15 534 1246556 N/A N/A 12478 12493
AGCTAGATACTCAATT 2 535 1246582 N/A N/A 12652 12667 GAATATATACTAGGAT
5 536 1246608 N/A N/A 12782 12797 CCTCAAATGAGGCGGC 47 537 1246634
N/A N/A 13730 13745 ATTAAGTACTGTGAGA 1 538 1246660 N/A N/A 13897
13912 CATCTATCATGCCTTC 18 539 1246686 N/A N/A 14048 14063
ATTACATATCAATGCC 36 540 1246712 N/A N/A 14250 14265
AGCGAATGTTAAAACT 16 541 1246738 N/A N/A 14439 14454
TCCTTATACTGAAGGC 22 542 1246764 N/A N/A 14936 14951
CTCATTATAAGCTAAC 13 543 1246790 N/A N/A 15350 15365
AGTAGTGGAGCCAGAC 39 544 1246816 N/A N/A 15425 15440
TCATATCCAGTAGGTG 32 545 1246842 N/A N/A 16129 16144
TCCATAATAATAGCTC 69 546 1246868 N/A N/A 16905 16920
CGTCAAAAACCGTCAA 20 547 1246894 N/A N/A 17923 17938
GAGTATTTCCTCTGGG 23 548 1246920 N/A N/A 18506 18521
ACTAATTTAGTCAACT 18 549 1246946 N/A N/A 18846 18861
TTTAACTACCCTCACA 0 550 1246972 N/A N/A 19487 19502 TCTAGAATTAAGGGCT
45 551 1246998 N/A N/A 19701 19716 CTGATTAATCTTGATG 32 552 1247024
N/A N/A 19911 19926 GCATCTTAAGATACCC 82 553 1247050 N/A N/A 20249
20264 GCCTAAACAAACACTA 37 554 1247076 N/A N/A 20481 20496
CATAGTGGACTTCATT 34 555
TABLE-US-00008 TABLE 8 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO: 1, and 2 SEQ SEQ ID SEQ ID SEQ NO: 1
ID NO: NO: 2 ID NO: HSD17B13 SEQ Compound Start 1 Stop Start 2 Stop
(% ID Number Site Site Site Site Sequence (5' to 3') Inhibition) NO
1245075 11 26 3105 3120 GTAGTCCTAGGGAGGA 77 556 1245101 67 82 3161
3176 TCTAGGATGATGTTCA 64 557 1245127 118 133 3212 3227
ACCAACGACTCCAAGT 16 558 1245153 208 223 3302 3317 GTAGTCTGCCTGCCTA
68 559 1245179 269 284 N/A N/A CACACCGCGCTTATTA 11 560 1245205 317
332 7606 7621 CGCATGCGCAGTGACG 46 561 1245231 366 381 7655 7670
GATTTAGAGAGCGATA 44 562 1245257 409 424 8803 8818 TTATTCACCACGATTG
40 563 1245283 439 454 8833 8848 AGAAGATCGGCTGGAT 29 564 1245309
483 498 8877 8892 TGTTGACCTCAAATGT 14 565 1245335 529 544 10415
10430 ATCATCGATGGAAGAA 30 566 1245361 576 591 10462 10477
GGCCGCACACTGAAGC 9 567 1245387 632 647 12050 12065 GCCAACAGCGGCAAAT
30 568 1245413 693 708 12111 12126 ATGAGGTTTTGATACC 47 569 1245439
766 781 15647 15662 GTCTCCAATACAGGCC 47 570 1245465 798 813 15679
15694 TTCCATCTATCAGACT 33 571 1245491* 866 881 N/A N/A
AAACTTCTGTAGTCTC 67 572 1245517* 927 942 20742 20757
CCACTGCTTCAAATTG 77 573 1245543* 981 996 20796 20811
CATACATCTCTGGCTG 69 574 1245569 1021 1036 20836 20851
TTTGCAGCATTGATTC 53 575 1245595 1109 1124 20924 20939
CAGGTAATTAATCTTG 54 576 1245621 1267 1282 21082 21097
TTAGGGAGGTAGCTTT 54 577 1245647 1321 1336 21136 21151
ACTTGAACAGTCTTAA 63 578 1245673 1348 1363 21163 21178
TGTGGCATGGCTACAG 24 579 1245699 1392 1407 21207 21222
TGATCTCTTAGCTGTG 59 580 1245725 1431 1446 21246 21261
AAATATGTCCAGGTTG 68 581 1245751 1506 1521 21321 21336
CCAGAATAGAGTTGCA 62 582 1245777 1565 1580 21380 21395
GAGGGTCCACTTTTGG 23 583 1245803 1624 1639 21439 21454
ATAGAGTCGGTCACCT 60 584 1245829 1721 1736 21536 21551
ATTGTCTAAACATCTC 84 585 1245855 1779 1794 21594 21609
TTATGTAATAGCCAGT 77 586 1245881 2184 2199 21999 22014
TGTAGTGGGAGTCGGA 62 587 1245907 2255 2270 22070 22085
ACAAGAGGATAGTCCA 64 588 1245933 N/A N/A 3488 3503 CAGACTAAGGGACCAG
75 589 1245959 N/A N/A 3612 3627 CTCATTTAGCAGCTTG 70 590 1245985
N/A N/A 4136 4151 CAAGGAGTACTTCACA 66 591 1246011 N/A N/A 4643 4658
TAATACGACTTCCTTC 32 592 1246037 N/A N/A 5125 5140 GCAAAAGGAGCCAGTT
57 593 1246063 N/A N/A 5290 5305 GTTTTATAACTGAGCT 84 594 1246089
N/A N/A 5871 5886 CTAAACCCTGGAGCAG 42 595 1246115 N/A N/A 6040 6055
AAATTATACTTTTCCG 85 596 1246141 N/A N/A 6337 6352 GAAGAAGGACTTTCAT
40 597 1246167 N/A N/A 6609 6624 CTCTAAAGCAGGCTAC 51 598 1246193
N/A N/A 7758 7773 TCCAATTTAAATCAGG 61 599 1246219 N/A N/A 7977 7992
GCAAAGTTAATAGGAC 52 600 1246245 N/A N/A 8282 8297 TGGTCTAAAGTGCTGG
61 601 1246271 N/A N/A 8895 8910 CCCAAAAATGTCCTAG 18 602 1246297
N/A N/A 9111 9126 GACCAAGTAGCTTACA 28 603 1246323 N/A N/A 9379 9394
ATGGATCTAGAACACT 43 604 1246349 N/A N/A 9600 9615 ATATGTGAAGAGCTGG
51 605 1246375 N/A N/A 9762 9777 ACCCAAGCTACCTCCA 9 606 1246401 N/A
N/A 10002 10017 AGTGAAATCTTGTGTA 41 607 1246427 N/A N/A 10380 10395
GATCATTGCAGAAAGA 23 608 1246453 N/A N/A 10849 10864
ACATATGGTGTACACT 19 609 1246479 N/A N/A 11468 11483
GCAAATACAGCAGTAC 56 610 1246505 N/A N/A 11791 11806
TCTATTGATTGGCTTA 39 611 1246531 N/A N/A 12039 12054
CAAATTTGCTGGAACT 39 612 1246557 N/A N/A 12482 12497
AAGGAGCTAGATACTC 19 613 1246583 N/A N/A 12654 12669
CAGAATATATACTAGG 55 614 1246609 N/A N/A 12795 12810
TAAGAGTCAGTATCCT 52 615 1246635 N/A N/A 13731 13746
TATTAAGTACTGTGAG 0 616 1246661 N/A N/A 13915 13930 CATTATCCTTACTCCC
16 617 1246687 N/A N/A 14049 14064 CATTACATATCAATGC 29 618 1246713
N/A N/A 14262 14277 AGTTAGGGAGCCAGCG 38 619 1246739 N/A N/A 14465
14480 CTGGAGGTATGTCATA 23 620 1246765 N/A N/A 15022 15037
TGATAAAATAGGGTGC 44 621 1246791 N/A N/A 15351 15366
GAGTAGTGGAGCCAGA 44 622 1246817 N/A N/A 15427 15442
TTTCATATCCAGTAGG 36 623 1246843 N/A N/A 16189 16204
AATAACTGTTCTCCCC 20 624 1246869 N/A N/A 16956 16971
GACAACAAACAATGGG 39 625 1246895 N/A N/A 17924 17939
AGAGTATTTCCTCTGG 32 626 1246921 N/A N/A 18507 18522
CACTAATTTAGTCAAC 7 627 1246947 N/A N/A 18847 18862 TTTTAACTACCCTCAC
2 628 1246973 N/A N/A 19488 19503 ATCTAGAATTAAGGGC 41 629 1246999
N/A N/A 19702 19717 GCTGATTAATCTTGAT 48 630 1247025 N/A N/A 19921
19936 TCCAAGGAGTGCATCT 46 631 1247051 N/A N/A 20356 20371
TTATTGCCTGAACACA 58 632 1247077 N/A N/A 20482 20497
TCATAGTGGACTTCAT 36 633
TABLE-US-00009 TABLE 9 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO: 1, and 2 SEQ SEQ ID SEQ ID SEQ NO: 1
ID NO: NO: 2 ID NO: HSD17B13 SEQ Compound Start 1 Stop Start 2 Stop
(% ID Number Site Site Site Site Sequence (5' to 3') Inhibition) NO
1245076 12 27 3106 3121 TGTAGTCCTAGGGAGG 86 634 1245102 68 83 3162
3177 TTCTAGGATGATGTTC 72 635 1245128 119 134 3213 3228
CACCAACGACTCCAAG 16 636 1245154 211 226 3305 3320 TAAGTAGTCTGCCTGC
19 637 1245180 271 286 N/A N/A TCCACACCGCGCTTAT 32 638 1245206 318
333 7607 7622 ACGCATGCGCAGTGAC 52 639 1245232 367 382 7656 7671
TGATTTAGAGAGCGAT 35 640 1245258 410 425 8804 8819 ATTATTCACCACGATT
29 641 1245284 440 455 8834 8849 GAGAAGATCGGCTGGA 6 642 1245310 484
499 8878 8893 ATGTTGACCTCAAATG 0 643 1245336 530 545 10416 10431
CATCATCGATGGAAGA 14 644 1245362 577 592 10463 10478
TGGCCGCACACTGAAG 0 645 1245388 638 653 12056 12071 GTGAAAGCCAACAGCG
62 646 1245414 696 711 12114 12129 GACATGAGGTTTTGAT 52 647 1245440
767 782 15648 15663 TGTCTCCAATACAGGC 39 648 1245466 799 814 15680
15695 ATTCCATCTATCAGAC 7 649 1245492* 867 882 N/A N/A
GAAACTTCTGTAGTCT 86 650 1245518* 931 946 20746 20761
CCAACCACTGCTTCAA 98 651 1245544* 982 997 20797 20812
GCATACATCTCTGGCT 27 652 1245570 1023 1038 20838 20853
GCTTTGCAGCATTGAT 61 653 1245596 1110 1125 20925 20940
ACAGGTAATTAATCTT 39 654 1245622 1268 1283 21083 21098
TTTAGGGAGGTAGCTT 24 655 1245648 1322 1337 21137 21152
TACTTGAACAGTCTTA 48 656 1245674 1349 1364 21164 21179
CTGTGGCATGGCTACA 66 657 1245700 1393 1408 21208 21223
TTGATCTCTTAGCTGT 74 658 1245726 1461 1476 21276 21291
CTAGGGAAATCTTTCA 48 659 1245752 1507 1522 21322 21337
TCCAGAATAGAGTTGC 46 660 1245778 1566 1581 21381 21396
AGAGGGTCCACTTTTG 34 661 1245804 1625 1640 21440 21455
AATAGAGTCGGTCACC 58 662 1245830 1728 1743 21543 21558
GCCTAAAATTGTCTAA 32 663 1245841 1765 1780 21580 21595
GTACAGTTCCTTTTCC 49 38 1245856 1780 1795 21595 21610
CTTATGTAATAGCCAG 74 664 1245882 2185 2200 22000 22015
ATGTAGTGGGAGTCGG 72 665 1245908 2256 2271 22071 22086
AACAAGAGGATAGTCC 54 666 1245934 N/A N/A 3489 3504 ACAGACTAAGGGACCA
68 667 1245960 N/A N/A 3613 3628 CCTCATTTAGCAGCTT 81 668 1245986
N/A N/A 4138 4153 CTCAAGGAGTACTTCA 82 669 1246012 N/A N/A 4644 4659
TTAATACGACTTCCTT 35 670 1246038 N/A N/A 5126 5141 GGCAAAAGGAGCCAGT
43 671 1246064 N/A N/A 5655 5670 GTTACCAGAGCATTCA 73 672 1246065
N/A N/A 5659 5674 ATAAGTTACCAGAGCA 89 48 1246090 N/A N/A 5872 5887
GCTAAACCCTGGAGCA 5 673 1246116 N/A N/A 6089 6104 CAAGTTTTCACCTCAG
93 674 1246142 N/A N/A 6357 6372 GGGAAAGAAGTCTCCT 13 675 1246168
N/A N/A 6610 6625 TCTCTAAAGCAGGCTA 60 676 1246194 N/A N/A 7770 7785
TAGCAGCTAAAATCCA 66 677 1246220 N/A N/A 7978 7993 TGCAAAGTTAATAGGA
43 678 1246246 N/A N/A 8487 8502 CTATATAAATTCTGAC 0 679 1246272 N/A
N/A 8939 8954 TAAGAGAAGGTGCACA 12 680 1246298 N/A N/A 9130 9145
GATACTGGTGGACAAG 13 681 1246324 N/A N/A 9410 9425 GTATAGCTGCATTTCT
35 682 1246350 N/A N/A 9601 9616 CATATGTGAAGAGCTG 25 683 1246376
N/A N/A 9776 9791 AACTAGAACTCCCAAC 0 684 1246402 N/A N/A 10025
10040 GGCTTTATCATTCTAA 20 685 1246428 N/A N/A 10384 10399
TAAGGATCATTGCAGA 0 686 1246454 N/A N/A 10855 10870 CCATTTACATATGGTG
28 687 1246480 N/A N/A 11469 11484 GGCAAATACAGCAGTA 64 688 1246506
N/A N/A 11792 11807 CTCTATTGATTGGCTT 65 689 1246532 N/A N/A 12168
12183 CTTACCTTGTGCTTGG 34 690 1246558 N/A N/A 12486 12501
GACTAAGGAGCTAGAT 25 691 1246584 N/A N/A 12655 12670
GCAGAATATATACTAG 55 692 1246610 N/A N/A 12799 12814
GCTGTAAGAGTCAGTA 89 693 1246636 N/A N/A 13733 13748
CTTATTAAGTACTGTG 0 694 1246662 N/A N/A 13916 13931 CCATTATCCTTACTCC
27 695 1246688 N/A N/A 14089 14104 CTACATGGATCCAACA 5 696 1246714
N/A N/A 14266 14281 GAGGAGTTAGGGAGCC 36 697 1246740 N/A N/A 14469
14484 ACAACTGGAGGTATGT 0 698 1246766 N/A N/A 15023 15038
TTGATAAAATAGGGTG 46 699 1246792 N/A N/A 15353 15368
AGGAGTAGTGGAGCCA 16 700 1246818 N/A N/A 15443 15458
TATCAGAAACTTATAC 0 701 1246844 N/A N/A 16191 16206 GAAATAACTGTTCTCC
32 702 1246870 N/A N/A 16969 16984 TCCAATATATACTGAC 72 703 1246896
N/A N/A 17930 17945 GCTGAGAGAGTATTTC 51 704 1246922 N/A N/A 18508
18523 ACACTAATTTAGTCAA 16 705 1246948 N/A N/A 18848 18863
CTTTTAACTACCCTCA 16 706 1246974 N/A N/A 19490 19505
CCATCTAGAATTAAGG 0 707 1247000 N/A N/A 19731 19746 ACTGAAGGTCTGAGCT
20 708 1247026 N/A N/A 19922 19937 CTCCAAGGAGTGCATC 53 709 1247052
N/A N/A 20359 20374 AAATTATTGCCTGAAC 32 710 1247078 N/A N/A 20484
20499 CTTCATAGTGGACTTC 79 711
TABLE-US-00010 TABLE 10 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO: 1, and 2 SEQ SEQ ID SEQ ID SEQ NO: 1
ID NO: NO: 2 ID NO: HSD17B13 SEQ Compound Start 1 Stop Start 2 Stop
(% ID Number Site Site Site Site Sequence (5' to 3') Inhibition) NO
1245077 13 28 3107 3122 GTGTAGTCCTAGGGAG 67 712 1245103 71 86 3165
3180 GATTTCTAGGATGATG 57 713 1245129 120 135 3214 3229
TCACCAACGACTCCAA 19 714 1245155 212 227 3306 3321 ATAAGTAGTCTGCCTG
43 715 1245181 272 287 N/A N/A CTCCACACCGCGCTTA 7 716 1245207 319
334 7608 7623 TACGCATGCGCAGTGA 60 717 1245233 368 383 7657 7672
CTGATTTAGAGAGCGA 61 718 1245259 411 426 8805 8820 CATTATTCACCACGAT
33 719 1245285 441 456 8835 8850 TGAGAAGATCGGCTGG 37 720 1245311
485 500 8879 8894 GATGTTGACCTCAAAT 0 721 1245337 531 546 10417
10432 CCATCATCGATGGAAG 8 722 1245363 578 593 10464 10479
GTGGCCGCACACTGAA 41 723 1245389 642 657 12060 12075
CTCTGTGAAAGCCAAC 50 724 1245415 698 713 12116 12131
GAGACATGAGGTTTTG 77 725 1245441 768 783 15649 15664
CTGTCTCCAATACAGG 29 726 1245467 801 816 15682 15697
GTATTCCATCTATCAG 52 727 1245493* 877 892 N/A N/A CGTTCAGGAAGAAACT
70 728 1245519* 932 947 20747 20762 GCCAACCACTGCTTCA 97 729
1245545* 983 998 20798 20813 TGCATACATCTCTGGC 53 730 1245571 1024
1039 20839 20854 AGCTTTGCAGCATTGA 62 731 1245597 1111 1126 20926
20941 GACAGGTAATTAATCT 60 732 1245623 1269 1284 21084 21099
TTTTAGGGAGGTAGCT 39 733 1245649 1323 1338 21138 21153
CTACTTGAACAGTCTT 80 734 1245675 1350 1365 21165 21180
TCTGTGGCATGGCTAC 67 735 1245701 1394 1409 21209 21224
CTTGATCTCTTAGCTG 51 736 1245727 1462 1477 21277 21292
GCTAGGGAAATCTTTC 66 737 1245753 1508 1523 21323 21338
GTCCAGAATAGAGTTG 60 738 1245779 1567 1582 21382 21397
TAGAGGGTCCACTTTT 36 739 1245805 1626 1641 21441 21456
AAATAGAGTCGGTCAC 59 740 1245831 1729 1744 21544 21559
AGCCTAAAATTGTCTA 53 741 1245857 1781 1796 21596 21611
TCTTATGTAATAGCCA 77 742 1245883 2186 2201 22001 22016
GATGTAGTGGGAGTCG 67 743 1245909 2257 2272 22072 22087
AAACAAGAGGATAGTC 48 744 1245935 N/A N/A 3492 3507 TATACAGACTAAGGGA
24 745 1245961 N/A N/A 3629 3644 GATAATATGTGACTTG 68 746 1245987
N/A N/A 4139 4154 TCTCAAGGAGTACTTC 80 747 1246013 N/A N/A 4645 4660
TTTAATACGACTTCCT 72 748 1246039 N/A N/A 5156 5171 CAAACTGCTACTGTGT
57 749 1246065 N/A N/A 5659 5674 ATAAGTTACCAGAGCA 91 48 1246091 N/A
N/A 5875 5890 TAGGCTAAACCCTGGA 64 750 1246117 N/A N/A 6134 6149
CTCTAATGTTTCTTGA 53 751 1246143 N/A N/A 6422 6437 TAAACTGTATGCCTCT
49 752 1246169 N/A N/A 6622 6637 CAGTAGGCAGTTTCTC 72 753 1246195
N/A N/A 7776 7791 TTCAGTTAGCAGCTAA 72 754 1246221 N/A N/A 7979 7994
CTGCAAAGTTAATAGG 57 755 1246247 N/A N/A 8529 8544 GTTTATCAGTAAAGTG
64 756 1246273 N/A N/A 8940 8955 TTAAGAGAAGGTGCAC 38 757 1246299
N/A N/A 9146 9161 GCCAAGCTTTGTGTCA 64 758 1246325 N/A N/A 9413 9428
TCTGTATAGCTGCATT 47 759 1246351 N/A N/A 9603 9618 CACATATGTGAAGAGC
71 760 1246377 N/A N/A 9780 9795 ATAGAACTAGAACTCC 22 761 1246403
N/A N/A 10058 10073 GATAATTTGGTGTCAT 59 762 1246429 N/A N/A 10385
10400 TTAAGGATCATTGCAG 14 763 1246455 N/A N/A 10931 10946
CATAAGGCCGATTCAT 32 764 1246481 N/A N/A 11482 11497
GGAAAGGATATTTGGC 58 765 1246507 N/A N/A 11793 11808
ACTCTATTGATTGGCT 57 766 1246533 N/A N/A 12178 12193
TGATTTTGACCTTACC 11 767 1246559 N/A N/A 12487 12502
TGACTAAGGAGCTAGA 31 768 1246585 N/A N/A 12685 12700
ATTAAGCTTAGTATAT 10 769 1246611 N/A N/A 12810 12825
AGCTAACTCAGGCTGT 14 770 1246637 N/A N/A 13738 13753
GCATACTTATTAAGTA 32 771 1246663 N/A N/A 13917 13932
TCCATTATCCTTACTC 15 772 1246689 N/A N/A 14090 14105
TCTACATGGATCCAAC 26 773 1246715 N/A N/A 14280 14295
TGTAAAGGCTGGGTGA 26 774 1246741 N/A N/A 14473 14488
TATGACAACTGGAGGT 14 775 1246767 N/A N/A 15024 15039
GTTGATAAAATAGGGT 42 776 1246793 N/A N/A 15354 15369
AAGGAGTAGTGGAGCC 38 777 1246819 N/A N/A 15445 15460
GTTATCAGAAACTTAT 31 778 1246845 N/A N/A 16219 16234
TTATAGACTGGGTAGG 51 779 1246871 N/A N/A 17017 17032
GTTTAGCAATTTAGCA 50 780 1246897 N/A N/A 17956 17971
ATTTAGAAACTGCTCC 21 781 1246923 N/A N/A 18521 18536
GCTTAGTACCAAGACA 62 782 1246949 N/A N/A 18849 18864
CCTTTTAACTACCCTC 22 783 1246975 N/A N/A 19533 19548
AGGCTAAAATGGTCAT 36 784 1247001 N/A N/A 19736 19751
CTAAAACTGAAGGTCT 40 785 1247027 N/A N/A 19936 19951
TAGGAACATTCCCTCT 24 786 1247053 N/A N/A 20362 20377
TCTAAATTATTGCCTG 43 787 1247079 N/A N/A 20485 20500
ACTTCATAGTGGACTT 61 788
TABLE-US-00011 TABLE 11 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO: 1, and 2 SEQ SEQ ID SEQ ID SEQ NO: 1
ID NO: NO: 2 ID NO: HSD17B13 SEQ Compound Start 1 Stop Start 2 Stop
(% ID Number Site Site Site Site Sequence (5' to 3') Inhibition) NO
1245078 14 29 3108 3123 TGTGTAGTCCTAGGGA 50 789 1245104 72 87 3166
3181 GGATTTCTAGGATGAT 58 790 1245130 121 136 3215 3230
TTCACCAACGACTCCA 62 791 1245156 213 228 3307 3322 CATAAGTAGTCTGCCT
31 792 1245182 273 288 N/A N/A CCTCCACACCGCGCTT 16 793 1245208 320
335 7609 7624 ATACGCATGCGCAGTG 38 794 1245234 369 384 7658 7673
CCTGATTTAGAGAGCG 42 795 1245260 412 427 8806 8821 GCATTATTCACCACGA
59 796 1245286 442 457 8836 8851 CTGAGAAGATCGGCTG 37 797 1245312
486 501 8880 8895 GGATGTTGACCTCAAA 5 798 1245338 532 547 10418
10433 TCCATCATCGATGGAA 31 799 1245364 579 594 10465 10480
CGTGGCCGCACACTGA 42 800 1245390 645 660 12063 12078
GACCTCTGTGAAAGCC 46 801 1245416 715 730 12133 12148
TTCACAAAAACTGGGC 37 802 1245442 769 784 15650 15665
TCTGTCTCCAATACAG 13 803 1245468 802 817 15683 15698
AGTATTCCATCTATCA 62 804 1245494* 891 906 20706 20721
AAATCGCTGAGGCGCG 89 805 1245520* 933 948 20748 20763
GGCCAACCACTGCTTC 93 806 1245546* 984 999 20799 20814
ATGCATACATCTCTGG 53 807 1245572 1025 1040 20840 20855
AAGCTTTGCAGCATTG 59 808 1245598 1112 1127 20927 20942
AGACAGGTAATTAATC 29 809 1245624 1270 1285 21085 21100
CTTTTAGGGAGGTAGC 62 810 1245650 1324 1339 21139 21154
GCTACTTGAACAGTCT 66 811 1245676 1351 1366 21166 21181
TTCTGTGGCATGGCTA 78 812 1245702 1395 1410 21210 21225
ACTTGATCTCTTAGCT 59 813 1245728 1463 1478 21278 21293
GGCTAGGGAAATCTTT 57 814 1245754 1509 1524 21324 21339
AGTCCAGAATAGAGTT 58 815 1245780 1568 1583 21383 21398
ATAGAGGGTCCACTTT 21 816 1245806 1627 1642 21442 21457
AAAATAGAGTCGGTCA 71 817 1245832 1730 1745 21545 21560
GAGCCTAAAATTGTCT 49 818 1245858 1782 1797 21597 21612
TTCTTATGTAATAGCC 71 819 1245884 2187 2202 22002 22017
TGATGTAGTGGGAGTC 65 820 1245910 2349 2364 22164 22179
CTACAAGAGGTTATTT 31 821 1245936 N/A N/A 3493 3508 ATATACAGACTAAGGG
24 822 1245962 N/A N/A 3671 3686 AAGTTATTATCCCCAC 60 823 1245988
N/A N/A 4220 4235 AACTAAACATGACAGC 72 824 1246014 N/A N/A 4646 4661
TTTTAATACGACTTCC 57 825 1246040 N/A N/A 5164 5179 ATAAGAGCCAAACTGC
49 826 1246066 N/A N/A 5660 5675 CATAAGTTACCAGAGC 80 827 1246092
N/A N/A 5878 5893 CTGTAGGCTAAACCCT 47 828 1246118 N/A N/A 6135 6150
GCTCTAATGTTTCTTG 62 829 1246144 N/A N/A 6423 6438 GTAAACTGTATGCCTC
74 830 1246170 N/A N/A 6624 6639 TACAGTAGGCAGTTTC 60 831 1246196
N/A N/A 7777 7792 CTTCAGTTAGCAGCTA 50 832 1246222 N/A N/A 8039 8054
ACTACATTAACACCAA 46 833 1246248 N/A N/A 8534 8549 TGCAAGTTTATCAGTA
70 834 1246274 N/A N/A 8941 8956 CTTAAGAGAAGGTGCA 43 835 1246300
N/A N/A 9188 9203 CTTAACAAACCTCCAC 3 836 1246326 N/A N/A 9424 9439
ATTATATGAGGTCTGT 59 837 1246352 N/A N/A 9604 9619 TCACATATGTGAAGAG
27 838 1246378 N/A N/A 9781 9796 CATAGAACTAGAACTC 19 839 1246404
N/A N/A 10059 10074 TGATAATTTGGTGTCA 3 840 1246430 N/A N/A 10386
10401 CTTAAGGATCATTGCA 29 841 1246456 N/A N/A 10971 10986
GTAATCTTGAGGCAGG 51 842 1246482 N/A N/A 11511 11526
TATTATGAGGATCTGG 44 843 1246508 N/A N/A 11853 11868
AGCAGAATTGTGAACG 67 844 1246534 N/A N/A 12194 12209
CATACCCATTCTAACT 6 845 1246560 N/A N/A 12488 12503 TTGACTAAGGAGCTAG
20 846 1246586 N/A N/A 12686 12701 CATTAAGCTTAGTATA 19 847 1246612
N/A N/A 12813 12828 CATAGCTAACTCAGGC 29 848 1246638 N/A N/A 13748
13763 CTTACATATTGCATAC 35 849 1246664 N/A N/A 13951 13966
CTAAGTTAGCCCCCAG 15 850 1246690 N/A N/A 14091 14106
ATCTACATGGATCCAA 12 851 1246716 N/A N/A 14283 14298
GAATGTAAAGGCTGGG 42 852 1246742 N/A N/A 14477 14492
GGAGTATGACAACTGG 28 853 1246768 N/A N/A 15170 15185
CGTTTAAATCAGAGCA 54 854 1246794 N/A N/A 15355 15370
TAAGGAGTAGTGGAGC 18 855 1246820 N/A N/A 15492 15507
ATTAATGCCACCCTAC 6 856 1246846 N/A N/A 16223 16238 CTTTTTATAGACTGGG
67 857 1246872 N/A N/A 17019 17034 AGGTTTAGCAATTTAG 54 858 1246898
N/A N/A 17985 18000 ATAGTTATCTTCTCAC 48 859 1246924 N/A N/A 18585
18600 TATTAATATGACTTGC 25 860 1246950 N/A N/A 18850 18865
GCCTTTTAACTACCCT 0 861 1246976 N/A N/A 19534 19549 TAGGCTAAAATGGTCA
59 862 1247002 N/A N/A 19739 19754 GATCTAAAACTGAAGG 44 863 1247028
N/A N/A 19970 19985 AATTTCATACAGTTCG 66 864 1247054 N/A N/A 20363
20378 GTCTAAATTATTGCCT 45 865 1247080 N/A N/A 20489 20504
CATAACTTCATAGTGG 31 866
TABLE-US-00012 TABLE 12 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO: 1, and 2 SEQ SEQ ID SEQ ID SEQ NO: 1
ID NO: NO: 2 ID NO: HSD17B13 SEQ Compound Start 1 Stop Start 2 Stop
(% ID Number Site Site Site Site Sequence (5' to 3') Inhibition) NO
1245079 15 30 3109 3124 TTGTGTAGTCCTAGGG 64 867 1245105 75 90 3169
3184 GAAGGATTTCTAGGAT 71 868 1245131 122 137 3216 3231
CTTCACCAACGACTCC 8 869 1245157 214 229 3308 3323 TCATAAGTAGTCTGCC
62 870 1245183 274 289 7563 7578 TCCTCCACACCGCGCT 20 871 1245209
321 336 7610 7625 CATACGCATGCGCAGT 60 872 1245235 370 385 7659 7674
ACCTGATTTAGAGAGC 65 873 1245261 413 428 8807 8822 AGCATTATTCACCACG
53 874 1245287 443 458 8837 8852 GCTGAGAAGATCGGCT 10 875 1245313
487 502 8881 8896 AGGATGTTGACCTCAA 4 876 1245339 533 548 10419
10434 CTCCATCATCGATGGA 0 877 1245365 593 608 10479 10494
GTAAGGAATCCCTTCG 22 878 1245391 646 661 12064 12079
AGACCTCTGTGAAAGC 50 879 1245417 723 738 12141 12156
ACCCAGTATTCACAAA 10 880 1245443 770 785 15651 15666
ATCTGTCTCCAATACA 55 881 1245469 803 818 15684 15699
AAGTATTCCATCTATC 52 882 1245495* 892 907 20707 20722
AAAATCGCTGAGGCGC 97 883 1245521* 934 949 20749 20764
TGGCCAACCACTGCTT 98 884 1245547* 985 1000 20800 20815
CATGCATACATCTCTG 55 885 1245573 1029 1044 20844 20859
AATAAAGCTTTGCAGC 26 886 1245599 1117 1132 20932 20947
CAGGAAGACAGGTAAT 60 887 1245625 1271 1286 21086 21101
ACTTTTAGGGAGGTAG 20 888 1245651 1325 1340 21140 21155
TGCTACTTGAACAGTC 81 889 1245677 1353 1368 21168 21183
TATTCTGTGGCATGGC 71 890 1245703 1396 1411 21211 21226
AACTTGATCTCTTAGC 64 891 1245729 1464 1479 21279 21294
AGGCTAGGGAAATCTT 62 892 1245755 1510 1525 21325 21340
AAGTCCAGAATAGAGT 60 893 1245781 1569 1584 21384 21399
TATAGAGGGTCCACTT 17 894 1245807 1628 1643 21443 21458
TAAAATAGAGTCGGTC 81 895 1245833 1731 1746 21546 21561
TGAGCCTAAAATTGTC 30 896 1245841 1765 1780 21580 21595
GTACAGTTCCTTTTCC 57 38 1245859 1784 1799 21599 21614
GTTTCTTATGTAATAG 46 897 1245885 2188 2203 22003 22018
TTGATGTAGTGGGAGT 68 898 1245911 2350 2365 22165 22180
ACTACAAGAGGTTATT 46 899 1245937 N/A N/A 3494 3509 CATATACAGACTAAGG
57 900 1245963 N/A N/A 3672 3687 TAAGTTATTATCCCCA 70 901 1245989
N/A N/A 4249 4264 CTCTAAGTGTAAGAGA 28 902 1246015 N/A N/A 4647 4662
TTTTTAATACGACTTC 52 903 1246041 N/A N/A 5165 5180 CATAAGAGCCAAACTG
27 904 1246065 N/A N/A 5659 5674 ATAAGTTACCAGAGCA 90 48 1246067 N/A
N/A 5661 5676 GCATAAGTTACCAGAG 79 905 1246093 N/A N/A 5889 5904
GTATTTCGCTACTGTA 76 906 1246119 N/A N/A 6149 6164 CCTAAGATAAAATTGC
18 907 1246145 N/A N/A 6425 6440 TGGTAAACTGTATGCC 76 908 1246171
N/A N/A 6625 6640 GTACAGTAGGCAGTTT 50 909 1246197 N/A N/A 7782 7797
AACTACTTCAGTTAGC 53 910 1246223 N/A N/A 8043 8058 GAAGACTACATTAACA
36 911 1246249 N/A N/A 8562 8577 AAATTTCAGTACCCAG 46 912 1246275
N/A N/A 8942 8957 TCTTAAGAGAAGGTGC 39 913 1246301 N/A N/A 9189 9204
CCTTAACAAACCTCCA 27 914 1246327 N/A N/A 9426 9441 CAATTATATGAGGTCT
36 915 1246353 N/A N/A 9610 9625 GCCAATTCACATATGT 34 916 1246379
N/A N/A 9887 9902 TATATGTTGATGTTAC 34 917 1246405 N/A N/A 10060
10075 ATGATAATTTGGTGTC 55 918 1246431 N/A N/A 10387 10402
TCTTAAGGATCATTGC 0 919 1246457 N/A N/A 10973 10988 TTGTAATCTTGAGGCA
27 920 1246483 N/A N/A 11512 11527 TTATTATGAGGATCTG 50 921 1246509
N/A N/A 11854 11869 AAGCAGAATTGTGAAC 18 922 1246535 N/A N/A 12201
12216 CATACCACATACCCAT 0 923 1246561 N/A N/A 12489 12504
CTTGACTAAGGAGCTA 24 924 1246587 N/A N/A 12687 12702
TCATTAAGCTTAGTAT 31 925 1246613 N/A N/A 12814 12829
ACATAGCTAACTCAGG 38 926 1246639 N/A N/A 13763 13778
GTACTATAGTATTTAC 27 927 1246665 N/A N/A 13952 13967
TCTAAGTTAGCCCCCA 36 928 1246691 N/A N/A 14092 14107
CATCTACATGGATCCA 63 929 1246717 N/A N/A 14316 14331
TTAAGATGTCCAGGCA 35 930 1246743 N/A N/A 14479 14494
AAGGAGTATGACAACT 28 931 1246769 N/A N/A 15211 15226
CATAAAGCTGGATTGT 0 932 1246795 N/A N/A 15356 15371 GTAAGGAGTAGTGGAG
37 933 1246821 N/A N/A 15493 15508 CATTAATGCCACCCTA 8 934 1246847
N/A N/A 16254 16269 AGTAGATTTGGTAGAG 67 935 1246873 N/A N/A 17041
17056 GCTTATCGAGTTTAGC 17 936 1246899 N/A N/A 17987 18002
GTATAGTTATCTTCTC 59 937 1246925 N/A N/A 18662 18677
ATACTATTCTCCAACT 25 938 1246951 N/A N/A 18871 18886
ATAAGAAGAGAGCTCA 14 939 1246977 N/A N/A 19544 19559
GTTTAGCTGATAGGCT 47 940 1247003 N/A N/A 19749 19764
TATGAGTAAAGATCTA 10 941 1247029 N/A N/A 20004 20019
GTAATCAGTTTTCCTC 79 942 1247055 N/A N/A 20373 20388
GTAAGGTAAAGTCTAA 37 943 1247081 N/A N/A 20490 20505
ACATAACTTCATAGTG 27 944
TABLE-US-00013 TABLE 13 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO: 1, and 2 SEQ SEQ ID SEQ ID SEQ NO: 1
ID NO: NO: 2 ID NO: HSD17B13 SEQ Compound Start 1 Stop Start 2 Stop
(% ID Number Site Site Site Site Sequence (5' to 3') Inhibition) NO
1245080 16 31 3110 3125 CTTGTGTAGTCCTAGG 71 945 1245106 91 106 3185
3200 ATGGTGATCAGAAGCA 85 946 1245132 123 138 3217 3232
ACTTCACCAACGACTC 15 947 1245158 215 230 3309 3324 TTCATAAGTAGTCTGC
64 948 1245184 275 290 7564 7579 TTCCTCCACACCGCGC 47 949 1245210
322 337 7611 7626 ACATACGCATGCGCAG 20 950 1245236 371 386 7660 7675
CACCTGATTTAGAGAG 11 951 1245262 416 431 8810 8825 CCCAGCATTATTCACC
19 952 1245288 444 459 8838 8853 TGCTGAGAAGATCGGC 7 953 1245314 488
503 8882 8897 TAGGATGTTGACCTCA 19 954 1245340 534 549 10420 10435
TCTCCATCATCGATGG 24 955 1245366 594 609 10480 10495
GGTAAGGAATCCCTTC 43 956 1245392 649 664 12067 12082
GTCAGACCTCTGTGAA 34 957 1245418 724 739 12142 12157
AACCCAGTATTCACAA 0 958 1245444 771 786 15652 15667 CATCTGTCTCCAATAC
32 959 1245470 804 819 15685 15700 TAAGTATTCCATCTAT 31 960 1245496*
893 908 20708 20723 TAAAATCGCTGAGGCG 87 961 1245522* 935 950 20750
20765 GTGGCCAACCACTGCT 99 962 1245548* 986 1001 20801 20816
TCATGCATACATCTCT 70 963 1245574 1055 1070 20870 20885
ATATTATCAGGACTGA 47 964 1245600 1136 1151 20951 20966
CGTAAATATTCTTGAG 61 965 1245626 1272 1287 21087 21102
TACTTTTAGGGAGGTA 28 966 1245652 1326 1341 21141 21156
ATGCTACTTGAACAGT 47 967 1245678 1354 1369 21169 21184
ATATTCTGTGGCATGG 69 968 1245704 1403 1418 21218 21233
CTGCTGAAACTTGATC 50 969 1245730 1465 1480 21280 21295
GAGGCTAGGGAAATCT 56 970 1245756 1516 1531 21331 21346
GTAATAAAGTCCAGAA 66 971 1245782 1570 1585 21385 21400
ATATAGAGGGTCCACT 18 972 1245808 1629 1644 21444 21459
TTAAAATAGAGTCGGT 65 973 1245834 1732 1747 21547 21562
TTGAGCCTAAAATTGT 36 974 1245841 1765 1780 21580 21595
GTACAGTTCCTTTTCC 58 38 1245860 1792 1807 21607 21622
GGTCCATTGTTTCTTA 36 975 1245886 2189 2204 22004 22019
CTTGATGTAGTGGGAG 83 976 1245912 2351 2366 22166 22181
AACTACAAGAGGTTAT 57 977 1245938 N/A N/A 3495 3510 ACATATACAGACTAAG
46 978 1245964 N/A N/A 3673 3688 CTAAGTTATTATCCCC 70 979 1245990
N/A N/A 4296 4311 GTATAGTATTCTTCAC 81 980 1246016 N/A N/A 4649 4664
CATTTTTAATACGACT 57 981 1246042 N/A N/A 5166 5181 GCATAAGAGCCAAACT
67 982 1246065 N/A N/A 5659 5674 ATAAGTTACCAGAGCA 87 48 1246068 N/A
N/A 5662 5677 AGCATAAGTTACCAGA 87 983 1246094 N/A N/A 5891 5906
TTGTATTTCGCTACTG 58 984 1246120 N/A N/A 6170 6185 CCTAAATTCAAAGACC
64 985 1246146 N/A N/A 6429 6444 GTAATGGTAAACTGTA 70 986 1246172
N/A N/A 6737 6752 TGAGATTACCCCTGGC 53 987 1246198 N/A N/A 7785 7800
CATAACTACTTCAGTT 3 988 1246224 N/A N/A 8121 8136 CTTAGTTCATTGTGAT
69 989 1246250 N/A N/A 8564 8579 CTAAATTTCAGTACCC 33 990 1246276
N/A N/A 8943 8958 ATCTTAAGAGAAGGTG 43 991 1246302 N/A N/A 9190 9205
CCCTTAACAAACCTCC 43 992 1246328 N/A N/A 9429 9444 AACCAATTATATGAGG
38 993 1246354 N/A N/A 9632 9647 GTGTAGTTTGGTGGGC 33 994 1246380
N/A N/A 9908 9923 CCTATTTGTAATATTG 0 995 1246406 N/A N/A 10062
10077 TTATGATAATTTGGTG 0 996 1246432 N/A N/A 10388 10403
ATCTTAAGGATCATTG 7 997 1246458 N/A N/A 10976 10991 GCATTGTAATCTTGAG
35 998 1246484 N/A N/A 11513 11528 TTTATTATGAGGATCT 43 999 1246510
N/A N/A 11856 11871 TTAAGCAGAATTGTGA 7 1000 1246536 N/A N/A 12203
12218 ATCATACCACATACCC 45 1001 1246562 N/A N/A 12501 12516
GCAGAAATTCACCTTG 74 1002 1246588 N/A N/A 12690 12705
GAATCATTAAGCTTAG 63 1003 1246614 N/A N/A 12816 12831
CCACATAGCTAACTCA 53 1004 1246640 N/A N/A 13768 13783
CAATAGTACTATAGTA 14 1005 1246666 N/A N/A 13953 13968
CTCTAAGTTAGCCCCC 38 1006 1246692 N/A N/A 14126 14141
AATTACTCCGTTCTGC 6 1007 1246718 N/A N/A 14317 14332
ATTAAGATGTCCAGGC 31 1008 1246744 N/A N/A 14480 14495
CAAGGAGTATGACAAC 6 1009 1246770 N/A N/A 15213 15228
TCCATAAAGCTGGATT 13 1010 1246796 N/A N/A 15358 15373
TGGTAAGGAGTAGTGG 34 1011 1246822 N/A N/A 15494 15509
GCATTAATGCCACCCT 36 1012 1246848 N/A N/A 16255 16270
CAGTAGATTTGGTAGA 49 1013 1246874 N/A N/A 17042 17057
AGCTTATCGAGTTTAG 54 1014 1246900 N/A N/A 17988 18003
AGTATAGTTATCTTCT 67 1015 1246926 N/A N/A 18663 18678
GATACTATTCTCCAAC 44 1016 1246952 N/A N/A 18872 18887
GATAAGAAGAGAGCTC 36 1017 1246978 N/A N/A 19549 19564
ATATTGTTTAGCTGAT 14 1018 1247004 N/A N/A 19751 19766
GATATGAGTAAAGATC 23 1019 1247030 N/A N/A 20006 20021
GAGTAATCAGTTTTCC 65 1020 1247056 N/A N/A 20374 20389
AGTAAGGTAAAGTCTA 55 1021 1247082 N/A N/A 20492 20507
TGACATAACTTCATAG 51 1022
TABLE-US-00014 TABLE 14 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO: 1, and 2 SEQ SEQ ID SEQ ID SEQ NO: 1
ID NO: NO: 2 ID NO: HSD17B13 SEQ Compound Start 1 Stop Start 2 Stop
(% ID Number Site Site Site Site Sequence (5' to 3') Inhibition) NO
1245081 17 32 3111 3126 CCTTGTGTAGTCCTAG 67 1023 1245107 92 107
3186 3201 GATGGTGATCAGAAGC 52 1024 1245133 124 139 3218 3233
AACTTCACCAACGACT 0 1025 1245159 216 231 3310 3325 ATTCATAAGTAGTCTG
35 1026 1245185 276 291 7565 7580 TTTCCTCCACACCGCG 18 1027 1245211
323 338 7612 7627 CACATACGCATGCGCA 59 1028 1245237 372 387 7661
7676 TCACCTGATTTAGAGA 13 1029 1245263 418 433 8812 8827
GTCCCAGCATTATTCA 21 1030 1245289 445 460 8839 8854 GTGCTGAGAAGATCGG
0 1031 1245315 489 504 8883 8898 CTAGGATGTTGACCTC 0 1032 1245341
535 550 10421 10436 CTCTCCATCATCGATG 0 1033 1245367 595 610 10481
10496 AGGTAAGGAATCCCTT 0 1034 1245393 650 665 12068 12083
TGTCAGACCTCTGTGA 0 1035 1245419 725 740 12143 12158
GAACCCAGTATTCACA 0 1036 1245445 777 792 15658 15673
CGACTTCATCTGTCTC 19 1037 1245471 805 820 15686 15701
GTAAGTATTCCATCTA 45 1038 1245497* 894 909 20709 20724
TTAAAATCGCTGAGGC 67 1039 1245523* 936 951 20751 20766
TGTGGCCAACCACTGC 75 1040 1245549* 987 1002 20802 20817
ATCATGCATACATCTC 62 1041 1245575 1075 1090 20890 20905
GTGCCAAACCAATGTT 43 1042 1245601 1150 1165 20965 20980
CCTATGAAAAACTACG 36 1043 1245627 1277 1292 21092 21107
GTATTTACTTTTAGGG 61 1044 1245653 1327 1342 21142 21157
AATGCTACTTGAACAG 54 1045 1245679 1355 1370 21170 21185
GATATTCTGTGGCATG 46 1046 1245705 1404 1419 21219 21234
CCTGCTGAAACTTGAT 19 1047 1245731 1466 1481 21281 21296
AGAGGCTAGGGAAATC 63 1048 1245757 1517 1532 21332 21347
AGTAATAAAGTCCAGA 43 1049 1245783 1571 1586 21386 21401
AATATAGAGGGTCCAC 7 1050 1245809 1630 1645 21445 21460
TTTAAAATAGAGTCGG 69 1051 1245835 1733 1748 21548 21563
TTTGAGCCTAAAATTG 26 1052 1245841 1765 1780 21580 21595
GTACAGTTCCTTTTCC 47 38 1245861 1793 1808 21608 21623
GGGTCCATTGTTTCTT 21 1053 1245887 2190 2205 22005 22020
TCTTGATGTAGTGGGA 44 1054 1245913 2352 2367 22167 22182
TAACTACAAGAGGTTA 22 1055 1245939 N/A N/A 3507 3522 AACTAACCTGACACAT
20 1056 1245965 N/A N/A 3674 3689 CCTAAGTTATTATCCC 18 1057 1245991
N/A N/A 4360 4375 ATACATCAACTCCTCT 64 1058 1246017 N/A N/A 4650
4665 TCATTTTTAATACGAC 48 1059 1246043 N/A N/A 5167 5182
TGCATAAGAGCCAAAC 56 1060 1246065 N/A N/A 5659 5674 ATAAGTTACCAGAGCA
84 48 1246069 N/A N/A 5663 5678 GAGCATAAGTTACCAG 61 1061 1246095
N/A N/A 5916 5931 CTTGAATGAGTGGTCT 64 1062 1246121 N/A N/A 6184
6199 CAATTTACTTTCAGCC 71 1063 1246147 N/A N/A 6437 6452
AACTAGTGGTAATGGT 32 1064 1246173 N/A N/A 6741 6756 GCAATGAGATTACCCC
83 1065 1246199 N/A N/A 7786 7801 ACATAACTACTTCAGT 28 1066 1246225
N/A N/A 8122 8137 GCTTAGTTCATTGTGA 45 1067 1246251 N/A N/A 8587
8602 GGGATAAACTGTTCTT 47 1068 1246277 N/A N/A 8944 8959
TATCTTAAGAGAAGGT 29 1069 1246303 N/A N/A 9191 9206 ACCCTTAACAAACCTC
36 1070 1246329 N/A N/A 9430 9445 TAACCAATTATATGAG 0 1071 1246355
N/A N/A 9636 9651 CTCCGTGTAGTTTGGT 28 1072 1246381 N/A N/A 9922
9937 GAATTCACTATCTCCC 38 1073 1246407 N/A N/A 10063 10078
CTTATGATAATTTGGT 2 1074 1246433 N/A N/A 10389 10404
GATCTTAAGGATCATT 0 1075 1246459 N/A N/A 11000 11015
TAAATCCAAATCACTC 39 1076 1246485 N/A N/A 11514 11529
TTTTATTATGAGGATC 18 1077 1246511 N/A N/A 11857 11872
ATTAAGCAGAATTGTG 8 1078 1246537 N/A N/A 12205 12220
TTATCATACCACATAC 19 1079 1246563 N/A N/A 12512 12527
CAAGAGTTCTTGCAGA 17 1080 1246589 N/A N/A 12692 12707
TCGAATCATTAAGCTT 34 1081 1246615 N/A N/A 12817 12832
ACCACATAGCTAACTC 50 1082 1246641 N/A N/A 13769 13784
GCAATAGTACTATAGT 39 1083 1246667 N/A N/A 13954 13969
CCTCTAAGTTAGCCCC 97 1084 1246693 N/A N/A 14127 14142
AAATTACTCCGTTCTG 28 1085 1246719 N/A N/A 14321 14336
TCAAATTAAGATGTCC 6 1086 1246745 N/A N/A 14499 14514
TGAGAATTTAAGAGGG 25 1087 1246771 N/A N/A 15217 15232
GTATTCCATAAAGCTG 10 1088 1246797 N/A N/A 15359 15374
ATGGTAAGGAGTAGTG 17 1089 1246823 N/A N/A 15495 15510
TGCATTAATGCCACCC 22 1090 1246849 N/A N/A 16257 16272
GACAGTAGATTTGGTA 34 1091 1246875 N/A N/A 17043 17058
AAGCTTATCGAGTTTA 26 1092 1246901 N/A N/A 17989 18004
TAGTATAGTTATCTTC 28 1093 1246927 N/A N/A 18666 18681
TGGGATACTATTCTCC 18 1094 1246953 N/A N/A 18873 18888
GGATAAGAAGAGAGCT 46 1095 1246979 N/A N/A 19550 19565
GATATTGTTTAGCTGA 59 1096 1247005 N/A N/A 19753 19768
CTGATATGAGTAAAGA 21 1097 1247031 N/A N/A 20008 20023
GAGAGTAATCAGTTTT 27 1098 1247057 N/A N/A 20375 20390
AAGTAAGGTAAAGTCT 20 1099 1247083 N/A N/A 20571 20586
TTTAACTTTCCTCCGT 16 1100
TABLE-US-00015 TABLE 15 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO: 1, and 2 SEQ SEQ ID SEQ ID SEQ NO: 1
ID NO: NO: 2 ID NO: HSD17B13 SEQ Compound Start 1 Stop Start 2 Stop
(% ID Number Site Site Site Site Sequence (5' to 3') Inhibition) NO
1245082 18 33 3112 3127 TCCTTGTGTAGTCCTA 61 1101 1245108 93 108
3187 3202 TGATGGTGATCAGAAG 0 1102 1245134 125 140 3219 3234
AAACTTCACCAACGAC 27 1103 1245160 217 232 3311 3326 AATTCATAAGTAGTCT
28 1104 1245186 277 292 7566 7581 GTTTCCTCCACACCGC 45 1105 1245212
324 339 7613 7628 CCACATACGCATGCGC 68 1106 1245238 373 388 N/A N/A
TTCACCTGATTTAGAG 9 1107 1245264 419 434 8813 8828 TGTCCCAGCATTATTC
31 1108 1245290 446 461 8840 8855 GGTGCTGAGAAGATCG 33 1109 1245316
490 505 8884 8899 CCTAGGATGTTGACCT 3 1110 1245342 536 551 10422
10437 TCTCTCCATCATCGAT 24 1111 1245368 596 611 10482 10497
GAGGTAAGGAATCCCT 27 1112 1245394 651 666 12069 12084
ATGTCAGACCTCTGTG 19 1113 1245420 726 741 12144 12159
TGAACCCAGTATTCAC 10 1114 1245446 778 793 15659 15674
ACGACTTCATCTGTCT 8 1115 1245472 806 821 15687 15702
GGTAAGTATTCCATCT 12 1116 1245498* 895 910 20710 20725
TTTAAAATCGCTGAGG 24 1117 1245524* 937 952 20752 20767
TTGTGGCCAACCACTG 83 1118 1245550* 988 1003 20803 20818
TATCATGCATACATCT 45 1119 1245576 1076 1091 20891 20906
AGTGCCAAACCAATGT 62 1120 1245602 1154 1169 20969 20984
CAGACCTATGAAAAAC 26 1121 1245628 1296 1311 21111 21126
GTGTAAATAAGTTCTC 61 1122 1245654 1328 1343 21143 21158
GAATGCTACTTGAACA 44 1123 1245680 1356 1371 21171 21186
TGATATTCTGTGGCAT 69 1124 1245706 1405 1420 21220 21235
GCCTGCTGAAACTTGA 18 1125 1245732 1483 1498 21298 21313
GGGCTAATGAAAAAGG 14 1126 1245758 1520 1535 21335 21350
TCAAGTAATAAAGTCC 49 1127 1245784 1572 1587 21387 21402
AAATATAGAGGGTCCA 0 1128 1245810 1631 1646 21446 21461
ATTTAAAATAGAGTCG 24 1129 1245836 1738 1753 21553 21568
TAATTTTTGAGCCTAA 41 1130 1245841 1765 1780 21580 21595
GTACAGTTCCTTTTCC 55 38 1245862 1794 1809 21609 21624
TGGGTCCATTGTTTCT 35 1131 1245888 2191 2206 22006 22021
GTCTTGATGTAGTGGG 67 1132 1245914 2353 2368 22168 22183
ATAACTACAAGAGGTT 64 1133 1245940 N/A N/A 3508 3523 TAACTAACCTGACACA
57 1134 1245966 N/A N/A 3675 3690 CCCTAAGTTATTATCC 25 1135 1245992
N/A N/A 4361 4376 TATACATCAACTCCTC 39 1136 1246018 N/A N/A 4652
4667 AGTCATTTTTAATACG 13 1137 1246044 N/A N/A 5168 5183
TTGCATAAGAGCCAAA 46 1138 1246065 N/A N/A 5659 5674 ATAAGTTACCAGAGCA
75 48 1246070 N/A N/A 5736 5751 TAGTTGGTAGCTTGCT 66 1139 1246096
N/A N/A 5918 5933 ACCTTGAATGAGTGGT 26 1140 1246122 N/A N/A 6185
6200 GCAATTTACTTTCAGC 66 1141 1246148 N/A N/A 6441 6456
TCTAAACTAGTGGTAA 24 1142 1246174 N/A N/A 6743 6758 TTGCAATGAGATTACC
29 1143 1246200 N/A N/A 7787 7802 GACATAACTACTTCAG 66 1144 1246226
N/A N/A 8133 8148 TTTGTTAGAGTGCTTA 80 1145 1246252 N/A N/A 8596
8611 CATAAAGGTGGGATAA 23 1146 1246278 N/A N/A 8945 8960
GTATCTTAAGAGAAGG 30 1147 1246304 N/A N/A 9208 9223 AAAGATGTACACTGAC
57 1148 1246330 N/A N/A 9431 9446 CTAACCAATTATATGA 21 1149 1246356
N/A N/A 9648 9663 AATGTATGAGGTCTCC 65 1150 1246382 N/A N/A 9926
9941 GATTGAATTCACTATC 0 1151 1246408 N/A N/A 10064 10079
CCTTATGATAATTTGG 29 1152 1246434 N/A N/A 10390 10405
TGATCTTAAGGATCAT 0 1153 1246460 N/A N/A 11030 11045
CATTCTAAACTACTAT 11 1154 1246486 N/A N/A 11542 11557
GACAATGGTTGCCACT 63 1155 1246512 N/A N/A 11858 11873
GATTAAGCAGAATTGT 37 1156 1246538 N/A N/A 12209 12224
CAATTTATCATACCAC 37 1157 1246564 N/A N/A 12513 12528
ACAAGAGTTCTTGCAG 29 1158 1246590 N/A N/A 12693 12708
TTCGAATCATTAAGCT 63 1159 1246616 N/A N/A 12862 12877
CACCATGAAGGACTCC 48 1160 1246642 N/A N/A 13770 13785
TGCAATAGTACTATAG 24 1161 1246668 N/A N/A 13975 13990
ATTTAGCATTGCCTGT 10 1162 1246694 N/A N/A 14128 14143
TAAATTACTCCGTTCT 36 1163 1246720 N/A N/A 14362 14377
GTGCAAGATGATGACA 19 1164 1246746 N/A N/A 14541 14556
GTATTTGAGATTCACC 41 1165 1246772 N/A N/A 15244 15259
GCTAAGTATACTTTCT 37 1166 1246798 N/A N/A 15360 15375
GATGGTAAGGAGTAGT 28 1167 1246824 N/A N/A 15496 15511
CTGCATTAATGCCACC 67 1168 1246850 N/A N/A 16272 16287
CAAAGTTTGGGCAGAG 44 1169 1246876 N/A N/A 17046 17061
AAAAAGCTTATCGAGT 8 1170 1246902 N/A N/A 17991 18006
GTTAGTATAGTTATCT 66 1171 1246928 N/A N/A 18671 18686
TTTACTGGGATACTAT 25 1172 1246954 N/A N/A 18901 18916
AGGGAAGATCTGGCTG 4 1173 1246980 N/A N/A 19563 19578
AGCTATTGTCTTTGAT 39 1174 1247006 N/A N/A 19760 19775
CTCTTATCTGATATGA 7 1175 1247032 N/A N/A 20037 20052
GCATTAAAACTCTCAT 35 1176 1247058 N/A N/A 20376 20391
CAAGTAAGGTAAAGTC 33 1177 1247084 N/A N/A 20572 20587
GTTTAACTTTCCTCCG 30 1178
TABLE-US-00016 TABLE 16 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO: 1, and 2 SEQ SEQ SEQ SEQ ID NO: ID NO:
ID NO: ID NO: 1 1 2 2 HSD17B13 SEQ Compound Start Stop Start Stop
(% ID Number Site Site Site Site Sequence (5' to 3') Inhibition) NO
1245083 19 34 3113 3128 GTCCTTGTGTAGTCCT 62 1179 1245109 98 113
3192 3207 GTAGATGATGGTGATC 36 1180 1245135 126 141 3220 3235
AAAACTTCACCAACGA 29 1181 1245161 240 255 3334 3349 CCAATATGCTCTGTCG
65 1182 1245187 278 293 7567 7582 AGTTTCCTCCACACCG 28 1183 1245213
325 340 7614 7629 ACCACATACGCATGCG 45 1184 1245239 374 389 N/A N/A
CTTCACCTGATTTAGA 7 1185 1245265 421 436 8815 8830 ACTGTCCCAGCATTAT
40 1186 1245291 452 467 8846 8861 ATCCTTGGTGCTGAGA 13 1187 1245317
491 506 8885 8900 TCCTAGGATGTTGACC 0 1188 1245343 537 552 10423
10438 TTCTCTCCATCATCGA 35 1189 1245369 597 612 10483 10498
TGAGGTAAGGAATCCC 2 1190 1245395 652 667 12070 12085
GATGTCAGACCTCTGT 6 1191 1245421 727 742 12145 12160
GTGAACCCAGTATTCA 1 1192 1245447 779 794 15660 15675
TACGACTTCATCTGTC 29 1193 1245473 807 822 15688 15703
TGGTAAGTATTCCATC 26 1194 1245499* 896 911 20711 20726
ATTTAAAATCGCTGAG 30 1195 1245525* 938 953 20753 20768
TTTGTGGCCAACCACT 88 1196 1245551* 989 1004 20804 20819
TTATCATGCATACATC 52 1197 1245577 1077 1092 20892 20907
TAGTGCCAAACCAATG 46 1198 1245603 1180 1195 20995 21010
GTTTTTAAGAGGCATG 63 1199 1245629 1298 1313 21113 21128
CTGTGTAAATAAGTTC 38 1200 1245655 1329 1344 21144 21159
GGAATGCTACTTGAAC 63 1201 1245681 1357 1372 21172 21187
TTGATATTCTGTGGCA 87 1202 1245707 1406 1421 21221 21236
TGCCTGCTGAAACTTG 31 1203 1245733 1488 1503 21303 21318
GTTTTGGGCTAATGAA 54 1204 1245759 1538 1553 21353 21368
GTTATACAGAAGACAG 54 1205 1245785 1573 1588 21388 21403
GAAATATAGAGGGTCC 22 1206 1245811 1654 1669 21469 21484
GGGCTAGAACTTAAAA 35 1207 1245837 1742 1757 21557 21572
GCTTTAATTTTTGAGC 26 1208 1245863 1795 1810 21610 21625
TTGGGTCCATTGTTTC 44 1209 1245889 2192 2207 22007 22022
AGTCTTGATGTAGTGG 63 1210 1245915 2354 2369 22169 22184
TATAACTACAAGAGGT 46 1211 1245941 N/A N/A 3509 3524 CTAACTAACCTGACAC
23 1212 1245967 N/A N/A 3703 3718 TAATTTTCAGATCCCG 75 1213 1245993
N/A N/A 4362 4377 ATATACATCAACTCCT 43 1214 1246019 N/A N/A 4991
5006 GAATTTTTGAGGTTGG 77 1215 1246045 N/A N/A 5173 5188
TTAGATTGCATAAGAG 61 1216 1246071 N/A N/A 5738 5753 TTTAGTTGGTAGCTTG
63 1217 1246097 N/A N/A 5919 5934 AACCTTGAATGAGTGG 50 1218 1246123
N/A N/A 6204 6219 CATAGGACATGGAGAC 69 1219 1246149 N/A N/A 6443
6458 ATTCTAAACTAGTGGT 39 1220 1246175 N/A N/A 6784 6799
CTCCTTATTTGTTAGA 26 1221 1246201 N/A N/A 7788 7803 TGACATAACTACTTCA
22 1222 1246227 N/A N/A 8137 8152 AAAGTTTGTTAGAGTG 75 1223 1246253
N/A N/A 8597 8612 TCATAAAGGTGGGATA 40 1224 1246279 N/A N/A 8959
8974 GTTATAAGTTTCATGT 21 1225 1246305 N/A N/A 9215 9230
GCATTGAAAAGATGTA 0 1226 1246331 N/A N/A 9476 9491 TCTATACAAAGGCAGT
53 1227 1246357 N/A N/A 9649 9664 TAATGTATGAGGTCTC 51 1228 1246383
N/A N/A 9928 9943 ATGATTGAATTCACTA 33 1229 1246409 N/A N/A 10112
10127 TAAACAATATTAAGGG 0 1230 1246435 N/A N/A 10494 10509
CCAATATGGGATGAGG 60 1231 1246461 N/A N/A 11074 11089
TTACAACCTGGTTTCA 25 1232 1246487 N/A N/A 11543 11558
TGACAATGGTTGCCAC 40 1233 1246513 N/A N/A 11859 11874
TGATTAAGCAGAATTG 57 1234 1246539 N/A N/A 12210 12225
TCAATTTATCATACCA 26 1235 1246565 N/A N/A 12514 12529
GACAAGAGTTCTTGCA 22 1236 1246591 N/A N/A 12694 12709
TTTCGAATCATTAAGC 30 1237 1246617 N/A N/A 12875 12890
ACCTATGGTCTAACAC 14 1238 1246643 N/A N/A 13771 13786
TTGCAATAGTACTATA 3 1239 1246669 N/A N/A 13976 13991
TATTTAGCATTGCCTG 12 1240 1246695 N/A N/A 14129 14144
CTAAATTACTCCGTTC 20 1241 1246721 N/A N/A 14377 14392
TAGAATTGTCTGTTAG 9 1242 1246747 N/A N/A 14542 14557
CGTATTTGAGATTCAC 59 1243 1246773 N/A N/A 15245 15260
AGCTAAGTATACTTTC 18 1244 1246799 N/A N/A 15361 15376
AGATGGTAAGGAGTAG 26 1245 1246825 N/A N/A 15511 15526
ATATTCCAGGATTTGC 26 1246 1246851 N/A N/A 16273 16288
GCAAAGTTTGGGCAGA 50 1247 1246877 N/A N/A 17047 17062
AAAAAAGCTTATCGAG 7 1248 1246903 N/A N/A 17992 18007
AGTTAGTATAGTTATC 74 1249 1246929 N/A N/A 18695 18710
AAAGACTTTGAGACTC 68 1250 1246955 N/A N/A 18925 18940
GAAAGATGGAATGAGC 54 1251 1246981 N/A N/A 19588 19603
AGGTAAACTAAAGTAC 6 1252 1247007 N/A N/A 19778 19793
CATACCACTCTTCTCA 24 1253 1247033 N/A N/A 20039 20054
ATGCATTAAAACTCTC 12 1254 1247059 N/A N/A 20377 20392
ACAAGTAAGGTAAAGT 38 1255 1247085 N/A N/A 20589 20604
AGAGTTATCTGGTTTG 56 1256
TABLE-US-00017 TABLE 17 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO: 1, and 2 SEQ SEQ SEQ SEQ ID NO: ID NO:
ID NO: ID NO: 1 1 2 2 HSD17B13 SEQ Compound Start Stop Start Stop
(% ID Number Site Site Site Site Sequence (5' to 3') Inhibition) NO
1245084 20 35 3114 3129 AGTCCTTGTGTAGTCC 64 1257 1245110 100 115
3194 3209 GAGTAGATGATGGTGA 28 1258 1245136 127 142 3221 3236
AAAAACTTCACCAACG 8 1259 1245162 241 256 3335 3350 ACCAATATGCTCTGTC
67 1260 1245188 289 304 7578 7593 CACTCAGCTGCAGTTT 13 1261 1245214
326 341 7615 7630 TACCACATACGCATGC 33 1262 1245240 375 390 N/A N/A
TCTTCACCTGATTTAG 24 1263 1245266 422 437 8816 8831 TACTGTCCCAGCATTA
21 1264 1245292 453 468 8847 8862 CATCCTTGGTGCTGAG 12 1265 1245318
492 507 8886 8901 GTCCTAGGATGTTGAC 1 1266 1245344 538 553 10424
10439 TTTCTCTCCATCATCG 27 1267 1245370 598 613 10484 10499
ATGAGGTAAGGAATCC 0 1268 1245396 654 669 12072 12087
CTGATGTCAGACCTCT 35 1269 1245422 728 743 12146 12161
GGTGAACCCAGTATTC 7 1270 1245448 780 795 15661 15676
TTACGACTTCATCTGT 36 1271 1245474 810 825 15691 15706
TATTGGTAAGTATTCC 67 1272 1245500* 897 912 20712 20727
GATTTAAAATCGCTGA 49 1273 1245526* 939 954 20754 20769
TTTTGTGGCCAACCAC 77 1274 1245552* 992 1007 20807 20822
TCATTATCATGCATAC 67 1275 1245578 1078 1093 20893 20908
CTAGTGCCAAACCAAT 49 1276 1245604 1183 1198 20998 21013
GAAGTTTTTAAGAGGC 64 1277 1245630 1299 1314 21114 21129
CCTGTGTAAATAAGTT 18 1278 1245656 1331 1346 21146 21161
TTGGAATGCTACTTGA 72 1279 1245682 1358 1373 21173 21188
GTTGATATTCTGTGGC 80 1280 1245708 1408 1423 21223 21238
GCTGCCTGCTGAAACT 38 1281 1245734 1489 1504 21304 21319
CGTTTTGGGCTAATGA 48 1282 1245760 1540 1555 21355 21370
GAGTTATACAGAAGAC 61 1283 1245786 1574 1589 21389 21404
GGAAATATAGAGGGTC 50 1284 1245812 1668 1683 21483 21498
AAAAGGTTATCATGGG 49 1285 1245838 1750 1765 21565 21580
CTGTGTTAGCTTTAAT 67 1286 1245841 1765 1780 21580 21595
GTACAGTTCCTTTTCC 61 38 1245864 1796 1811 21611 21626
CTTGGGTCCATTGTTT 44 1287 1245890 2193 2208 22008 22023
TAGTCTTGATGTAGTG 55 1288 1245916 2355 2370 22170 22185
TTATAACTACAAGAGG 68 1289 1245942 N/A N/A 3511 3526 ATCTAACTAACCTGAC
0 1290 1245968 N/A N/A 3704 3719 GTAATTTTCAGATCCC 82 1291 1245994
N/A N/A 4363 4378 TATATACATCAACTCC 61 1292 1246020 N/A N/A 5029
5044 GCTTAAATGTTTAACC 67 1293 1246046 N/A N/A 5175 5190
GTTTAGATTGCATAAG 46 1294 1246065 N/A N/A 5659 5674 ATAAGTTACCAGAGCA
88 48 1246072 N/A N/A 5739 5754 ATTTAGTTGGTAGCTT 35 1295 1246098
N/A N/A 5920 5935 AAACCTTGAATGAGTG 37 1296 1246124 N/A N/A 6205
6220 CCATAGGACATGGAGA 68 1297 1246150 N/A N/A 6444 6459
AATTCTAAACTAGTGG 31 1298 1246176 N/A N/A 6795 6810 TAAAAATTGGCCTCCT
29 1299 7104 7119 1246202 N/A N/A 7804 7819 ATATATCCTTCCTTGG 20
1300 1246228 N/A N/A 8139 8154 GTAAAGTTTGTTAGAG 54 1301 1246254 N/A
N/A 8598 8613 GTCATAAAGGTGGGAT 28 1302 1246280 N/A N/A 8960 8975
CGTTATAAGTTTCATG 33 1303 1246306 N/A N/A 9256 9271 AATCATGGTGTGGAGG
11 1304 1246332 N/A N/A 9497 9512 GGAAGATTAATCATAA 32 1305 1246358
N/A N/A 9650 9665 CTAATGTATGAGGTCT 46 1306 1246384 N/A N/A 9937
9952 TAATGAATCATGATTG 2 1307 1246410 N/A N/A 10145 10160
GAATCAAATAGATCCT 46 1308 1246436 N/A N/A 10495 10510
ACCAATATGGGATGAG 24 1309 1246462 N/A N/A 11078 11093
ATAATTACAACCTGGT 44 1310 1246488 N/A N/A 11547 11562
CTCTTGACAATGGTTG 50 1311 11572 11587 1246514 N/A N/A 11861 11876
CATGATTAAGCAGAAT 42 1312 1246540 N/A N/A 12211 12226
ATCAATTTATCATACC 11 1313 1246566 N/A N/A 12515 12530
AGACAAGAGTTCTTGC 30 1314 1246592 N/A N/A 12701 12716
AAATTGGTTTCGAATC 32 1315 1246618 N/A N/A 12889 12904
CTTTAGTCAACAGTAC 12 1316 1246644 N/A N/A 13783 13798
AACAATCAGGAGTTGC 31 1317 1246670 N/A N/A 13997 14012
CTCTATAAAATCAATC 0 1318 1246696 N/A N/A 14130 14145
TCTAAATTACTCCGTT 15 1319 1246722 N/A N/A 14378 14393
GTAGAATTGTCTGTTA 51 1320 1246748 N/A N/A 14556 14571
TCCGGTAAGAATTTCG 63 1321 1246774 N/A N/A 15246 15261
TAGCTAAGTATACTTT 10 1322 1246800 N/A N/A 15364 15379
ATTAGATGGTAAGGAG 4 1323 1246826 N/A N/A 15570 15585
GTAAATGATGGCAGGA 34 1324 1246852 N/A N/A 16274 16289
AGCAAAGTTTGGGCAG 44 1325 1246878 N/A N/A 17077 17092
AAATTAGAGGCCCAGG 43 1326 1246904 N/A N/A 17994 18009
GAAGTTAGTATAGTTA 59 1327 1246930 N/A N/A 18732 18747
CTAGTTACAAACCACC 43 1328 1246956 N/A N/A 18958 18973
AGATTTACTTCCTTGT 41 1329 1246982 N/A N/A 19590 19605
TAAGGTAAACTAAAGT 9 1330 1247008 N/A N/A 19781 19796
ATACATACCACTCTTC 18 1331 1247034 N/A N/A 20087 20102
AGTAACTTTATTAACG 12 1332 1247060 N/A N/A 20381 20396
AATCACAAGTAAGGTA 52 1333 1247086 N/A N/A 20599 20614
GAATACGCTGAGAGTT 11 1334
TABLE-US-00018 TABLE 18 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO: 1, and 2 SEQ SEQ SEQ SEQ ID NO: ID NO:
ID NO: ID NO: 1 1 2 2 HSD17B13 SEQ Compound Start Stop Start Stop
(% ID Number Site Site Site Site Sequence (5' to 3') Inhibition) NO
1245085 21 36 3115 3130 CAGTCCTTGTGTAGTC 70 1335 1245111 101 116
3195 3210 GGAGTAGATGATGGTG 31 1336 1245137 154 169 3248 3263
GCCACAGATTTTCTCC 49 1337 1245163 242 257 3336 3351 AACCAATATGCTCTGT
51 1338 1245189 290 305 7579 7594 GCACTCAGCTGCAGTT 29 1339 1245215
327 342 7616 7631 CTACCACATACGCATG 25 1340 1245241 392 407 8786
8801 TACATCACCCACTTCT 37 1341 1245267 423 438 8817 8832
ATACTGTCCCAGCATT 32 1342 1245293 454 469 8848 8863 TCATCCTTGGTGCTGA
12 1343 1245319 493 508 8887 8902 TGTCCTAGGATGTTGA 41 1344 1245345
548 563 10434 10449 GTGGCCATGATTTCTC 40 1345 1245371 599 614 10485
10500 GATGAGGTAAGGAATC 0 1346 1245397 655 670 12073 12088
TCTGATGTCAGACCTC 42 1347 1245423 729 744 12147 12162
TGGTGAACCCAGTATT 0 1348 1245449 781 796 15662 15677
CTTACGACTTCATCTG 38 1349 1245475 812 827 15693 15708
CTTATTGGTAAGTATT 22 1350 1245501* 898 913 20713 20728
CGATTTAAAATCGCTG 40 1351 1245527* 940 955 20755 20770
ATTTTGTGGCCAACCA 59 1352 1245553 996 1011 20811 20826
CATATCATTATCATGC 66 1353 1245579 1079 1094 20894 20909
GCTAGTGCCAAACCAA 70 1354 1245605 1192 1207 21007 21022
GTAAGCACAGAAGTTT 55 1355 1245631 1300 1315 21115 21130
CCCTGTGTAAATAAGT 41 1356 1245657 1332 1347 21147 21162
ATTGGAATGCTACTTG 53 1357 1245683 1359 1374 21174 21189
TGTTGATATTCTGTGG 68 1358 1245709 1412 1427 21227 21242
TAAAGCTGCCTGCTGA 44 1359 1245735 1490 1505 21305 21320
CCGTTTTGGGCTAATG 58 1360 1245761 1545 1560 21360 21375
CTTCAGAGTTATACAG 35 1361 1245787 1575 1590 21390 21405
AGGAAATATAGAGGGT 54 1362 1245813 1670 1685 21485 21500
GAAAAAGGTTATCATG 31 1363 1245839 1751 1766 21566 21581
CCTGTGTTAGCTTTAA 67 1364 1245841 1765 1780 21580 21595
GTACAGTTCCTTTTCC 58 38 1245865 1797 1812 21612 21627
TCTTGGGTCCATTGTT 60 1365 1245891 2194 2209 22009 22024
TTAGTCTTGATGTAGT 61 1366 1245917 2378 2393 22193 22208
GTTTAGAAGTCAAACG 0 1367 1245943 N/A N/A 3512 3527 CATCTAACTAACCTGA
0 1368 1245969 N/A N/A 3750 3765 TAAAGGTTTCTGTTGC 66 1369 1245995
N/A N/A 4405 4420 ATTCGAATTTCTTCAA 65 1370 1246021 N/A N/A 5042
5057 GAATCATTCAGTAGCT 65 1371 1246047 N/A N/A 5177 5192
CAGTTTAGATTGCATA 60 1372 1246065 N/A N/A 5659 5674 ATAAGTTACCAGAGCA
85 48 1246073 N/A N/A 5740 5755 GATTTAGTTGGTAGCT 63 1373 1246099
N/A N/A 5921 5936 CAAACCTTGAATGAGT 53 1374 1246125 N/A N/A 6206
6221 ACCATAGGACATGGAG 62 1375 1246151 N/A N/A 6445 6460
TAATTCTAAACTAGTG 11 1376 1246177 N/A N/A 6796 6811 ATAAAAATTGGCCTCC
41 1377 1246203 N/A N/A 7828 7843 TGGATTACATACAAGA 68 1378 1246229
N/A N/A 8140 8155 TGTAAAGTTTGTTAGA 35 1379 1246255 N/A N/A 8599
8614 TGTCATAAAGGTGGGA 48 1380 1246281 N/A N/A 8961 8976
CCGTTATAAGTTTCAT 54 1381 1246307 N/A N/A 9257 9272 AAATCATGGTGTGGAG
1 1382 1246333 N/A N/A 9499 9514 CTGGAAGATTAATCAT 31 1383 1246359
N/A N/A 9652 9667 AGCTAATGTATGAGGT 56 1384 1246385 N/A N/A 9938
9953 CTAATGAATCATGATT 20 1385 1246411 N/A N/A 10180 10195
CTAATCTCAGTACTCC 53 1386 1246437 N/A N/A 10496 10511
TACCAATATGGGATGA 1 1387 1246463 N/A N/A 11079 11094
TATAATTACAACCTGG 46 1388 1246489 N/A N/A 11548 11563
TCTCTTGACAATGGTT 70 1389 11573 11588 1246515 N/A N/A 11865 11880
CTTACATGATTAAGCA 44 1390 1246541 N/A N/A 12238 12253
GCCTAAACATTTCTCA 2 1391 1246567 N/A N/A 12516 12531
GAGACAAGAGTTCTTG 19 1392 1246593 N/A N/A 12703 12718
AAAAATTGGTTTCGAA 13 1393 1246619 N/A N/A 13551 13566
CTCTCTAAAGGGCTGC 55 1394 1246645 N/A N/A 13813 13828
TTTTATTGGGCCCAAT 18 1395 1246671 N/A N/A 14007 14022
ATCTAGCAACCTCTAT 12 1396 1246697 N/A N/A 14131 14146
TTCTAAATTACTCCGT 53 1397 1246723 N/A N/A 14380 14395
GTGTAGAATTGTCTGT 42 1398 1246749 N/A N/A 14557 14572
TTCCGGTAAGAATTTC 33 1399 1246775 N/A N/A 15248 15263
TATAGCTAAGTATACT 23 1400 1246801 N/A N/A 15365 15380
CATTAGATGGTAAGGA 32 1401 1246827 N/A N/A 15571 15586
AGTAAATGATGGCAGG 40 1402 1246853 N/A N/A 16287 16302
TAGAATAGTCTTCAGC 70 1403 1246879 N/A N/A 17135 17150
AATAGCCATGTAGCTA 28 1404 1246905 N/A N/A 17995 18010
TGAAGTTAGTATAGTT 43 1405 1246931 N/A N/A 18733 18748
CCTAGTTACAAACCAC 51 1406 1246957 N/A N/A 18962 18977
TGCAAGATTTACTTCC 45 1407 1246983 N/A N/A 19598 19613
CTCTATAATAAGGTAA 0 1408 1247009 N/A N/A 19782 19797
GATACATACCACTCTT 52 1409 1247035 N/A N/A 20110 20125
CAAGACATTCTAGCCT 58 1410 1247061 N/A N/A 20383 20398
GTAATCACAAGTAAGG 70 1411 1247087 N/A N/A 20600 20615
AGAATACGCTGAGAGT 56 1412
TABLE-US-00019 TABLE 19 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO: 1, and 2 SEQ SEQ SEQ SEQ ID NO: ID NO:
ID NO: ID NO: 1 1 2 2 HSD17B13 SEQ Compound Start Stop Start Stop
(% ID Number Site Site Site Site Sequence (5' to 3') Inhibition) NO
1245086 22 37 3116 3131 TCAGTCCTTGTGTAGT 72 1413 1245112 103 118
3197 3212 TAGGAGTAGATGATGG 15 1414 1245138 166 181 3260 3275
ACAATCTCCCCAGCCA 67 1415 1245164 243 258 3337 3352 GAACCAATATGCTCTG
61 1416 1245190 291 306 7580 7595 GGCACTCAGCTGCAGT 49 1417 1245216
328 343 7617 7632 TCTACCACATACGCAT 55 1418 1245242 393 408 8787
8802 TTACATCACCCACTTC 37 1419 1245268 424 439 8818 8833
TATACTGTCCCAGCAT 40 1420 1245294 456 471 8850 8865 CTTCATCCTTGGTGCT
30 1421 1245320 494 509 8888 8903 ATGTCCTAGGATGTTG 50 1422 1245346
551 566 10437 10452 GATGTGGCCATGATTT 9 1423 1245372 606 621 10492
10507 AATATGGGATGAGGTA 53 1424 1245398 656 671 12074 12089
TTCTGATGTCAGACCT 42 1425 1245424 730 745 12148 12163
TTGGTGAACCCAGTAT 31 1426 1245450 782 797 15663 15678
TCTTACGACTTCATCT 34 1427 1245476 813 828 15694 15709
TCTTATTGGTAAGTAT 25 1428 1245502* 899 914 20714 20729
ACGATTTAAAATCGCT 44 1429 1245528* 941 956 20756 20771
GATTTTGTGGCCAACC 91 1430 1245554 1006 1021 20821 20836
CGAAACTATTCATATC 66 1431 1245580 1080 1095 20895 20910
TGCTAGTGCCAAACCA 78 1432 1245606 1198 1213 21013 21028
GTTTATGTAAGCACAG 67 1433 1245632 1301 1316 21116 21131
TCCCTGTGTAAATAAG 35 1434 1245658 1333 1348 21148 21163
GATTGGAATGCTACTT 58 1435 1245684 1364 1379 21179 21194
GTTCTTGTTGATATTC 84 1436 1245710 1414 1429 21229 21244
GATAAAGCTGCCTGCT 42 1437 1245736 1491 1506 21306 21321
ACCGTTTTGGGCTAAT 78 1438 1245762 1547 1562 21362 21377
GACTTCAGAGTTATAC 16 1439 1245788 1589 1604 21404 21419
GACTATAAAAAGGGAG 40 1440 1245814 1702 1717 21517 21532
GACCAAGGATATATGA 48 1441 1245840 1752 1767 21567 21582
TCCTGTGTTAGCTTTA 56 1442 1245841 1765 1780 21580 21595
GTACAGTTCCTTTTCC 57 38 1245866 1798 1813 21613 21628
CTCTTGGGTCCATTGT 40 1443 1245892 2195 2210 22010 22025
ATTAGTCTTGATGTAG 67 1444 1245918 2379 2394 22194 22209
AGTTTAGAAGTCAAAC 23 1445 1245944 N/A N/A 3530 3545 TCTTAATTACATTCCC
64 1446 1245970 N/A N/A 3751 3766 CTAAAGGTTTCTGTTG 34 1447 1245996
N/A N/A 4406 4421 CATTCGAATTTCTTCA 77 1448 1246022 N/A N/A 5045
5060 AGTGAATCATTCAGTA 86 1449 1246048 N/A N/A 5178 5193
ACAGTTTAGATTGCAT 84 1450 1246065 N/A N/A 5659 5674 ATAAGTTACCAGAGCA
82 48 1246074 N/A N/A 5741 5756 TGATTTAGTTGGTAGC 79 1451 1246100
N/A N/A 5923 5938 GGCAAACCTTGAATGA 61 1452 1246126 N/A N/A 6207
6222 AACCATAGGACATGGA 71 1453 1246152 N/A N/A 6446 6461
GTAATTCTAAACTAGT 39 1454 1246178 N/A N/A 6914 6929 CTCGGGAAGTTTAGAC
47 1455 1246204 N/A N/A 7829 7844 GTGGATTACATACAAG 57 1456 1246230
N/A N/A 8141 8156 ATGTAAAGTTTGTTAG 12 1457 1246256 N/A N/A 8610
8625 CAAGGGAACACTGTCA 58 1458 1246282 N/A N/A 8962 8977
TCCGTTATAAGTTTCA 65 1459 1246308 N/A N/A 9260 9275 ACAAAATCATGGTGTG
26 1460 1246334 N/A N/A 9510 9525 ATATTGAGGCACTGGA 53 1461 1246360
N/A N/A 9653 9668 TAGCTAATGTATGAGG 48 1462 1246386 N/A N/A 9939
9954 ACTAATGAATCATGAT 39 1463 1246412 N/A N/A 10181 10196
ACTAATCTCAGTACTC 45 1464 1246438 N/A N/A 10498 10513
CTTACCAATATGGGAT 11 1465 1246464 N/A N/A 11155 11170
TGGAAACATGCTTGGC 62 1466 1246490 N/A N/A 11549 11564
TTCTCTTGACAATGGT 67 1467 11574 11589 1246516 N/A N/A 11892 11907
GTATAAATGGCAATTC 56 1468 1246542 N/A N/A 12251 12266
TATTAGTTGGCCTGCC 14 1469 1246568 N/A N/A 12598 12613
TCTTATCCACACCTTC 31 1470 1246594 N/A N/A 12704 12719
AAAAAATTGGTTTCGA 20 1471 1246620 N/A N/A 13574 13589
CTATCAGAACAGTTCA 48 1472 1246646 N/A N/A 13814 13829
TTTTTATTGGGCCCAA 51 1473 1246672 N/A N/A 14008 14023
AATCTAGCAACCTCTA 22 1474 1246698 N/A N/A 14132 14147
TTTCTAAATTACTCCG 54 1475 1246724 N/A N/A 14382 14397
TAGTGTAGAATTGTCT 46 1476 1246750 N/A N/A 14600 14615
AGAAATCTAAGAACCC 25 1477 1246776 N/A N/A 15252 15267
ATTCTATAGCTAAGTA 23 1478 1246802 N/A N/A 15366 15381
GCATTAGATGGTAAGG 64 1479 1246828 N/A N/A 15633 15648
CCATAATCTGTGATTA 9 1480 1246854 N/A N/A 16289 16304
GTTAGAATAGTCTTCA 46 1481 1246880 N/A N/A 17136 17151
GAATAGCCATGTAGCT 21 1482 1246906 N/A N/A 17996 18011
ATGAAGTTAGTATAGT 55 1483 1246932 N/A N/A 18734 18749
GCCTAGTTACAAACCA 56 1484 1246958 N/A N/A 18968 18983
GACTAATGCAAGATTT 55 1485 1246984 N/A N/A 19599 19614
ACTCTATAATAAGGTA 42 1486 1247010 N/A N/A 19785 19800
ACTGATACATACCACT 52 1487 1247036 N/A N/A 20112 20127
ATCAAGACATTCTAGC 61 1488 1247062 N/A N/A 20385 20400
TAGTAATCACAAGTAA 30 1489 1247088 N/A N/A 20601 20616
TAGAATACGCTGAGAG 47 1490
TABLE-US-00020 TABLE 20 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO: 1, and 2 SEQ SEQ SEQ SEQ ID NO: ID NO:
ID NO: ID NO: 1 1 2 2 HSD17B13 SEQ Compound Start Stop Start Stop
(% ID Number Site Site Site Site Sequence (5' to 3') Inhibition) NO
1245087 23 38 3117 3132 TTCAGTCCTTGTGTAG 45 1491 1245113 104 119
3198 3213 GTAGGAGTAGATGATG 7 1492 1245139 167 182 3261 3276
AACAATCTCCCCAGCC 59 1493 1245165 244 259 3338 3353 AGAACCAATATGCTCT
38 1494 1245191 292 307 7581 7596 CGGCACTCAGCTGCAG 55 1495 1245217
329 344 7618 7633 GTCTACCACATACGCA 66 1496 1245243 394 409 8788
8803 GTTACATCACCCACTT 41 1497 1245269 425 440 8819 8834
ATATACTGTCCCAGCA 43 1498 1245295 457 472 8851 8866 TCTTCATCCTTGGTGC
48 1499 1245321 495 510 8889 8904 AATGTCCTAGGATGTT 70 1500 1245347
552 567 10438 10453 CGATGTGGCCATGATT 44 1501 1245373 607 622 10493
10508 CAATATGGGATGAGGT 62 1502 1245399 657 672 12075 12090
GTTCTGATGTCAGACC 55 1503 1245425 731 746 12149 12164
TTTGGTGAACCCAGTA 34 1504 1245451 783 798 15664 15679
TTCTTACGACTTCATC 47 1505 1245477 835 850 15716 15731
TACGATGGAACAAAAA 20 1506 1245503* 900 915 20715 20730
TACGATTTAAAATCGC 0 1507 1245529* 942 957 20757 20772
TGATTTTGTGGCCAAC 72 1508 1245555 1007 1022 20822 20837
TCGAAACTATTCATAT 64 1509 1245581 1081 1096 20896 20911
CTGCTAGTGCCAAACC 74 1510 1245607 1202 1217 21017 21032
GTATGTTTATGTAAGC 80 1511 1245633 1305 1320 21120 21135
ACCTTCCCTGTGTAAA 60 1512 1245659 1334 1349 21149 21164
AGATTGGAATGCTACT 63 1513 1245685 1366 1381 21181 21196
GTGTTCTTGTTGATAT 81 1514 1245711 1415 1430 21230 21245
AGATAAAGCTGCCTGC 48 1515 1245737 1492 1507 21307 21322
CACCGTTTTGGGCTAA 85 1516 1245763 1548 1563 21363 21378
GGACTTCAGAGTTATA 36 1517 1245789 1599 1614 21414 21429
TATCTTATAAGACTAT 43 1518 1245815 1703 1718 21518 21533
GGACCAAGGATATATG 56 1519 1245841 1765 1780 21580 21595
GTACAGTTCCTTTTCC 67 38 1245867 1799 1814 21614 21629
TCTCTTGGGTCCATTG 63 1520 1245893 2196 2211 22011 22026
GATTAGTCTTGATGTA 65 1521 1245919 N/A N/A 3356 3371 ACCTTATTAATATCCC
71 1522 1245945 N/A N/A 3532 3547 GTTCTTAATTACATTC 64 1523 1245971
N/A N/A 3753 3768 CACTAAAGGTTTCTGT 56 1524 1245997 N/A N/A 4407
4422 TCATTCGAATTTCTTC 76 1525 1246023 N/A N/A 5046 5061
GAGTGAATCATTCAGT 87 1526 1246049 N/A N/A 5179 5194 AACAGTTTAGATTGCA
71 1527 1246075 N/A N/A 5742 5757 CTGATTTAGTTGGTAG 78 1528 1246101
N/A N/A 5928 5943 TTTAGGGCAAACCTTG 67 1529 1246127 N/A N/A 6208
6223 TAACCATAGGACATGG 70 1530 1246153 N/A N/A 6447 6462
AGTAATTCTAAACTAG 31 1531 1246179 N/A N/A 7101 7116 AAATTGGCCTCCTGGG
44 1532 1246205 N/A N/A 7846 7861 ATAATGGGCAGAGCTG 53 1533 1246231
N/A N/A 8165 8180 TTATTGTAGGGATTGA 63 1534 1246257 N/A N/A 8612
8627 GCCAAGGGAACACTGT 61 1535 1246283 N/A N/A 8975 8990
GAAGTATGTGAACTCC 56 1536 1246309 N/A N/A 9312 9327 ATTACTTCTGATGTCC
65 1537 1246335 N/A N/A 9511 9526 AATATTGAGGCACTGG 54 1538 1246361
N/A N/A 9656 9671 AGGTAGCTAATGTATG 53 1539 1246387 N/A N/A 9940
9955 CACTAATGAATCATGA 25 1540 1246413 N/A N/A 10182 10197
CACTAATCTCAGTACT 48 1541 1246439 N/A N/A 10501 10516
ATACTTACCAATATGG 0 1542 1246465 N/A N/A 11156 11171
ATGGAAACATGCTTGG 48 1543 1246491 N/A N/A 11565 11580
CAATGGTTGATAGTTT 47 1544 1246517 N/A N/A 11894 11909
GAGTATAAATGGCAAT 53 1545 1246543 N/A N/A 12252 12267
CTATTAGTTGGCCTGC 32 1546 1246569 N/A N/A 12600 12615
GTTCTTATCCACACCT 57 1547 1246595 N/A N/A 12705 12720
TAAAAAATTGGTTTCG 22 1548 1246621 N/A N/A 13575 13590
ACTATCAGAACAGTTC 62 1549 1246647 N/A N/A 13815 13830
GTTTTTATTGGGCCCA 67 1550 1246673 N/A N/A 14009 14024
CAATCTAGCAACCTCT 51 1551 1246699 N/A N/A 14166 14181
AGCAAGCCAACAGAGA 40 1552 1246725 N/A N/A 14384 14399
CTTAGTGTAGAATTGT 56 1553 1246751 N/A N/A 14614 14629
AATTATTTCTTGCGAG 16 1554 1246777 N/A N/A 15253 15268
AATTCTATAGCTAAGT 9 1555 1246803 N/A N/A 15367 15382
GGCATTAGATGGTAAG 62 1556 1246829 N/A N/A 15634 15649
GCCATAATCTGTGATT 0 1557 1246855 N/A N/A 16290 16305
AGTTAGAATAGTCTTC 67 1558 1246881 N/A N/A 17139 17154
ATTGAATAGCCATGTA 39 1559 1246907 N/A N/A 17997 18012
TATGAAGTTAGTATAG 30 1560 1246933 N/A N/A 18746 18761
TATATACCTGTTGCCT 55 1561 1246959 N/A N/A 19388 19403
ATGAGTAGGCAACTGA 61 1562 1246985 N/A N/A 19608 19623
CTATTATGCACTCTAT 32 1563 1247011 N/A N/A 19786 19801
CACTGATACATACCAC 64 1564 1247037 N/A N/A 20114 20129
GCATCAAGACATTCTA 72 1565 1247063 N/A N/A 20387 20402
TATAGTAATCACAAGT 53 1566 1247089 N/A N/A 20602 20617
TTAGAATACGCTGAGA 48 1567
TABLE-US-00021 TABLE 21 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO: 1, and 2 SEQ SEQ SEQ SEQ ID NO: ID NO:
ID NO: ID NO: 1 1 2 2 HSD17B13 SEQ Compound Start Stop Start Stop
(% ID Number Site Site Site Site Sequence (5' to 3') Inhibition) NO
1245088 24 39 3118 3133 GTTCAGTCCTTGTGTA 38 1568 1245114 105 120
3199 3214 AGTAGGAGTAGATGAT 0 1569 1245140 168 183 3262 3277
GAACAATCTCCCCAGC 63 1570 1245166 245 260 3339 3354 CAGAACCAATATGCTC
56 1571 1245192 293 308 7582 7597 TCGGCACTCAGCTGCA 52 1572 1245218
330 345 7619 7634 AGTCTACCACATACGC 65 1573 1245244 395 410 8789
8804 TGTTACATCACCCACT 35 1574 1245270 426 441 8820 8835
GATATACTGTCCCAGC 34 1575 1245296 458 473 8852 8867 CTCTTCATCCTTGGTG
25 1576 1245322 496 511 8890 8905 AAATGTCCTAGGATGT 36 1577 1245348
553 568 10439 10454 ACGATGTGGCCATGAT 52 1578 1245374 608 623 N/A
N/A ACAATATGGGATGAGG 71 1579 1245400 658 673 12076 12091
AGTTCTGATGTCAGAC 40 1580 1245426 749 764 N/A N/A TAATCTTGTGCTTGGA
54 1581 1245452 784 799 15665 15680 CTTCTTACGACTTCAT 45 1582
1245478 836 851 15717 15732 ATACGATGGAACAAAA 27 1583 1245504* 901
916 20716 20731 ATACGATTTAAAATCG 17 1584 1245530* 966 981 20781
20796 GGAGCTTATTTATTCA 38 1585 1245556 1008 1023 20823 20838
TTCGAAACTATTCATA 44 1586 1245582 1082 1097 20897 20912
GCTGCTAGTGCCAAAC 67 1587 1245608 1250 1265 21065 21080
GTCCACCTTTAAATGG 33 1588 1245634 1306 1321 21121 21136
AACCTTCCCTGTGTAA 38 1589 1245660 1335 1350 21150 21165
CAGATTGGAATGCTAC 74 1590 1245686 1367 1382 21182 21197
TGTGTTCTTGTTGATA 69 1591 1245712 1416 1431 21231 21246
GAGATAAAGCTGCCTG 67 1592 1245738 1493 1508 21308 21323
GCACCGTTTTGGGCTA 74 1593 1245764 1551 1566 21366 21381
GGTGGACTTCAGAGTT 26 1594 1245790 1600 1615 21415 21430
GTATCTTATAAGACTA 81 1595 1245816 1704 1719 21519 21534
GGGACCAAGGATATAT 17 1596 1245841 1765 1780 21580 21595
GTACAGTTCCTTTTCC 54 38 1245842 1766 1781 21581 21596
AGTACAGTTCCTTTTC 69 1597 1245868 1800 1815 21615 21630
TTCTCTTGGGTCCATT 44 1598 1245894 2197 2212 22012 22027
AGATTAGTCTTGATGT 63 1599 1245920 N/A N/A N/A N/A CACCTTATTAATATCC
34 1600 1245946 N/A N/A 3537 3552 GCTTAGTTCTTAATTA 28 1601 1245972
N/A N/A 3754 3769 GCACTAAAGGTTTCTG 75 1602 1245998 N/A N/A 4408
4423 TTCATTCGAATTTCTT 71 1603 1246024 N/A N/A 5051 5066
CCTTAGAGTGAATCAT 65 1604 1246050 N/A N/A 5180 5195 CAACAGTTTAGATTGC
66 1605 1246065 N/A N/A 5659 5674 ATAAGTTACCAGAGCA 91 48 1246076
N/A N/A 5743 5758 ACTGATTTAGTTGGTA 55 1606 1246102 N/A N/A 5929
5944 ATTTAGGGCAAACCTT 35 1607 1246128 N/A N/A 6209 6224
ATAACCATAGGACATG 70 1608 1246154 N/A N/A 6453 6468 CTAAGTAGTAATTCTA
35 1609 1246180 N/A N/A 7103 7118 AAAAATTGGCCTCCTG 41 1610 1246206
N/A N/A 7847 7862 AATAATGGGCAGAGCT 43 1611 1246232 N/A N/A 8166
8181 GTTATTGTAGGGATTG 69 1612 1246258 N/A N/A 8643 8658
CAAGACAGACTGTTGA 39 1613 1246284 N/A N/A 8976 8991 AGAAGTATGTGAACTC
41 1614 1246310 N/A N/A 9315 9330 GTAATTACTTCTGATG 41 1615 1246336
N/A N/A 9512 9527 TAATATTGAGGCACTG 33 1616 1246362 N/A N/A 9659
9674 TATAGGTAGCTAATGT 31 1617 1246388 N/A N/A 9941 9956
ACACTAATGAATCATG 7 1618 1246414 N/A N/A 10183 10198
ACACTAATCTCAGTAC 6 1619 1246440 N/A N/A 10502 10517
GATACTTACCAATATG 22 1620 1246466 N/A N/A 11210 11225
CTGTAGGTTTTGCTTC 27 1621 1246492 N/A N/A 11567 11582
GACAATGGTTGATAGT 67 1622 1246518 N/A N/A 11925 11940
GCCAAAAATCAGCCAC 11 1623 1246544 N/A N/A 12253 12268
TCTATTAGTTGGCCTG 26 1624 1246570 N/A N/A 12609 12624
AATTTTCGGGTTCTTA 35 1625 1246596 N/A N/A 12710 12725
TCCAGTAAAAAATTGG 12 1626 1246622 N/A N/A 13577 13592
CCACTATCAGAACAGT 31 1627 1246648 N/A N/A 13841 13856
ACGAAGCCTGAATGCC 52 1628 1246674 N/A N/A 14010 14025
ACAATCTAGCAACCTC 44 1629 1246700 N/A N/A 14167 14182
TAGCAAGCCAACAGAG 21 1630 1246726 N/A N/A 14390 14405
CATAGGCTTAGTGTAG 38 1631 1246752 N/A N/A 14615 14630
GAATTATTTCTTGCGA 61 1632 1246778 N/A N/A 15279 15294
TCAAAGCCTGTTGGAT 35 1633 1246804 N/A N/A 15368 15383
AGGCATTAGATGGTAA 51 1634 1246830 N/A N/A 15750 15765
TACTTACTTCTGTAGT 12 1635 1246856 N/A N/A 16291 16306
TAGTTAGAATAGTCTT 23 1636 1246882 N/A N/A 17143 17158
GTAAATTGAATAGCCA 55 1637 1246908 N/A N/A 17999 18014
CTTATGAAGTTAGTAT 43 1638 1246934 N/A N/A 18747 18762
ATATATACCTGTTGCC 28 1639 1246960 N/A N/A 19389 19404
GATGAGTAGGCAACTG 42 1640 1246986 N/A N/A 19609 19624
TCTATTATGCACTCTA 55 1641 1247012 N/A N/A 19815 19830
GTTCAAATTGGATGCA 68 1642 1247038 N/A N/A 20124 20139
TCTGATTACAGCATCA 48 1643 1247064 N/A N/A 20388 20403
CTATAGTAATCACAAG 35 1644 1247090 N/A N/A 20603 20618
TTTAGAATACGCTGAG 44 1645
TABLE-US-00022 TABLE 22 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO: 1, and 2 SEQ SEQ SEQ SEQ ID NO: ID NO:
ID NO: ID NO: 1 1 2 2 HSD17B13 SEQ Compound Start Stop Start Stop
(% ID Number Site Site Site Site Sequence (5' to 3') Inhibition) NO
1245089 25 40 3119 3134 GGTTCAGTCCTTGTGT 57 1646 1245115 106 121
3200 3215 AAGTAGGAGTAGATGA 0 1647 1245141 171 186 3265 3280
TGAGAACAATCTCCCC 69 1648 1245167 246 261 3340 3355 ACAGAACCAATATGCT
40 1649 1245193 294 309 7583 7598 TTCGGCACTCAGCTGC 41 1650 1245219
354 369 7643 7658 GATAGATCTCTTCTCT 0 1651 1245245 396 411 8790 8805
TTGTTACATCACCCAC 34 1652 1245271 427 442 8821 8836 GGATATACTGTCCCAG
9 1653 1245297 464 479 8858 8873 GGTAATCTCTTCATCC 9 1654 1245323
497 512 8891 8906 AAAATGTCCTAGGATG 0 1655 1245349 554 569 10440
10455 GACGATGTGGCCATGA 42 1656 1245375 609 624 N/A N/A
AACAATATGGGATGAG 39 1657 1245401 659 674 12077 12092
AAGTTCTGATGTCAGA 7 1658 1245427 750 765 N/A N/A ATAATCTTGTGCTTGG 36
1659 1245453 785 800 15666 15681 ACTTCTTACGACTTCA 43 1660 1245479
837 852 15718 15733 TATACGATGGAACAAA 4 1661 1245505* 902 917 20717
20732 CATACGATTTAAAATC 13 1662 1245531* 967 982 20782 20797
TGGAGCTTATTTATTC 39 1663 1245557 1009 1024 20824 20839
ATTCGAAACTATTCAT 24 1664 1245583 1083 1098 20898 20913
TGCTGCTAGTGCCAAA 58 1665 1245609 1251 1266 21066 21081
TGTCCACCTTTAAATG 29 1666 1245635 1307 1322 21122 21137
AAACCTTCCCTGTGTA 34 1667 1245661 1336 1351 21151 21166
ACAGATTGGAATGCTA 50 1668 1245687 1379 1394 21194 21209
GTGCACTCATTCTGTG 6 1669 1245713 1418 1433 21233 21248
TTGAGATAAAGCTGCC 49 1670 1245739 1494 1509 21309 21324
TGCACCGTTTTGGGCT 36 1671 1245765 1552 1567 21367 21382
TGGTGGACTTCAGAGT 17 1672 1245791 1601 1616 21416 21431
TGTATCTTATAAGACT 45 1673 1245817 1705 1720 21520 21535
TGGGACCAAGGATATA 20 1674 1245841 1765 1780 21580 21595
GTACAGTTCCTTTTCC 48 38 1245843 1767 1782 21582 21597
CAGTACAGTTCCTTTT 43 1675 1245869 1801 1816 21616 21631
CTTCTCTTGGGTCCAT 51 1676 1245895 2198 2213 22013 22028
AAGATTAGTCTTGATG 25 1677 1245921 N/A N/A N/A N/A TCACCTTATTAATATC 0
1678 1245947 N/A N/A 3546 3561 AAAATCGCTGCTTAGT 35 1679 1245973 N/A
N/A 3755 3770 GGCACTAAAGGTTTCT 62 1680 1245999 N/A N/A 4409 4424
GTTCATTCGAATTTCT 76 1681 1246025 N/A N/A 5053 5068 AGCCTTAGAGTGAATC
74 1682 1246051 N/A N/A 5187 5202 CCCAACGCAACAGTTT 66 1683 1246065
N/A N/A 5659 5674 ATAAGTTACCAGAGCA 84 48 1246077 N/A N/A 5759 5774
AATAGGAGAGTCTTTC 47 1684 1246103 N/A N/A 5930 5945 TATTTAGGGCAAACCT
40 1685 1246129 N/A N/A 6210 6225 CATAACCATAGGACAT 41 1686 1246155
N/A N/A 6454 6469 GCTAAGTAGTAATTCT 57 1687 1246181 N/A N/A 7119
7134 GATTAGTTAACCTTTT 58 1688 1246207 N/A N/A 7848 7863
TAATAATGGGCAGAGC 30 1689 1246233 N/A N/A 8171 8186 ACAGAGTTATTGTAGG
58 1690 1246259 N/A N/A 8670 8685 ATTGTATGAGGTCTCT 49 1691 1246285
N/A N/A 8977 8992 CAGAAGTATGTGAACT 22 1692 1246311 N/A N/A 9329
9344 CTATATACATCCAAGT 6 1693 1246337 N/A N/A 9513 9528
CTAATATTGAGGCACT 51 1694 1246363 N/A N/A 9661 9676 GCTATAGGTAGCTAAT
20 1695 1246389 N/A N/A 9942 9957 CACACTAATGAATCAT 30 1696 1246415
N/A N/A 10185 10200 CAACACTAATCTCAGT 4 1697 1246441 N/A N/A 10520
10535 ATAACATGGCTGGCAT 14 1698 1246467 N/A N/A 11235 11250
CATAGACATGTGTTCA 52 1699 1246493 N/A N/A 11568 11583
TGACAATGGTTGATAG 16 1700 1246519 N/A N/A 11953 11968
GTATCATTTGGCTTAA 29 1701 1246545 N/A N/A 12254 12269
TTCTATTAGTTGGCCT 28 1702 1246571 N/A N/A 12610 12625
TAATTTTCGGGTTCTT 40 1703 1246597 N/A N/A 12723 12738
GGATTAATTCCCTTCC 10 1704 1246623 N/A N/A 13594 13609
GATAGAGCACATGGCC 20 1705 1246649 N/A N/A 13842 13857
CACGAAGCCTGAATGC 24 1706 1246675 N/A N/A 14011 14026
CACAATCTAGCAACCT 40 1707 1246701 N/A N/A 14170 14185
GAATAGCAAGCCAACA 64 1708 1246727 N/A N/A 14391 14406
ACATAGGCTTAGTGTA 0 1709 1246753 N/A N/A 14616 14631
CGAATTATTTCTTGCG 58 1710 1246779 N/A N/A 15280 15295
CTCAAAGCCTGTTGGA 10 1711 1246805 N/A N/A 15380 15395
AAAATGGTGGCGAGGC 0 1712 1246831* N/A N/A 15751 15766
GTACTTACTTCTGTAG 0 1713 1246857 N/A N/A 16292 16307
TTAGTTAGAATAGTCT 8 1714 1246883 N/A N/A 17144 17159
AGTAAATTGAATAGCC 39 1715 1246909 N/A N/A 18000 18015
GCTTATGAAGTTAGTA 67 1716 1246935 N/A N/A 18798 18813
CGTAAAATTGTGTCTC 43 1717 1246961 N/A N/A 19397 19412
GCATAAGAGATGAGTA 33 1718 1246987 N/A N/A 19610 19625
ATCTATTATGCACTCT 24 1719 1247013 N/A N/A 19819 19834
CATAGTTCAAATTGGA 39 1720 1247039 N/A N/A 20138 20153
GGGAAAAAGTGTGTTC 20 1721 1247065 N/A N/A 20395 20410
GTAATTGCTATAGTAA 33 1722 1247091 N/A N/A 20604 20619
ATTTAGAATACGCTGA 19 1723
TABLE-US-00023 TABLE 23 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO: 1, and 2 SEQ SEQ SEQ SEQ ID NO: ID NO:
ID NO: ID NO: 1 1 2 2 HSD17B13 SEQ Compound Start Stop Start Stop
(% ID Number Site Site Site Site Sequence (5' to 3') Inhibition) NO
1245090 26 41 3120 3135 TGGTTCAGTCCTTGTG 50 1724 1245116 107 122
3201 3216 CAAGTAGGAGTAGATG 5 1725 1245142 172 187 3266 3281
ATGAGAACAATCTCCC 65 1726 1245168 247 262 3341 3356 CACAGAACCAATATGC
54 1727 1245194 295 310 7584 7599 TTTCGGCACTCAGCTG 29 1728 1245220
355 370 7644 7659 CGATAGATCTCTTCTC 15 1729 1245246 398 413 8792
8807 GATTGTTACATCACCC 65 1730 1245272 428 443 8822 8837
TGGATATACTGTCCCA 24 1731 1245298 465 480 8859 8874 TGGTAATCTCTTCATC
23 1732 1245324 500 515 8894 8909 CCAAAAATGTCCTAGG 38 1733 1245350
557 572 10443 10458 TGTGACGATGTGGCCA 42 1734 1245376 610 625 N/A
N/A GAACAATATGGGATGA 26 1735 1245402 660 675 12078 12093
GAAGTTCTGATGTCAG 0 1736 1245428 751 766 N/A N/A CATAATCTTGTGCTTG 37
1737 1245454 786 801 15667 15682 GACTTCTTACGACTTC 38 1738 1245480
838 853 15719 15734 ATATACGATGGAACAA 0 1739 1245506* 903 918 20718
20733 GCATACGATTTAAAAT 0 1740 1245532* 969 984 20784 20799
GCTGGAGCTTATTTAT 16 1741 1245558 1010 1025 20825 20840
GATTCGAAACTATTCA 57 1742 1245584 1084 1099 20899 20914
CTGCTGCTAGTGCCAA 57 1743 1245610 1256 1271 21071 21086
GCTTTTGTCCACCTTT 68 1744 1245636 1308 1323 21123 21138
TAAACCTTCCCTGTGT 17 1745 1245662 1337 1352 21152 21167
TACAGATTGGAATGCT 46 1746 1245688 1380 1395 21195 21210
TGTGCACTCATTCTGT 18 1747 1245714 1419 1434 21234 21249
GTTGAGATAAAGCTGC 54 1748 1245740 1495 1510 21310 21325
TTGCACCGTTTTGGGC 45 1749 1245766 1553 1568 21368 21383
TTGGTGGACTTCAGAG 8 1750 1245792 1602 1617 21417 21432
ATGTATCTTATAAGAC 0 1751 1245818 1706 1721 21521 21536
CTGGGACCAAGGATAT 32 1752 1245841 1765 1780 21580 21595
GTACAGTTCCTTTTCC 50 38 1245844 1768 1783 21583 21598
CCAGTACAGTTCCTTT 66 1753 1245870 1802 1817 21617 21632
TCTTCTCTTGGGTCCA 59 1754 1245896 2199 2214 22014 22029
CAAGATTAGTCTTGAT 27 1755 1245922 N/A N/A 3357 3372 TACCTTATTAATATCC
54 1756 1245948 N/A N/A 3547 3562 AAAAATCGCTGCTTAG 25 1757 1245974
N/A N/A 3834 3849 GACTACGGACTGGCAA 60 1758 1246000 N/A N/A 4414
4429 AGAAAGTTCATTCGAA 61 1759 1246026 N/A N/A 5057 5072
TTACAGCCTTAGAGTG 21 1760 1246052 N/A N/A 5200 5215 TTTGAACCGTATTCCC
69 1761 1246065 N/A N/A 5659 5674 ATAAGTTACCAGAGCA 77 48 1246078
N/A N/A 5760 5775 GAATAGGAGAGTCTTT 58 1762 1246104 N/A N/A 5955
5970 ATTGAGATGACAGTGG 70 1763 1246130 N/A N/A 6211 6226
CCATAACCATAGGACA 63 1764 1246156 N/A N/A 6455 6470 TGCTAAGTAGTAATTC
32 1765 1246182 N/A N/A 7121 7136 AAGATTAGTTAACCTT 24 1766 1246208
N/A N/A 7851 7866 CAATAATAATGGGCAG 43 1767 1246234 N/A N/A 8205
8220 GAGTCATAATTTGCTT 57 1768 1246260 N/A N/A 8672 8687
CTATTGTATGAGGTCT 42 1769 1246286 N/A N/A 8978 8993 CCAGAAGTATGTGAAC
8 1770 1246312 N/A N/A 9330 9345 CCTATATACATCCAAG 53 1771 1246338
N/A N/A 9514 9529 ACTAATATTGAGGCAC 19 1772 1246364 N/A N/A 9662
9677 AGCTATAGGTAGCTAA 0 1773 1246390 N/A N/A 9943 9958
CCACACTAATGAATCA 43 1774 1246416 N/A N/A 10202 10217
TATGGTAAGCCCCATG 30 1775 1246442 N/A N/A 10522 10537
ATATAACATGGCTGGC 29 1776 1246468 N/A N/A 11236 11251
ACATAGACATGTGTTC 35 1777 1246494 N/A N/A 11590 11605
CTCAATAACTGAGTTA 4 1778 1246520 N/A N/A 11962 11977
GAGAAGGCGGTATCAT 48 1779 1246546 N/A N/A 12255 12270
CTTCTATTAGTTGGCC 11 1780 1246572 N/A N/A 12611 12626
TTAATTTTCGGGTTCT 31 1781 1246598 N/A N/A 12724 12739
AGGATTAATTCCCTTC 19 1782 1246624 N/A N/A 13595 13610
GGATAGAGCACATGGC 33 1783 1246650 N/A N/A 13845 13860
GTACACGAAGCCTGAA 42 1784 1246676 N/A N/A 14012 14027
TCACAATCTAGCAACC 4 1785 1246702 N/A N/A 14171 14186
TGAATAGCAAGCCAAC 4 1786 1246728 N/A N/A 14393 14408
AAACATAGGCTTAGTG 16 1787 1246754 N/A N/A 14724 14739
AATACCCTTGGTGGAG 16 1788 1246780 N/A N/A 15312 15327
TAATCATGGGACAGGA 15 1789 1246806 N/A N/A 15381 15396
CAAAATGGTGGCGAGG 10 1790 1246832 N/A N/A 15771 15786
GTATTTGGGTGTTCTG 36 1791 1246858 N/A N/A 16293 16308
TTTAGTTAGAATAGTC 15 1792 1246884 N/A N/A 17227 17242
GTACAAATTTATGCCA 45 1793 1246910 N/A N/A 18001 18016
GGCTTATGAAGTTAGT 59 1794 1246936 N/A N/A 18812 18827
TAATTGCATCTGCTCG 46 1795 1246962 N/A N/A 19398 19413
TGCATAAGAGATGAGT 19 1796 1246988 N/A N/A 19611 19626
TATCTATTATGCACTC 48 1797 1247014 N/A N/A 19820 19835
TCATAGTTCAAATTGG 47 1798 1247040 N/A N/A 20172 20187
CAATTATGAATCTGCA 25 1799 1247066 N/A N/A 20396 20411
AGTAATTGCTATAGTA 48 1800 1247092 N/A N/A 20605 20620
CATTTAGAATACGCTG 25 1801
TABLE-US-00024 TABLE 24 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO: 1, and 2 SEQ SEQ SEQ SEQ ID NO: ID NO:
ID NO: ID NO: 1 1 2 2 HSD17B13 SEQ Compound Start Stop Start Stop
(% ID Number Site Site Site Site Sequence (5' to 3') Inhibition) NO
1245091 27 42 3121 3136 CTGGTTCAGTCCTTGT 63 1802 1245117 108 123
3202 3217 CCAAGTAGGAGTAGAT 19 1803 1245143 175 190 3269 3284
GTAATGAGAACAATCT 48 1804 1245169 248 263 3342 3357 CCACAGAACCAATATG
49 1805 1245195 296 311 7585 7600 TTTTCGGCACTCAGCT 13 1806 1245221
356 371 7645 7660 GCGATAGATCTCTTCT 24 1807 1245247 399 414 8793
8808 CGATTGTTACATCACC 47 1808 1245273 429 444 8823 8838
CTGGATATACTGTCCC 20 1809 1245299 469 484 8863 8878 GTCTTGGTAATCTCTT
37 1810 1245325 511 526 N/A N/A GCTTTTGTGATCCAAA 43 1811 1245351
558 573 10444 10459 CTGTGACGATGTGGCC 28 1812 1245377 611 626 N/A
N/A GGAACAATATGGGATG 36 1813 1245403 665 680 12083 12098
GGCCTGAAGTTCTGAT 0 1814 1245429 752 767 N/A N/A CCATAATCTTGTGCTT 32
1815 1245455 787 802 15668 15683 AGACTTCTTACGACTT 41 1816 1245481
839 854 15720 15735 GATATACGATGGAACA 46 1817 1245507* 904 919 20719
20734 TGCATACGATTTAAAA 18 1818 1245533* 970 985 20785 20800
GGCTGGAGCTTATTTA 57 1819 1245559 1011 1026 20826 20841
TGATTCGAAACTATTC 29 1820 1245585 1085 1100 20900 20915
ACTGCTGCTAGTGCCA 47 1821 1245611 1257 1272 21072 21087
AGCTTTTGTCCACCTT 57 1822 1245637 1310 1325 21125 21140
CTTAAACCTTCCCTGT 22 1823 1245663 1338 1353 21153 21168
CTACAGATTGGAATGC 52 1824 1245689 1381 1396 21196 21211
CTGTGCACTCATTCTG 51 1825 1245715 1420 1435 21235 21250
GGTTGAGATAAAGCTG 76 1826 1245741 1496 1511 21311 21326
GTTGCACCGTTTTGGG 56 1827 1245767 1554 1569 21369 21384
TTTGGTGGACTTCAGA 16 1828 1245793 1613 1628 21428 21443
CACCTTTCATAATGTA 59 1829 1245819 1707 1722 21522 21537
TCTGGGACCAAGGATA 30 1830 1245841 1765 1780 21580 21595
GTACAGTTCCTTTTCC 50 38 1245845 1769 1784 21584 21599
GCCAGTACAGTTCCTT 61 1831 1245871 2174 2189 21989 22004
GTCGGATTATTTTTTC 61 1832 1245897 2200 2215 22015 22030
ACAAGATTAGTCTTGA 45 1833 1245923 N/A N/A 3368 3383 GATGTATACATTACCT
67 1834 1245949 N/A N/A 3549 3564 ATAAAAATCGCTGCTT 11 1835 1245975
N/A N/A 3877 3892 ATCATATGCTAAGTGC 73 1836 1246001 N/A N/A 4415
4430 CAGAAAGTTCATTCGA 67 1837 1246027 N/A N/A 5061 5076
TACATTACAGCCTTAG 75 1838 1246053 N/A N/A 5204 5219 GTTTTTTGAACCGTAT
71 1839 1246065 N/A N/A 5659 5674 ATAAGTTACCAGAGCA 74 48 1246079
N/A N/A 5761 5776 AGAATAGGAGAGTCTT 64 1840 1246105 N/A N/A 5957
5972 GTATTGAGATGACAGT 68 1841 1246131 N/A N/A 6212 6227
CCCATAACCATAGGAC 47 1842 1246157 N/A N/A 6464 6479 GCAGTAAAGTGCTAAG
83 1843 1246183 N/A N/A 7122 7137 GAAGATTAGTTAACCT 13 1844 1246209
N/A N/A 7938 7953 CATATTCCCTGATGAT 14 1845 1246235 N/A N/A 8238
8253 AACTACATGACCTGGG 27 1846 1246261 N/A N/A 8674 8689
TTCTATTGTATGAGGT 0 1847 1246287 N/A N/A 8980 8995 GTCCAGAAGTATGTGA
9 1848 1246313 N/A N/A 9331 9346 TCCTATATACATCCAA 45 1849 1246339
N/A N/A 9515 9530 CACTAATATTGAGGCA 31 1850 1246365 N/A N/A 9663
9678 CAGCTATAGGTAGCTA 0 1851 1246391 N/A N/A 9966 9981
TAGTGTAAGCTGAGAG 75 1852 1246417 N/A N/A 10203 10218
GTATGGTAAGCCCCAT 36 1853 1246443 N/A N/A 10523 10538
TATATAACATGGCTGG 8 1854 1246469 N/A N/A 11238 11253
TGACATAGACATGTGT 42 1855 1246495 N/A N/A 11621 11636
CTGTAGGACTCTGCTC 48 1856 1246521 N/A N/A 11963 11978
TGAGAAGGCGGTATCA 20 1857 1246547 N/A N/A 12337 12352
CCCTAATGTGTTTTCC 25 1858 1246573 N/A N/A 12612 12627
CTTAATTTTCGGGTTC 37 1859 1246599 N/A N/A 12725 12740
TAGGATTAATTCCCTT 0 1860 1246625 N/A N/A 13601 13616
AATACAGGATAGAGCA 0 1861 1246651 N/A N/A 13859 13874
TAGGAAAGCTCATGGT 27 1862 1246677 N/A N/A 14018 14033
GGAAATTCACAATCTA 22 1863 1246703 N/A N/A 14172 14187
TTGAATAGCAAGCCAA 31 1864 1246729 N/A N/A 14394 14409
TAAACATAGGCTTAGT 34 1865 1246755 N/A N/A 14726 14741
TAAATACCCTTGGTGG 7 1866 1246781 N/A N/A 15313 15328
TTAATCATGGGACAGG 27 1867 1246807 N/A N/A 15382 15397
TCAAAATGGTGGCGAG 31 1868 1246833 N/A N/A 15772 15787
AGTATTTGGGTGTTCT 17 1869 1246859 N/A N/A 16327 16342
TCACTATATTGCATTC 35 1870 1246885 N/A N/A 17239 17254
AGGGAATGTTATGTAC 49 1871 1246911 N/A N/A 18012 18027
AAAAGGCCCAAGGCTT 30 1872 1246937 N/A N/A 18813 18828
GTAATTGCATCTGCTC 51 1873 1246963 N/A N/A 19399 19414
ATGCATAAGAGATGAG 30 1874 1246989 N/A N/A 19649 19664
CTATGCAAGCCTTCAC 19 1875 1247015 N/A N/A 19827 19842
GTAATATTCATAGTTC 49 1876 1247041 N/A N/A 20173 20188
CCAATTATGAATCTGC 61 1877 1247067 N/A N/A 20397 20412
TAGTAATTGCTATAGT 7 1878 1247093 N/A N/A 20606 20621
TCATTTAGAATACGCT 20 1879
TABLE-US-00025 TABLE 25 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO: 1, and 2 SEQ SEQ SEQ SEQ ID NO: ID NO:
ID NO: ID NO: 1 1 2 2 HSD17B13 SEQ Compound Start Stop Start Stop
(% ID Number Site Site Site Site Sequence (5' to 3') Inhibition) NO
1245092 31 46 3125 3140 CCTTCTGGTTCAGTCC 72 1880 1245118 109 124
3203 3218 TCCAAGTAGGAGTAGA 24 1881 1245144 176 191 3270 3285
AGTAATGAGAACAATC 45 1882 1245170 249 264 3343 3358 CCCACAGAACCAATAT
16 1883 1245196 297 312 7586 7601 GTTTTCGGCACTCAGC 51 1884 1245222
357 372 7646 7661 AGCGATAGATCTCTTC 31 1885 1245248 400 415 8794
8809 ACGATTGTTACATCAC 53 1886 1245274 430 445 8824 8839
GCTGGATATACTGTCC 36 1887 1245300 471 486 8865 8880 ATGTCTTGGTAATCTC
23 1888 1245326 513 528 N/A N/A GTGCTTTTGTGATCCA 62 1889 1245352
559 574 10445 10460 ACTGTGACGATGTGGC 40 1890 1245378 612 627 N/A
N/A TGGAACAATATGGGAT 46 1891 1245404 667 682 12085 12100
AAGGCCTGAAGTTCTG 5 1892 1245430 755 770 N/A N/A AGGCCATAATCTTGTG 33
1893 1245456 788 803 15669 15684 CAGACTTCTTACGACT 33 1894 1245482
840 855 15721 15736 TGATATACGATGGAAC 13 1895 1245508* 905 920 20720
20735 CTGCATACGATTTAAA 32 1896 1245534* 971 986 20786 20801
TGGCTGGAGCTTATTT 87 1897 1245560 1012 1027 20827 20842
TTGATTCGAAACTATT 55 1898 1245586 1086 1101 20901 20916
GACTGCTGCTAGTGCC 67 1899 1245612 1258 1273 21073 21088
TAGCTTTTGTCCACCT 60 1900 1245638 1312 1327 21127 21142
GTCTTAAACCTTCCCT 63 1901 1245664 1339 1354 21154 21169
GCTACAGATTGGAATG 47 1902 1245690 1383 1398 21198 21213
AGCTGTGCACTCATTC 57 1903 1245716 1421 1436 21236 21251
AGGTTGAGATAAAGCT 74 1904 1245742 1497 1512 21312 21327
AGTTGCACCGTTTTGG 55 1905 1245768 1556 1571 21371 21386
CTTTTGGTGGACTTCA 10 1906 1245794 1615 1630 21430 21445
GTCACCTTTCATAATG 45 1907 1245820 1708 1723 21523 21538
CTCTGGGACCAAGGAT 51 1908 1245841 1765 1780 21580 21595
GTACAGTTCCTTTTCC 55 38 1245846 1770 1785 21585 21600
AGCCAGTACAGTTCCT 58 1909 1245872 2175 2190 21990 22005
AGTCGGATTATTTTTT 42 1910 1245898 2201 2216 22016 22031
AACAAGATTAGTCTTG 40 1911 1245924 N/A N/A 3401 3416 CATATCTTACTCTGTG
47 1912 1245950 N/A N/A 3550 3565 CATAAAAATCGCTGCT 45 1913 1245976
N/A N/A 3882 3897 CGTTTATCATATGCTA 88 1914 1246002 N/A N/A 4416
4431 CCAGAAAGTTCATTCG 81 1915 1246028 N/A N/A 5062 5077
TTACATTACAGCCTTA 67 1916 1246054 N/A N/A 5218 5233 TTAAACTCCAATGTGT
36 1917 1246065 N/A N/A 5659 5674 ATAAGTTACCAGAGCA 82 48 1246080
N/A N/A 5800 5815 CTCAAATAGCCTTTTG 64 1918 1246106 N/A N/A 5979
5994 CCTGAAAAGCCCTATT 0 1919 1246132 N/A N/A 6222 6237
ACCAAACTTGCCCATA 46 1920 1246158 N/A N/A 6465 6480 GGCAGTAAAGTGCTAA
62 1921 1246184 N/A N/A 7123 7138 TGAAGATTAGTTAACC 21 1922 1246210
N/A N/A 7941 7956 ATCCATATTCCCTGAT 26 1923 1246236 N/A N/A 8239
8254 TAACTACATGACCTGG 37 1924 1246262 N/A N/A 8688 8703
GATGAGAGTCTTTCTT 26 1925 1246288 N/A N/A 9000 9015 AAAGATCTGGCCAGTT
3 1926 1246314 N/A N/A 9332 9347 ATCCTATATACATCCA 76 1927 1246340
N/A N/A 9516 9531 ACACTAATATTGAGGC 68 1928 1246366 N/A N/A 9712
9727 GAACATACATTGTTGC 58 1929 1246392 N/A N/A 9972 9987
GTTGAGTAGTGTAAGC 53 1930 1246418 N/A N/A 10209 10224
TTATTGGTATGGTAAG 14 1931 1246444 N/A N/A 10728 10743
GTAATTGGCTCTTGAG 44 1932 1246470 N/A N/A 11239 11254
ATGACATAGACATGTG 23 1933 1246496 N/A N/A 11652 11667
CTACAAAACTGGTATC 0 1934 1246522 N/A N/A 11982 11997
ACCAATCCTCAGCTTT 11 1935 1246548 N/A N/A 12353 12368
GATCATTCCTGCTAGT 35 1936 1246574 N/A N/A 12613 12628
GCTTAATTTTCGGGTT 36 1937 1246600 N/A N/A 12726 12741
TTAGGATTAATTCCCT 14 1938 1246626 N/A N/A 13603 13618
ACAATACAGGATAGAG 23 1939 1246652 N/A N/A 13860 13875
TTAGGAAAGCTCATGG 26 1940 1246678 N/A N/A 14026 14041
CTTACTAAGGAAATTC 19 1941 1246704 N/A N/A 14174 14189
CCTTGAATAGCAAGCC 61 1942 1246730 N/A N/A 14395 14410
ATAAACATAGGCTTAG 41 1943 1246756 N/A N/A 14728 14743
TCTAAATACCCTTGGT 26 1944 1246782 N/A N/A 15314 15329
ATTAATCATGGGACAG 20 1945 1246808 N/A N/A 15383 15398
ATCAAAATGGTGGCGA 20 1946 1246834 N/A N/A 15773 15788
TAGTATTTGGGTGTTC 27 1947 1246860 N/A N/A 16377 16392
ACCAAACTTCCAGCAG 31 1948 1246886 N/A N/A 17675 17690
CAAAACCTTTGTTGCC 14 1949 1246912 N/A N/A 18015 18030
TCAAAAAGGCCCAAGG 46 1950 1246938 N/A N/A 18814 18829
AGTAATTGCATCTGCT 42 1951 1246964 N/A N/A 19404 19419
CAGGAATGCATAAGAG 33 1952 1246990 N/A N/A 19662 19677
ACCAGAATCCATTCTA 60 1953 1247016 N/A N/A 19860 19875
AATCAATCTGTCTGAA 34 1954 1247042 N/A N/A 20174 20189
CCCAATTATGAATCTG 62 1955 1247068 N/A N/A 20398 20413
ATAGTAATTGCTATAG 36 1956 1247094 N/A N/A 20607 20622
GTCATTTAGAATACGC 46 1957
TABLE-US-00026 TABLE 26 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO: 1, and 2 SEQ SEQ SEQ SEQ ID NO: ID NO:
ID NO: ID NO: 1 1 2 2 HSD17B13 SEQ Compound Start Stop Start Stop
(% ID Number Site Site Site Site Sequence (5' to 3') Inhibition) NO
1245093 58 73 3152 3167 ATGTTCATGGCTTTGC 73 1958 1245119 110 125
3204 3219 CTCCAAGTAGGAGTAG 5 1959 1245145 180 195 3274 3289
CTCCAGTAATGAGAAC 40 1960 1245171 250 265 3344 3359 TCCCACAGAACCAATA
24 1961 1245197 298 313 7587 7602 AGTTTTCGGCACTCAG 16 1962 1245223
358 373 7647 7662 GAGCGATAGATCTCTT 0 1963 1245249 401 416 8795 8810
CACGATTGTTACATCA 37 1964 1245275 431 446 8825 8840 GGCTGGATATACTGTC
18 1965 1245301 472 487 8866 8881 AATGTCTTGGTAATCT 20 1966 1245327
514 529 N/A N/A AGTGCTTTTGTGATCC 25 1967 1245353 560 575 10446
10461 CACTGTGACGATGTGG 10 1968 1245379 613 628 N/A N/A
CTGGAACAATATGGGA 38 1969 1245405 669 684 12087 12102
CCAAGGCCTGAAGTTC 20 1970 1245431 758 773 N/A N/A TACAGGCCATAATCTT
16 1971 1245457 789 804 15670 15685 TCAGACTTCTTACGAC 36 1972
1245483 841 856 15722 15737 TTGATATACGATGGAA 38 1973 1245509* 906
921 20721 20736 TCTGCATACGATTTAA 44 1974 1245535* 972 987 20787
20802 CTGGCTGGAGCTTATT 82 1975 1245561 1013 1028 20828 20843
ATTGATTCGAAACTAT 22 1976 1245587 1087 1102 20902 20917
TGACTGCTGCTAGTGC 50 1977 1245613 1259 1274 21074 21089
GTAGCTTTTGTCCACC 63 1978 1245639 1313 1328 21128 21143
AGTCTTAAACCTTCCC 77 1979 1245665 1340 1355 21155 21170
GGCTACAGATTGGAAT 23 1980 1245691 1384 1399 21199 21214
TAGCTGTGCACTCATT 40 1981 1245717 1422 1437 21237 21252
CAGGTTGAGATAAAGC 49 1982 1245743 1498 1513 21313 21328
GAGTTGCACCGTTTTG 48 1983 1245769 1557 1572 21372 21387
ACTTTTGGTGGACTTC 0 1984 1245795 1616 1631 21431 21446
GGTCACCTTTCATAAT 57 1985 1245821 1709 1724 21524 21539
TCTCTGGGACCAAGGA 56 1986 1245841 1765 1780 21580 21595
GTACAGTTCCTTTTCC 44 38 1245847 1771 1786 21586 21601
TAGCCAGTACAGTTCC 52 1987 1245873 2176 2191 21991 22006
GAGTCGGATTATTTTT 44 1988 1245899 2204 2219 22019 22034
CAAAACAAGATTAGTC 18 1989 1245925 N/A N/A 3403 3418 TACATATCTTACTCTG
40 1990 1245951 N/A N/A 3551 3566 TCATAAAAATCGCTGC 26 1991 1245977
N/A N/A 3902 3917 GTTTATCATGTGCCAC 83 1992 1246003 N/A N/A 4434
4449 GTAAATTCTTGCTATC 40 1993 1246029 N/A N/A 5063 5078
GTTACATTACAGCCTT 71 1994 1246055 N/A N/A 5221 5236 AGCTTAAACTCCAATG
40 1995 1246065 N/A N/A 5659 5674 ATAAGTTACCAGAGCA 80 48 1246081
N/A N/A 5816 5831 TCAAAGTCAGTATCCC 79 1996 1246107 N/A N/A 5983
5998 GATACCTGAAAAGCCC 49 1997 1246133 N/A N/A 6223 6238
TACCAAACTTGCCCAT 33 1998 1246159 N/A N/A 6473 6488 ATGTAATAGGCAGTAA
33 1999 1246185 N/A N/A 7481 7496 ACAATTAACATTCGGC 77 2000 1246211
N/A N/A 7950 7965 TAGGAAGTGATCCATA 30 2001 1246237 N/A N/A 8240
8255 ATAACTACATGACCTG 29 2002 1246263 N/A N/A 8693 8708
CCAAAGATGAGAGTCT 19 2003 1246289 N/A N/A 9001 9016 CAAAGATCTGGCCAGT
1 2004 1246315 N/A N/A 9346 9361 CAAAAGTGTCCTCGAT 5 2005 1246341
N/A N/A 9517 9532 TACACTAATATTGAGG 30 2006 1246367 N/A N/A 9713
9728 TGAACATACATTGTTG 29 2007 1246393 N/A N/A 9976 9991
GACAGTTGAGTAGTGT 46 2008 1246419 N/A N/A 10210 10225
TTTATTGGTATGGTAA 25 2009 1246445 N/A N/A 10729 10744
TGTAATTGGCTCTTGA 0 2010 1246471 N/A N/A 11248 11263
ACCAAGGCCATGACAT 17 2011 1246497 N/A N/A 11653 11668
TCTACAAAACTGGTAT 9 2012 1246523 N/A N/A 11983 11998
AACCAATCCTCAGCTT 0 2013 1246549 N/A N/A 12411 12426
GATCAAATGTATGTGC 25 2014 1246575 N/A N/A 12614 12629
GGCTTAATTTTCGGGT 17 2015 1246601 N/A N/A 12727 12742
TTTAGGATTAATTCCC 16 2016 1246627 N/A N/A 13604 13619
GACAATACAGGATAGA 43 2017 1246653 N/A N/A 13861 13876
CTTAGGAAAGCTCATG 0 2018 1246679 N/A N/A 14027 14042
CCTTACTAAGGAAATT 28 2019 1246705 N/A N/A 14194 14209
TGTGATTGAGTTCTCC 62 2020 1246731 N/A N/A 14397 14412
TCATAAACATAGGCTT 58 2021 1246757 N/A N/A 14729 14744
CTCTAAATACCCTTGG 7 2022 1246783 N/A N/A 15315 15330
GATTAATCATGGGACA 9 2023 1246809 N/A N/A 15384 15399
TATCAAAATGGTGGCG 18 2024 1246835 N/A N/A 15774 15789
TTAGTATTTGGGTGTT 29 2025 1246861 N/A N/A 16382 16397
TCCCAACCAAACTTCC 82 2026 1246887 N/A N/A 17766 17781
GCATATTCATTTGGCC 6 2027 1246913 N/A N/A 18018 18033
GTTTCAAAAAGGCCCA 39 2028 1246939 N/A N/A 18815 18830
TAGTAATTGCATCTGC 51 2029 1246965 N/A N/A 19436 19451
TGGAGGAAAGCTTCAA 10 2030 1246991 N/A N/A 19675 19690
ACCAAGAGACACCACC 41 2031 1247017 N/A N/A 19889 19904
CTTACGACAGGTCATC 39 2032 1247043 N/A N/A 20185 20200
TTAGAAGTCAGCCCAA 37 2033 1247069 N/A N/A 20400 20415
CTATAGTAATTGCTAT 0 2034 1247095 N/A N/A 20608 20623
GGTCATTTAGAATACG 39 2035
Example 2: Dose-Dependent Inhibition of Human HSD17B13 in HepaRG
Cells by cEt Gapmers
[0516] Certain modified oligonucleotides described in the studies
above exhibiting significant in vitro inhibition of HSD17B13 RNA
were selected and tested at various doses in HepaRG cells.
[0517] The modified oligonucleotides were tested in a series of
experiments using the same culture conditions. The results for each
experiment are presented in separate tables shown below. Cultured
HepaRG cells at a density of 30,000 cells per well were transfected
using electroporation with modified oligonucleotides diluted to
different concentrations as specified in the Tables below. After a
treatment period of approximately 24 hours, HSD17B13 RNA levels
were measured as previously described using the Human HSD17B13
primer-probe set RTS43553. HSD17B13 RNA levels were normalized to
total RNA, as measured by RIBOGREEN.RTM.. Results are presented in
the tables below as percent inhibition of HSD17B13, relative to
untreated control cells.
[0518] The half maximal inhibitory concentration (IC.sub.50) of
each modified oligonucleotide was calculated using a linear
regression on a log/linear plot of the data in excel and is also
presented in the Tables below.
TABLE-US-00027 TABLE 27 Multi-dose assay of modified
oligonucleotides in HepaRG cells ION % Inhibition IC50 No. 6 nM 32
nM 160 nM 800 nM 4000 nM (.mu.M) 1245651 0 6 24 57 82 0.6 1245927 0
19 55 80 90 0.2 1245930 0 0 30 77 86 0.4 1245957 8 8 49 77 87 0.2
1245984 12 14 62 78 90 0.1 1246065 0 10 46 65 89 0.3 1246066 0 13
35 58 76 0.5 1246068 0 5 30 61 83 0.5 1246110 3 12 44 82 87 0.2
1246115 8 14 45 75 89 0.2 1246116 6 17 48 72 83 0.2 1246134 3 21 55
79 91 0.2 1246163 2 15 43 75 92 0.2
TABLE-US-00028 TABLE 28 Multi-dose assay of modified
oligonucleotides in HepaRG cells ION % Inhibition IC50 No. 6 nM 32
nM 160 nM 800 nM 4000 nM (.mu.M) 1245681 0 12 38 72 90 0.3 1245790
1 8 37 67 93 0.3 1245968 15 23 49 75 93 0.2 1245976 0 16 49 73 88
0.2 1245977 0 10 41 75 77 0.3 1245999 1 14 48 82 90 0.2 1246022 13
24 56 83 93 0.1 1246023 13 24 66 90 93 0.1 1246104 0 0 35 67 87 0.4
1246157 0 22 40 75 84 0.3 1246226 11 7 40 71 88 0.3 1246667 89 95
97 98 100 <0.006 1246853 0 2 11 57 82 0.7 1246861 4 0 12 31 67
2.6
Example 3: Antisense Inhibition of Human HSD17B13 in HepaRG Cells
by cEt Gapmers
[0519] Additional modified oligonucleotides complementary to an
HSD17B13 nucleic acid were synthesized and tested for their effect
on HSD17B13 RNA levels in vitro. The modified oligonucleotides were
tested in a series of experiments using the same culture
conditions. The results for each experiment are presented in
separate tables shown below.
[0520] Cultured HepaRG cells at a density of 30,000 cells per well
were transfected using electroporation with 1,000 nM of modified
oligonucleotide. After a treatment period of approximately 24
hours, RNA was isolated from the cells and HSD17B13 RNA levels were
measured by quantitative real-time RTPCR. Human primer probe set
RTS43553 was used to measure RNA levels. HSD17B13 RNA levels were
adjusted according to total RNA content, as measured by
RIBOGREEN.RTM.. Results are presented as percent inhibition of
HSD17B13 relative to untreated control cells. As used herein, a
value of `0` indicates that treatment with the modified
oligonucleotide did not inhibit HSD17B13 mRNA levels. An asterisk
(*) indicates that the modified oligonucleotide is complementary to
the target transcript within the amplicon region of the primer
probe set and so, the associated data is not reliable. In such
instances, additional using alternate primer probe sets must be
performed to accurately assess the potency and efficacy of such
modified oligonucleotides.
[0521] The modified oligonucleotides described in the tables below
were 3-10-3 cEt gapmers. The internucleoside linkages throughout
each modified oligonucleotide were phosphorothioate (P.dbd.S)
linkages. All cytosine residues throughout each modified
oligonucleotide were 5-methylcytosines.
[0522] "Start site" indicates the 5'-most nucleoside of the target
sequence to which the modified oligonucleotide is complementary.
"Stop site" indicates the 3'-most nucleoside of the target sequence
to which the modified oligonucleotide is complementary. As shown in
the Tables below, the modified oligonucleotide are complementary to
either the human HSD17B13 mRNA, designated herein as SEQ ID NO: 1
(GENBANK Accession No. NM_178135.4) or to the human HSD17B13
genomic sequence, designated herein as SEQ ID NO: 2 (the complement
of GENBANK Accession No. NC_000004.12 truncated from nucleotides
87301001 to 87326000) or to both. `N/A` indicates that the modified
oligonucleotide is not complementary to that particular target
sequence with 100% complementarity.
TABLE-US-00029 TABLE 29 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO.: 1, and 2 SEQ SEQ SEQ SEQ ID NO: ID
NO: ID NO: ID NO: 1 1 2 2 SEQ Compound Start Stop Start Stop % ID
Number Site Site Site Site Sequence (5' to 3') Inhibition NO
1245927 N/A N/A 3433 3448 AGTAGATGGTAAGTCA 91 121 1246023 N/A N/A
5046 5061 GAGTGAATCATTCAGT 89 1526 1340071 N/A N/A 20191 20206
CAGTTATTAGAAGTCA 85 2036 1340085 N/A N/A 20588 20603
GAGTTATCTGGTTTGC 84 2037 1340086 N/A N/A 9335 9350 TCGATCCTATATACAT
40 2038 1340096 N/A N/A 19711 19726 GCTGAAACTGCTGATT 38 2039
1340099 1763 1778 21578 21593 ACAGTTCCTTTTCCTG 58 2040 1340104 N/A
N/A 10500 10515 TACTTACCAATATGGG 13 2041 1340120 N/A N/A 11585
11600 TAACTGAGTTATTCTC 41 2042 1340158 N/A N/A 6440 6455
CTAAACTAGTGGTAAT 23 2043 1340170 N/A N/A 9657 9672 TAGGTAGCTAATGTAT
34 2044 1340194 N/A N/A 11077 11092 TAATTACAACCTGGTT 52 2045
1340201 N/A N/A 14279 14294 GTAAAGGCTGGGTGAG 41 2046 1340204 N/A
N/A 12202 12217 TCATACCACATACCCA 41 2047 1340209 N/A N/A 18520
18535 CTTAGTACCAAGACAC 60 2048 1340231 N/A N/A 16134 16149
GATGCTCCATAATAAT 42 2049 1340239 N/A N/A 19912 19927
TGCATCTTAAGATACC 81 2050 1340247 N/A N/A 16286 16301
AGAATAGTCTTCAGCA 80 2051 1340256 N/A N/A 19532 19547
GGCTAAAATGGTCATC 75 2052 1340276 N/A N/A 19394 19409
TAAGAGATGAGTAGGC 46 2053 1340278 N/A N/A 15250 15265
TCTATAGCTAAGTATA 0 2054 1340279 N/A N/A 17802 17817
TATTCTTATGTCATCC 75 2055 1340290 809 824 15690 15705
ATTGGTAAGTATTCCA 50 2056 1340305 1177 1192 20992 21007
TTTAAGAGGCATGAAA 40 2057 1340308 N/A N/A 20111 20126
TCAAGACATTCTAGCC 79 2058 1340330 N/A N/A 12476 12491
CTAGATACTCAATTTA 30 2059 1340360 N/A N/A 12800 12815
GGCTGTAAGAGTCAGT 88 2060 1340368 N/A N/A 13827 13842
CCTACCAAGAGGGTTT 34 2061 1340380 N/A N/A 12005 12020
ATTGTTAGCTAAGGGA 22 2062 1340390 N/A N/A 14175 14190
GCCTTGAATAGCAAGC 32 2063 1340405 N/A N/A 13598 13613
ACAGGATAGAGCACAT 44 2064 1340412 N/A N/A 14914 14929
ACATTAGCAAGCTAAG 52 2065 1340423 N/A N/A 9538 9553 ATCCAGATCTGCCCTA
39 2066 1340427 N/A N/A 8535 8550 TTGCAAGTTTATCAGT 66 2067 1340432
N/A N/A 4225 4240 GTTTCAACTAAACATG 65 2068 1340438 N/A N/A 3479
3494 GGACCAGGGAATTTAT 55 2069 1340439 1255 1270 21070 21085
CTTTTGTCCACCTTTA 76 2070 1340448 N/A N/A 5672 5687 GTCAGTAGAGAGCATA
85 2071 1340453 N/A N/A 6084 6099 TTTCACCTCAGGTGAC 52 2072 1340459
N/A N/A 5083 5098 CTCGCCTAAAGGAGAT 56 2073 1340465 N/A N/A 5895
5910 TCCTTTGTATTTCGCT 68 2074 1340479 N/A N/A 6785 6800
CCTCCTTATTTGTTAG 41 2075 1340491 N/A N/A 3699 3714 TTTCAGATCCCGTTCT
45 2076 1340525 N/A N/A 9965 9980 AGTGTAAGCTGAGAGT 71 2077 1340542
N/A N/A 5186 5201 CCAACGCAACAGTTTA 77 2078 1340546 N/A N/A 5647
5662 AGCATTCATCAGATGT 83 2079 1340556 N/A N/A 5268 5283
TTGCAAAATGTGATGC 75 2080 1340563 N/A N/A 3990 4005 GTGTTTACAAGTAAGA
79 2081 1340567 N/A N/A 6260 6275 AGATGGGCAAGGCCAC 59 2082 1340576
N/A N/A 11499 11514 CTGGAGAAGAGTTTAC 38 2083 1340580 N/A N/A 8641
8656 AGACAGACTGTTGAGC 74 2084 1340597 N/A N/A 18036 18051
CATAGTTTATATGGAT 56 2085 1340601 N/A N/A 18138 18153
TGTTATCTCAAGTCAG 81 2086 1340613 N/A N/A 5832 5847 ATGTTAGGACCCAGTC
60 2087 1340661 N/A N/A 9201 9216 TACACTGACAACCCTT 56 2088 1340665
N/A N/A 14601 14616 GAGAAATCTAAGAACC 42 2089 1340667 N/A N/A 9936
9951 AATGAATCATGATTGA 33 2090 1340669 N/A N/A 10000 10015
TGAAATCTTGTGTAAC 43 2091 1340684 N/A N/A 8125 8140 AGTGCTTAGTTCATTG
84 2092 1340685 N/A N/A 16385 16400 CAATCCCAACCAAACT 49 2093
1340689 N/A N/A 3600 3615 CTTGGAAGGAGACTGG 60 2094 1340697 N/A N/A
4661 4676 CCGCCCTTAAGTCATT 53 2095 1340704 N/A N/A 6329 6344
ACTTTCATAGGGAGAC 80 2096 1340705 74 89 3168 3183 AAGGATTTCTAGGATG
71 2097 1340722 N/A N/A 5737 5752 TTAGTTGGTAGCTTGC 72 2098 1340767
N/A N/A 9441 9456 TCCCACAAAACTAACC 24 2099 1340773 N/A N/A 9773
9788 TAGAACTCCCAACCCA 44 2100 1340776 N/A N/A 6732 6747
TTACCCCTGGCTTTTC 26 2101 1340785 N/A N/A 7781 7796 ACTACTTCAGTTAGCA
79 2102 1340792 N/A N/A 9115 9130 GACAGACCAAGTAGCT 39 2103 1340812
N/A N/A 10264 10279 CTTCCAAGCATTCCAT 57 2104 1340813 N/A N/A 7526
7541 CCGAAAAAAGTGGAGG 31 2105 1340836 N/A N/A 18694 18709
AAGACTTTGAGACTCT 62 2106 1340850 N/A N/A 8744 8759 CACTTTCACTGGGTGT
7 2107 1340852 1424 1439 21239 21254 TCCAGGTTGAGATAAA 70 2108
1340872 1614 1629 21429 21444 TCACCTTTCATAATGT 63 2109 1340878 N/A
N/A 12627 12642 TTGTTAAGCAGATGGC 84 2110 1340889 N/A N/A 6597 6612
CTACTTTCAAACCTTG 57 2111 1340903 N/A N/A 20390 20405
TGCTATAGTAATCACA 65 2112
TABLE-US-00030 TABLE 30 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO.: 1, and 2 SEQ SEQ SEQ SEQ ID NO: ID
NO: ID NO: ID NO: 1 1 2 2 SEQ Compound Start Stop Start Stop % ID
Number Site Site Site Site Sequence (5' to 3') Inhibition NO
1245927 N/A N/A 3433 3448 AGTAGATGGTAAGTCA 84 121 1246023 N/A N/A
5046 5061 GAGTGAATCATTCAGT 89 1526 1340078 N/A N/A 16295 16310
CCTTTAGTTAGAATAG 37 2113 1340094 N/A N/A 19547 19562
ATTGTTTAGCTGATAG 61 2114 1340113 N/A N/A 12667 12682
TGTTAACCTGCAGCAG 39 2115 1340122 N/A N/A 14192 14207
TGATTGAGTTCTCCAC 48 2116 1340126 N/A N/A 19779 19794
ACATACCACTCTTCTC 35 2117 1340130 N/A N/A 17954 17969
TTAGAAACTGCTCCTC 48 2118 1340146 N/A N/A 8132 8147 TTGTTAGAGTGCTTAG
76 2119 1340149 N/A N/A 11545 11560 CTTGACAATGGTTGCC 58 2120
1340152 N/A N/A 10138 10153 ATAGATCCTTTTTTGG 6 2121 1340154 N/A N/A
6284 6299 ACATTCTTCAGGTGTT 88 2122 1340156 N/A N/A 20194 20209
TTGCAGTTATTAGAAG 13 2123 1340179 N/A N/A 14315 14330
TAAGATGTCCAGGCAT 17 2124 1340197 N/A N/A 10554 10569
GAAGTGTAATGCTCCC 71 2125 1340220 N/A N/A 14611 14626
TATTTCTTGCGAGAAA 30 2126 1340241 N/A N/A 16220 16235
TTTATAGACTGGGTAG 59 2127 1340255 1783 1798 21598 21613
TTTCTTATGTAATAGC 76 2128 1340260 1714 1729 21529 21544
AAACATCTCTGGGACC 76 2129 1340277 N/A N/A 19914 19929
AGTGCATCTTAAGATA 57 2130 1340291 N/A N/A 18540 18555
GAAACTCACTTCCTAC 56 2131 1340297 N/A N/A 14917 14932
AATACATTAGCAAGCT 45 2132 1340304 697 712 12115 12130
AGACATGAGGTTTTGA 59 2133 1340310 N/A N/A 13638 13653
GACAATGTGCAGCTCT 67 2134 1340321 N/A N/A 6606 6621 TAAAGCAGGCTACTTT
9 2135 1340323 N/A N/A 19396 19411 CATAAGAGATGAGTAG 44 2136 1340342
N/A N/A 5279 5294 GAGCTAGACAATTGCA 73 2137 1340350 N/A N/A 9716
9731 TAGTGAACATACATTG 23 2138 1340361 N/A N/A 5935 5950
GCTGCTATTTAGGGCA 53 2139 1340364 N/A N/A 5678 5693 TTCTAGGTCAGTAGAG
58 2140 1340369 1433 1448 21248 21263 TAAAATATGTCCAGGT 75 2141
1340385 N/A N/A 4389 4404 AGACCAAAAAGATGGC 80 2142 1340395 N/A N/A
11794 11809 AACTCTATTGATTGGC 72 2143 1340416 N/A N/A 12496 12511
AATTCACCTTGACTAA 9 2144 1340419 N/A N/A 12410 12425
ATCAAATGTATGTGCT 73 2145 1340443 N/A N/A 11117 11132
CTACAGAGGAGTTTGC 27 2146 1340445 N/A N/A 5847 5862 ACTCCCCAAACATGGA
48 2147 1340458 N/A N/A 7834 7849 GCTGAGTGGATTACAT 44 2148 1340469
N/A N/A 6456 6471 GTGCTAAGTAGTAATT 58 2149 1340476 815 830 15696
15711 TTTCTTATTGGTAAGT 44 2150 1340512 N/A N/A 6736 6751
GAGATTACCCCTGGCT 72 2151 1340522 N/A N/A 6915 6930 ACTCGGGAAGTTTAGA
26 2152 1340533 N/A N/A 9456 9471 GTTGATATTTCCATCT 55 2153 1340543
N/A N/A 20115 20130 AGCATCAAGACATTCT 79 2154 1340549 N/A N/A 9968
9983 AGTAGTGTAAGCTGAG 88 2155 1340552 N/A N/A 12802 12817
CAGGCTGTAAGAGTCA 56 2156 1340555 N/A N/A 5158 5173 GCCAAACTGCTACTGT
73 2157 1340558 N/A N/A 15423 15438 ATATCCAGTAGGTGTG 55 2158
1340606 N/A N/A 18046 18061 CAAGTTTGTTCATAGT 78 2159 1340614 1311
1326 21126 21141 TCTTAAACCTTCCCTG 21 2160 1340651 N/A N/A 9344 9359
AAAGTGTCCTCGATCC 36 2161 1340671 N/A N/A 10293 10308
TGAGAGAACTTATACA 32 2162 1340673 N/A N/A 5191 5206 TATTCCCAACGCAACA
62 2163 1340674 N/A N/A 4663 4678 ACCCGCCCTTAAGTCA 48 2164 1340679
N/A N/A 5758 5773 ATAGGAGAGTCTTTCA 77 2165 1340681 N/A N/A 8547
8562 GCACATCATGTTTTGC 44 2166 1340683 N/A N/A 9947 9962
TACACCACACTAATGA 26 2167 1340696 N/A N/A 8656 8671 CTCAGAGTTCAGGCAA
67 2168 1340713 N/A N/A 6191 6206 GACAGAGCAATTTACT 55 2169 1340734
N/A N/A 8964 8979 ACTCCGTTATAAGTTT 42 2170 1340747 218 233 3312
3327 AAATTCATAAGTAGTC 39 2171 1340757 N/A N/A 18143 18158
CCTTATGTTATCTCAA 67 2172 1340761 N/A N/A 4068 4083 CCTTACCAGAATTTAC
63 2173 1340762 N/A N/A 5651 5666 CCAGAGCATTCATCAG 83 2174 1340768
N/A N/A 9210 9225 GAAAAGATGTACACTG 56 2175 1340770 N/A N/A 3505
3520 CTAACCTGACACATAT 18 2176 1340771 1179 1194 20994 21009
TTTTTAAGAGGCATGA 60 2177 1340775 N/A N/A 9593 9608 AAGAGCTGGTAAAGGT
47 2178 1340798 N/A N/A 3619 3634 GACTTGCCTCATTTAG 69 2179 1340802
N/A N/A 9793 9808 CCTATGCAAATTCATA 34 2180 1340803 N/A N/A 6333
6348 AAGGACTTTCATAGGG 71 2181 1340824 N/A N/A 20421 20436
CAGTAAAATTATGCCT 38 2182 1340831 N/A N/A 3702 3717 AATTTTCAGATCCCGT
74 2183 1340833 N/A N/A 9117 9132 AAGACAGACCAAGTAG 16 2184 1340837
N/A N/A 13955 13970 ACCTCTAAGTTAGCCC 28 2185 1340845 N/A N/A 18697
18712 CAAAAGACTTTGAGAC 22 2186 1340863 N/A N/A 20598 20613
AATACGCTGAGAGTTA 48 2187 1340874 N/A N/A 7528 7543 TTCCGAAAAAAGTGGA
13 2188 1340891 N/A N/A 16895 16910 CGTCAAATAGGGCTGG 53 2189
TABLE-US-00031 TABLE 31 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO.: 1, and 2 SEQ SEQ SEQ SEQ ID NO: ID
NO: ID NO: ID NO: 1 1 2 2 SEQ Compound Start Stop Start Stop % ID
Number Site Site Site Site Sequence (5' to 3') Inhibition NO
1245927 N/A N/A 3433 3448 AGTAGATGGTAAGTCA 91 121 1246023 N/A N/A
5046 5061 GAGTGAATCATTCAGT 83 1526 1340082 N/A N/A 16329 16344
CTTCACTATATTGCAT 50 2190 1340083 N/A N/A 20116 20131
CAGCATCAAGACATTC 72 2191 1340092 N/A N/A 16221 16236
TTTTATAGACTGGGTA 53 2192 1340098 N/A N/A 19818 19833
ATAGTTCAAATTGGAT 48 2193 1340125 N/A N/A 15778 15793
TGTTTTAGTATTTGGG 48 2194 1340131 N/A N/A 18720 18735
CACCATGACAGCTTCA 65 2195 1340141 N/A N/A 11213 11228
CTTCTGTAGGTTTTGC 60 2196 1340142 N/A N/A 17984 17999
TAGTTATCTTCTCACT 52 2197 1340148 2240 2255 22055 22070
ATGCAAAAGCATTCTA 50 2198 1340164 N/A N/A 11546 11561
TCTTGACAATGGTTGC 77 2199 1340183 N/A N/A 11795 11810
TAACTCTATTGATTGG 51 2200 1340187 N/A N/A 20628 20643
GACAACAGAGTTCTGT 9 2201 1340192 N/A N/A 12498 12513
GAAATTCACCTTGACT 41 2202 1340206 1330 1345 21145 21160
TGGAATGCTACTTGAA 85 2203 1340208 N/A N/A 9969 9984 GAGTAGTGTAAGCTGA
80 2204 1340215 N/A N/A 12416 12431 ACGGTGATCAAATGTA 53 2205
1340221 N/A N/A 16900 16915 AAAACCGTCAAATAGG 28 2206 1340230 N/A
N/A 18658 18673 TATTCTCCAACTCAGG 54 2207 1340235 N/A N/A 18145
18160 CTCCTTATGTTATCTC 57 2208 1340245 N/A N/A 15446 15461
TGTTATCAGAAACTTA 44 2209 1340270 N/A N/A 7550 7565 GCTGTAATTAGGAAGA
24 2210 1340274 N/A N/A 10584 10599 AGAACCAGGACTCTCC 67 2211
1340275 219 234 3313 3328 CAAATTCATAAGTAGT 76 2212 1340284 1467
1482 21282 21297 AAGAGGCTAGGGAAAT 66 2213 1340292 N/A N/A 19417
19432 GACAACTGATGTCCAG 12 2214 1340312 N/A N/A 20423 20438
GACAGTAAAATTATGC 57 2215 1340314 N/A N/A 18075 18090
TTGTACCCTGTTCTCA 64 2216 1340320 N/A N/A 14318 14333
AATTAAGATGTCCAGG 13 2217 1340324 N/A N/A 9950 9965 TTCTACACCACACTAA
12 2218 1340329 1181 1196 20996 21011 AGTTTTTAAGAGGCAT 75 2219
1340337 N/A N/A 13659 13674 TCACAAAGTCCCTGAC 11 2220 1340353 N/A
N/A 7125 7140 CATGAAGATTAGTTAA 11 2221 1340355 N/A N/A 8657 8672
TCTCAGAGTTCAGGCA 54 2222 1340356 N/A N/A 5680 5695 GTTTCTAGGTCAGTAG
73 2223 1340366 N/A N/A 6457 6472 AGTGCTAAGTAGTAAT 71 2224 1340367
N/A N/A 5870 5885 TAAACCCTGGAGCAGC 66 2225 1340370 N/A N/A 5159
5174 AGCCAAACTGCTACTG 78 2226 1340426 N/A N/A 9597 9612
TGTGAAGAGCTGGTAA 41 2227 1340472 N/A N/A 6335 6350 AGAAGGACTTTCATAG
46 2228 1340475 N/A N/A 8136 8151 AAGTTTGTTAGAGTGC 74 2229 1340484
N/A N/A 12709 12724 CCAGTAAAAAATTGGT 23 2230 1340503 N/A N/A 14613
14628 ATTATTTCTTGCGAGA 60 2231 1340514 N/A N/A 9345 9360
AAAAGTGTCCTCGATC 17 2232 1340515 N/A N/A 5762 5777 AAGAATAGGAGAGTCT
70 2233 1340539 N/A N/A 3721 3736 GACTTTTGTTTGTAGC 74 2234 1340560
N/A N/A 6285 6300 TACATTCTTCAGGTGT 61 2235 1340577 N/A N/A 5280
5295 TGAGCTAGACAATTGC 78 2236 1340603 699 714 12117 12132
AGAGACATGAGGTTTT 77 2237 1340604 N/A N/A 20195 20210
ATTGCAGTTATTAGAA 42 2238 1340617 N/A N/A 3516 3531 CCTTCATCTAACTAAC
30 2239 1340636 N/A N/A 12804 12819 CTCAGGCTGTAAGAGT 21 2240
1340647 N/A N/A 5195 5210 ACCGTATTCCCAACGC 90 2241 1340659 N/A N/A
8965 8980 AACTCCGTTATAAGTT 11 2242 1340664 N/A N/A 3676 3691
CCCCTAAGTTATTATC 33 2243 1340690 N/A N/A 9726 9741 TGTGAGAGGATAGTGA
50 2244 1340724 N/A N/A 4862 4877 AACTGAAACGATCCTC 52 2245 1340725
N/A N/A 9466 9481 GGCAGTTGAAGTTGAT 46 2246 1340727 N/A N/A 8589
8604 GTGGGATAAACTGTTC 52 2247 1340746 N/A N/A 19564 19579
TAGCTATTGTCTTTGA 63 2248 1340781 N/A N/A 13956 13971
TACCTCTAAGTTAGCC 28 2249 1340789 N/A N/A 14193 14208
GTGATTGAGTTCTCCA 80 2250 1340790 N/A N/A 9118 9133 CAAGACAGACCAAGTA
27 2251 1340830 N/A N/A 7835 7850 AGCTGAGTGGATTACA 29 2252 1340834
N/A N/A 6203 6218 ATAGGACATGGAGACA 82 2253 1340835 N/A N/A 5653
5668 TACCAGAGCATTCATC 55 2254 1340838 N/A N/A 10294 10309
TTGAGAGAACTTATAC 21 2255 1340839 N/A N/A 19915 19930
GAGTGCATCTTAAGAT 43 2256 1340841 N/A N/A 4069 4084 GCCTTACCAGAATTTA
75 2257 1340864 N/A N/A 9796 9811 AATCCTATGCAAATTC 42 2258 1340865
1716 1731 21531 21546 CTAAACATCTCTGGGA 62 2259 1340870 N/A N/A 4402
4417 CGAATTTCTTCAAAGA 55 2260 1340875 N/A N/A 5974 5989
AAAGCCCTATTCTTCG 65 2261 1340876 N/A N/A 6626 6641 TGTACAGTAGGCAGTT
75 2262 1340883 N/A N/A 9224 9239 CAAGTGACAGCATTGA 48 2263 1340884
N/A N/A 6738 6753 ATGAGATTACCCCTGG 62 2264 1340885 N/A N/A 10184
10199 AACACTAATCTCAGTA 15 2265 1340892 N/A N/A 14918 14933
TAATACATTAGCAAGC 33 2266
TABLE-US-00032 TABLE 32 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO.: 1, and 2 SEQ SEQ SEQ SEQ ID NO: ID
NO: ID NO: ID NO: 1 1 2 2 SEQ Compound Start Stop Start Stop % ID
Number Site Site Site Site Sequence (5' to 3') Inhibition NO
1245927 N/A N/A 3433 3448 AGTAGATGGTAAGTCA 59 121 1246023 N/A N/A
5046 5061 GAGTGAATCATTCAGT 78 1526 1340075 N/A N/A 13957 13972
CTACCTCTAAGTTAGC 6 2267 1340077 1468 1483 21283 21298
GAAGAGGCTAGGGAAA 44 2268 1340093 N/A N/A 18744 18759
TATACCTGTTGCCTAG 11 2269 1340108 N/A N/A 10848 10863
CATATGGTGTACACTG 15 2270 1340129 N/A N/A 16904 16919
GTCAAAAACCGTCAAA 39 2271 1340144 254 269 3348 3363 AATATCCCACAGAACC
60 2272 1340151 N/A N/A 11796 11811 ATAACTCTATTGATTG 39 2273
1340157 N/A N/A 9147 9162 TGCCAAGCTTTGTGTC 38 2274 1340163 N/A N/A
14617 14632 CCGAATTATTTCTTGC 60 2275 1340166 N/A N/A 4412 4427
AAAGTTCATTCGAATT 63 2276 1340168 N/A N/A 18086 18101
ACCAATGCAGTTTGTA 75 2277 1340169 N/A N/A 6460 6475 TAAAGTGCTAAGTAGT
50 2278 1340171 N/A N/A 11553 11568 GTTTTTCTCTTGACAA 59 2279
1340176 N/A N/A 16117 16132 GCTCTATTGGGCCAGG 47 2280 1340181 N/A
N/A 18176 18191 CGCGAGATGATGTTGC 53 2281 1340211 N/A N/A 18661
18676 TACTATTCTCCAACTC 47 2282 1340226 1182 1197 20997 21012
AAGTTTTTAAGAGGCA 77 2283 1340233 N/A N/A 12499 12514
AGAAATTCACCTTGAC 39 2284 1340268 N/A N/A 16224 16239
TCTTTTTATAGACTGG 82 2285 1340273 N/A N/A 11237 11252
GACATAGACATGTGTT 26 2286 1340283 1717 1732 21532 21547
TCTAAACATCTCTGGG 40 2287 1340286 N/A N/A 19846 19861
AACCTATGTGTGCACC 73 2288 1340327 N/A N/A 12418 12433
TAACGGTGATCAAATG 17 2289 1340332 N/A N/A 10295 10310
TTTGAGAGAACTTATA 0 2290 1340334 N/A N/A 8973 8988 AGTATGTGAACTCCGT
81 2291 1340335 N/A N/A 5654 5669 TTACCAGAGCATTCAT 50 2292 1340352
N/A N/A 9970 9985 TGAGTAGTGTAAGCTG 62 2293 1340375 N/A N/A 19444
19459 TGGGATAGTGGAGGAA 13 2294 1340377 N/A N/A 17986 18001
TATAGTTATCTTCTCA 46 2295 1340386 N/A N/A 14919 14934
ATAATACATTAGCAAG 7 2296 1340387 N/A N/A 5873 5888 GGCTAAACCCTGGAGC
36 2297 1340388 N/A N/A 8164 8179 TATTGTAGGGATTGAA 40 2298 1340397
N/A N/A 3741 3756 CTGTTGCAAGTTCTTC 85 2299 1340398 N/A N/A 13688
13703 TTTACTCACTTCTGGT 30 2300 1340415 N/A N/A 12815 12830
CACATAGCTAACTCAG 42 2301 1340430 N/A N/A 5197 5212 GAACCGTATTCCCAAC
72 2302 1340433 N/A N/A 9467 9482 AGGCAGTTGAAGTTGA 47 2303 1340446
N/A N/A 15491 15506 TTAATGCCACCCTACC 19 2304 1340450 N/A N/A 5712
5727 GATTGCACAAACCACA 73 2305 1340451 N/A N/A 6301 6316
CTAGGAGATATAACAT 40 2306 1340452 N/A N/A 5978 5993 CTGAAAAGCCCTATTC
11 2307 1340454 N/A N/A 7680 7695 AATTTGTGAACCTGCA 20 2308 1340468
N/A N/A 20197 20212 ACATTGCAGTTATTAG 42 2309 1340471 N/A N/A 14385
14400 GCTTAGTGTAGAATTG 16 2310 1340478 N/A N/A 6740 6755
CAATGAGATTACCCCT 16 2311 1340489 N/A N/A 6388 6403 GATGATTCTGACTCAT
55 2312 1340498 N/A N/A 20470 20485 TCATTAGGAAAAGTGT 16 2313
1340521 N/A N/A 8593 8608 AAAGGTGGGATAAACT 33 2314 1340534 N/A N/A
10187 10202 GCCAACACTAATCTCA 40 2315 1340545 N/A N/A 20117 20132
ACAGCATCAAGACATT 53 2316 1340547 N/A N/A 4864 4879 TGAACTGAAACGATCC
58 2317 1340554 N/A N/A 9225 9240 ACAAGTGACAGCATTG 44 2318 1340566
700 715 12118 12133 CAGAGACATGAGGTTT 61 2319 1340574 N/A N/A 9599
9614 TATGTGAAGAGCTGGT 63 2320 1340578 N/A N/A 3678 3693
ATCCCCTAAGTTATTA 13 2321 1340585 N/A N/A 5782 5797 GGATTGCAGAAGAGTA
76 2322 1340610 N/A N/A 20629 20644 TGACAACAGAGTTCTG 11 2323
1340628 N/A N/A 19585 19600 TAAACTAAAGTACTTG 1 2324 1340631 N/A N/A
4071 4086 TGGCCTTACCAGAATT 46 2325 1340634 N/A N/A 7127 7142
GACATGAAGATTAGTT 3 2326 1340638 N/A N/A 9727 9742 CTGTGAGAGGATAGTG
33 2327 1340645 1352 1367 21167 21182 ATTCTGTGGCATGGCT 69 2328
1340668 2242 2257 22057 22072 CCATGCAAAAGCATTC 72 2329 1340701 N/A
N/A 3544 3559 AATCGCTGCTTAGTTC 41 2330 1340740 N/A N/A 19999 20014
CAGTTTTCCTCATGAT 65 2331 1340777 N/A N/A 14195 14210
ATGTGATTGAGTTCTC 36 2332 1340783 N/A N/A 9915 9930 CTATCTCCCTATTTGT
15 2333 1340821 N/A N/A 7942 7957 GATCCATATTCCCTGA 74 2334 1340822
N/A N/A 5281 5296 CTGAGCTAGACAATTG 56 2335 1340832 N/A N/A 8668
8683 TGTATGAGGTCTCTCA 66 2336 1340873 N/A N/A 6221 6236
CCAAACTTGCCCATAA 45 2337 1340879 N/A N/A 5161 5176 AGAGCCAAACTGCTAC
55 2338 1340894 N/A N/A 9372 9387 TAGAACACTTGCCTCA 31 2339 1340895
N/A N/A 9953 9968 GAGTTCTACACCACAC 76 2340 1340901 N/A N/A 16332
16347 CTACTTCACTATATTG 33 2341 1340902 N/A N/A 6628 6643
GCTGTACAGTAGGCAG 66 2342 1340910 N/A N/A 12722 12737
GATTAATTCCCTTCCA 30 2343
TABLE-US-00033 TABLE 33 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO.: 1, and 2 SEQ SEQ SEQ SEQ ID NO: ID
NO: ID NO: ID NO: 1 1 2 2 SEQ Compound Start Stop Start Stop % ID
Number Site Site Site Site Sequence (5' to 3') Inhibition NO
1245927 N/A N/A 3433 3448 AGTAGATGGTAAGTCA 85 121 1246023 N/A N/A
5046 5061 GAGTGAATCATTCAGT 79 1526 1340100 N/A N/A 19467 19482
CTGGAAGGAGGATTCA 39 2344 1340117 N/A N/A 12419 12434
GTAACGGTGATCAAAT 34 2345 1340119 N/A N/A 9971 9986 TTGAGTAGTGTAAGCT
52 2346 1340123 N/A N/A 9602 9617 ACATATGTGAAGAGCT 66 2347 1340127
1185 1200 21000 21015 CAGAAGTTTTTAAGAG 30 2348 1340135 N/A N/A
19847 19862 GAACCTATGTGTGCAC 53 2349 1340145 N/A N/A 6391 6406
CTTGATGATTCTGACT 57 2350 1340189 N/A N/A 20479 20494
TAGTGGACTTCATTAG 52 2351 1340190 N/A N/A 14921 14936
CTATAATACATTAGCA 3 2352 1340193 N/A N/A 14618 14633
CCCGAATTATTTCTTG 34 2353 1340196 N/A N/A 16225 16240
CTCTTTTTATAGACTG 63 2354 1340205 N/A N/A 19586 19601
GTAAACTAAAGTACTT 0 2355 1340212 N/A N/A 10930 10945
ATAAGGCCGATTCATG 38 2356 1340218 N/A N/A 20001 20016
ATCAGTTTTCCTCATG 48 2357 1340228 N/A N/A 20361 20376
CTAAATTATTGCCTGA 39 2358 1340229* N/A N/A 20685 20700
GAAGAAACCTGTACAA 85 2359 1340234 N/A N/A 16337 16352
ATTAACTACTTCACTA 14 2360 1340238 N/A N/A 11855 11870
TAAGCAGAATTGTGAA 35 2361 1340244 N/A N/A 16968 16983
CCAATATATACTGACA 68 2362 1340246 N/A N/A 13959 13974
GTCTACCTCTAAGTTA 3 2363 1340258 N/A N/A 11570 11585
CTTGACAATGGTTGAT 54 2364 1340266 N/A N/A 18748 18763
AATATATACCTGTTGC 38 2365 1340271 N/A N/A 17990 18005
TTAGTATAGTTATCTT 37 2366 1340309 N/A N/A 14196 14211
TATGTGATTGAGTTCT 28 2367 1340311 N/A N/A 18178 18193
CTCGCGAGATGATGTT 40 2368 1340339 N/A N/A 6467 6482 TAGGCAGTAAAGTGCT
48 2369 1340345 N/A N/A 18092 18107 TGATACACCAATGCAG 44 2370
1340348 N/A N/A 5283 5298 AACTGAGCTAGACAAT 44 2371 1340349 N/A N/A
6225 6240 TGTACCAAACTTGCCC 53 2372 1340354 N/A N/A 9148 9163
ATGCCAAGCTTTGTGT 50 2373 1340357 N/A N/A 3375 3390 GTTGGAAGATGTATAC
53 2374 1340402 N/A N/A 9958 9973 GCTGAGAGTTCTACAC 45 2375 1340406
N/A N/A 8594 8609 TAAAGGTGGGATAAAC 0 2376 1340428 N/A N/A 9921 9936
AATTCACTATCTCCCT 10 2377 1340440 1360 1375 21175 21190
TTGTTGATATTCTGTG 52 2378 1340449 N/A N/A 5198 5213 TGAACCGTATTCCCAA
76 2379 1340466 N/A N/A 6638 6653 TTGGTTGGAGGCTGTA 60 2380 1340492
N/A N/A 15497 15512 GCTGCATTAATGCCAC 46 2381 1340501 N/A N/A 6742
6757 TGCAATGAGATTACCC 54 2382 1340504 N/A N/A 12500 12515
CAGAAATTCACCTTGA 28 2383 1340505 N/A N/A 6302 6317 TCTAGGAGATATAACA
48 2384 1340506 N/A N/A 12758 12773 GAGAATTGTTTAGTTC 47 2385
1340548 N/A N/A 5715 5730 CCAGATTGCACAAACC 72 2386 1340553 N/A N/A
10188 10203 TGCCAACACTAATCTC 30 2387 1340571 N/A N/A 9498 9513
TGGAAGATTAATCATA 12 2388 1340582 2243 2258 22058 22073
TCCATGCAAAAGCATT 62 2389 1340626 N/A N/A 5657 5672 AAGTTACCAGAGCATT
70 2390 1340653 N/A N/A 5984 5999 GGATACCTGAAAAGCC 68 2391 1340655
701 716 12119 12134 GCAGAGACATGAGGTT 55 2392 1340657 N/A N/A 4076
4091 TTTCATGGCCTTACCA 52 2393 1340678 N/A N/A 7130 7145
TTGGACATGAAGATTA 18 2394 1340692 N/A N/A 3756 3771 AGGCACTAAAGGTTTC
61 2395 1340693 N/A N/A 4476 4491 GGACAAATGCCTGAGA 52 2396 1340695
N/A N/A 13689 13704 GTTTACTCACTTCTGG 29 2397 1340716 N/A N/A 8168
8183 GAGTTATTGTAGGGAT 69 2398 1340723 N/A N/A 8669 8684
TTGTATGAGGTCTCTC 50 2399 1340750 N/A N/A 7682 7697 GAAATTTGTGAACCTG
32 2400 1340759 N/A N/A 9755 9770 CTACCTCCAAATTCCC 27 2401 1340763
N/A N/A 7947 7962 GAAGTGATCCATATTC 44 2402 1340786 N/A N/A 12890
12905 TCTTTAGTCAACAGTA 68 2403 1340788 N/A N/A 18667 18682
CTGGGATACTATTCTC 57 2404 1340800 N/A N/A 14388 14403
TAGGCTTAGTGTAGAA 38 2405 1340805 N/A N/A 9319 9334 CCAAGTAATTACTTCT
68 2406 1340807 1471 1486 21286 21301 AAGGAAGAGGCTAGGG 57 2407
1340808 N/A N/A 5804 5819 TCCCCTCAAATAGCCT 60 2408 1340823 N/A N/A
20119 20134 TTACAGCATCAAGACA 46 2409 1340842 N/A N/A 16124 16139
AATAATAGCTCTATTG 0 2410 1340846 N/A N/A 8981 8996 TGTCCAGAAGTATGTG
0 2411 1340857 N/A N/A 5162 5177 AAGAGCCAAACTGCTA 63 2412 1340859
N/A N/A 3568 3583 TCAACCTGCACACCAT 72 2413 1340893 N/A N/A 5876
5891 GTAGGCTAAACCCTGG 62 2414 1340896 N/A N/A 11290 11305
ATGTTTTGATCCAGGG 46 2415 1340898 1720 1735 21535 21550
TTGTCTAAACATCTCT 60 2416 1340899 N/A N/A 3679 3694 CATCCCCTAAGTTATT
24 2417 1340904 N/A N/A 9381 9396 CCATGGATCTAGAACA 15 2418 1340905
N/A N/A 10345 10360 CGTTAGGTTTCCAAAT 0 2419 1340908 N/A N/A 5048
5063 TAGAGTGAATCATTCA 75 2420
TABLE-US-00034 TABLE 34 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO.: 1, and 2 SEQ SEQ SEQ SEQ ID NO: ID
NO: ID NO: ID NO: 1 1 2 2 SEQ Compound Start Stop Start Stop % ID
Number Site Site Site Site Sequence (5' to 3') Inhibition NO
1245927 N/A N/A 3433 3448 AGTAGATGGTAAGTCA 88 121 1246023 N/A N/A
5046 5061 GAGTGAATCATTCAGT 86 1526 1340080 N/A N/A 10970 10985
TAATCTTGAGGCAGGA 17 2421 1340088 N/A N/A 12420 12435
GGTAACGGTGATCAAA 51 2422 1340111 N/A N/A 9519 9534 TCTACACTAATATTGA
21 2423 1340121 N/A N/A 14619 14634 CCCCGAATTATTTCTT 35 2424
1340132 N/A N/A 16379 16394 CAACCAAACTTCCAGC 72 2425 1340133 N/A
N/A 12502 12517 TGCAGAAATTCACCTT 54 2426 1340160 N/A N/A 8675 8690
CTTCTATTGTATGAGG 40 2427 1340175 N/A N/A 11866 11881
TCTTACATGATTAAGC 35 2428 1340198 N/A N/A 15019 15034
TAAAATAGGGTGCAGT 58 2429 1340199 N/A N/A 20120 20135
ATTACAGCATCAAGAC 63 2430 1340200 N/A N/A 14197 14212
TTATGTGATTGAGTTC 34 2431 1340222 734 749 12152 12167
ATTTTTGGTGAACCCA 8 2432 1340243 N/A N/A 13690 13705
CGTTTACTCACTTCTG 21 2433 1340259 N/A N/A 16126 16141
ATAATAATAGCTCTAT 1 2434 1340261 1197 1212 21012 21027
TTTATGTAAGCACAGA 70 2435 1340264 2247 2262 22062 22077
ATAGTCCATGCAAAAG 43 2436 1340269 1371 1386 21186 21201
ATTCTGTGTTCTTGTT 67 2437 1340280 N/A N/A 17993 18008
AAGTTAGTATAGTTAT 20 2438 1340303 N/A N/A 17014 17029
TAGCAATTTAGCAAGA 54 2439 1340307 N/A N/A 11571 11586
TCTTGACAATGGTTGA 75 2440 1340318 N/A N/A 19607 19622
TATTATGCACTCTATA 9 2441 1340338 N/A N/A 18672 18687
TTTTACTGGGATACTA 27 2442 1340347 N/A N/A 9924 9939 TTGAATTCACTATCTC
45 2443 1340358 N/A N/A 5199 5214 TTGAACCGTATTCCCA 76 2444 1340363
N/A N/A 9975 9990 ACAGTTGAGTAGTGTA 72 2445 1340396 N/A N/A 20002
20017 AATCAGTTTTCCTCAT 53 2446 1340400 N/A N/A 20483 20498
TTCATAGTGGACTTCA 51 2447 1340418 N/A N/A 20378 20393
CACAAGTAAGGTAAAG 54 2448 1340425 N/A N/A 6747 6762 CTAGTTGCAATGAGAT
65 2449 1340431 N/A N/A 10199 10214 GGTAAGCCCCATGCCA 38 2450
1340437 N/A N/A 11307 11322 CACAAGCACACTGTAA 2 2451 1340455 N/A N/A
5716 5731 GCCAGATTGCACAAAC 60 2452 1340462 N/A N/A 16262 16277
GCAGAGACAGTAGATT 63 2453 1340470 N/A N/A 6228 6243 TTATGTACCAAACTTG
53 2454 1340493 N/A N/A 5985 6000 AGGATACCTGAAAAGC 81 2455 1340508
N/A N/A 14392 14407 AACATAGGCTTAGTGT 18 2456 1340510 N/A N/A 4103
4118 ATCCTGTAAACACTTC 79 2457 1340513 N/A N/A 7949 7964
AGGAAGTGATCCATAT 60 2458 1340518 N/A N/A 9004 9019 AGGCAAAGATCTGGCC
7 2459 1340519 N/A N/A 9386 9401 GCACCCCATGGATCTA 35 2460 1340524
1544 1559 21359 21374 TTCAGAGTTATACAGA 66 2461 1340527 N/A N/A 3680
3695 CCATCCCCTAAGTTAT 14 2462 1340544 1022 1037 20837 20852
CTTTGCAGCATTGATT 47 2463 1340561 N/A N/A 3782 3797 GAACTGTGTTGCTTGT
77 2464 1340570 N/A N/A 19887 19902 TACGACAGGTCATCTT 58 2465
1340572 N/A N/A 6426 6441 ATGGTAAACTGTATGC 78 2466 1340575 N/A N/A
9606 9621 ATTCACATATGTGAAG 0 2467 1340588 N/A N/A 4481 4496
TTTTTGGACAAATGCC 50 2468 1340609 N/A N/A 7683 7698 AGAAATTTGTGAACCT
39 2469 1340620 N/A N/A 18963 18978 ATGCAAGATTTACTTC 38 2470
1340640 N/A N/A 5049 5064 TTAGAGTGAATCATTC 69 2471 1340642 N/A N/A
6308 6323 TGCTACTCTAGGAGAT 60 2472 1340648 N/A N/A 5809 5824
CAGTATCCCCTCAAAT 53 2473 1340650 1722 1737 21537 21552
AATTGTCTAAACATCT 62 2474 1340670 N/A N/A 8170 8185 CAGAGTTATTGTAGGG
83 2475 1340680 N/A N/A 5169 5184 ATTGCATAAGAGCCAA 67 2476 1340687
519 534 10405 10420 GAAGAAGTGCTTTTGT 50 2477 1340691 N/A N/A 9757
9772 AGCTACCTCCAAATTC 0 2478 1340700 N/A N/A 14077 14092
AACAACCCAGCCTCGG 20 2479 1340711 N/A N/A 9959 9974 AGCTGAGAGTTCTACA
67 2480 1340717 N/A N/A 3569 3584 ATCAACCTGCACACCA 63 2481 1340742
N/A N/A 19472 19487 TATAACTGGAAGGAGG 44 2482 1340744 N/A N/A 12780
12795 TCAAATGAGGCGGCAC 46 2483 1340749 N/A N/A 6710 6725
GGAATGCTCATATTAA 19 2484 1340753 N/A N/A 15498 15513
TGCTGCATTAATGCCA 15 2485 1340756 N/A N/A 5284 5299 TAACTGAGCTAGACAA
53 2486 1340765 N/A N/A 9152 9167 GTACATGCCAAGCTTT 61 2487 1340778
N/A N/A 6468 6483 ATAGGCAGTAAAGTGC 56 2488 1340828 N/A N/A 8600
8615 CTGTCATAAAGGTGGG 59 2489 1340840 N/A N/A 9320 9335
TCCAAGTAATTACTTC 72 2490 1340843 N/A N/A 18505 18520
CTAATTTAGTCAACTT 40 2491 1340848 N/A N/A 5658 5673 TAAGTTACCAGAGCAT
77 2492 1340861 N/A N/A 3429 3444 GATGGTAAGTCAAATA 85 2493 1340871
N/A N/A 7426 7441 TTGGCCGAGGAGGGCG 3 2494 1340909 N/A N/A 13548
13563 TCTAAAGGGCTGCTCT 33 2495 1340913 N/A N/A 5883 5898
CGCTACTGTAGGCTAA 68 2496 1340916 N/A N/A 18094 18109
ATTGATACACCAATGC 66 2497
TABLE-US-00035 TABLE 35 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO.: 1, and 2 SEQ SEQ SEQ SEQ ID NO: ID
NO: ID NO: ID NO: 1 1 2 2 SEQ Compound Start Stop Start Stop % ID
Number Site Site Site Site Sequence (5' to 3') Inhibition NO
1245927 N/A N/A 3433 3448 AGTAGATGGTAAGTCA 84 121 1246023 N/A N/A
5046 5061 GAGTGAATCATTCAGT 81 1526 1340081 1028 1043 20843 20858
ATAAAGCTTTGCAGCA 54 2498 1340090 N/A N/A 9961 9976 TAAGCTGAGAGTTCTA
64 2499 1340106 N/A N/A 19473 19488 CTATAACTGGAAGGAG 43 2500
1340110 N/A N/A 17228 17243 TGTACAAATTTATGCC 67 2501 1340114 565
580 10451 10466 GAAGCCACTGTGACGA 58 2502 1340118 N/A N/A 9608 9623
CAATTCACATATGTGA 11 2503 1340128 N/A N/A 14461 14476
AGGTATGTCATACTTC 5 2504 1340143 N/A N/A 15021 15036
GATAAAATAGGGTGCA 52 2505 1340150 N/A N/A 15501 15516
ATTTGCTGCATTAATG 20 2506 1340165 N/A N/A 14198 14213
ATTATGTGATTGAGTT 46 2507 1340177 N/A N/A 3682 3697 GCCCATCCCCTAAGTT
33 2508 1340185 N/A N/A 14621 14636 TGCCCCGAATTATTTC 3 2509 1340191
N/A N/A 19890 19905 GCTTACGACAGGTCAT 73 2510 1340195 N/A N/A 16127
16142 CATAATAATAGCTCTA 41 2511 1340210 N/A N/A 18969 18984
TGACTAATGCAAGATT 45 2512 1340223 N/A N/A 13729 13744
TTAAGTACTGTGAGAC 35 2513 1340254 N/A N/A 13563 13578
GTTCAACTGAACCTCT 55 2514 1340265 N/A N/A 11897 11912
TGAGAGTATAAATGGC 67 2515 1340272 N/A N/A 11576 11591
TATTCTCTTGACAATG 47 2516 1340294 N/A N/A 19651 19666
TTCTATGCAAGCCTTC 51 2517 1340300 N/A N/A 17998 18013
TTATGAAGTTAGTATA 31 2518 1340302 N/A N/A 18509 18524
GACACTAATTTAGTCA 11 2519 1340319 2248 2263 22063 22078
GATAGTCCATGCAAAA 64 2520 1340322 735 750 12153 12168
GATTTTTGGTGAACCC 30 2521 1340336 N/A N/A 9925 9940 ATTGAATTCACTATCT
31 2522 1340372 N/A N/A 5988 6003 GCAAGGATACCTGAAA 67 2523 1340373
N/A N/A 6309 6324 CTGCTACTCTAGGAGA 66 2524 1340379 N/A N/A 18095
18110 AATTGATACACCAATG 55 2525 1340382 N/A N/A 3570 3585
TATCAACCTGCACACC 62 2526 1340384 N/A N/A 18673 18688
ATTTTACTGGGATACT 49 2527 1340394 N/A N/A 12503 12518
TTGCAGAAATTCACCT 36 2528 1340401 N/A N/A 5664 5679 AGAGCATAAGTTACCA
88 2529 1340404 N/A N/A 9977 9992 AGACAGTTGAGTAGTG 63 2530 1340414
N/A N/A 7954 7969 AAACTAGGAAGTGATC 39 2531 1340422 N/A N/A 5202
5217 TTTTTGAACCGTATTC 56 2532 1340429 N/A N/A 16275 16290
CAGCAAAGTTTGGGCA 37 2533 1340434 N/A N/A 20121 20136
GATTACAGCATCAAGA 52 2534 1340435 N/A N/A 3784 3799 TAGAACTGTGTTGCTT
78 2535 1340482 1199 1214 21014 21029 TGTTTATGTAAGCACA 74 2536
1340496 N/A N/A 8605 8620 GAACACTGTCATAAAG 43 2537 1340499 N/A N/A
20380 20395 ATCACAAGTAAGGTAA 62 2538 1340500 N/A N/A 16380 16395
CCAACCAAACTTCCAG 70 2539 1340526 N/A N/A 10974 10989
ATTGTAATCTTGAGGC 39 2540 1340529 N/A N/A 9158 9173 CTCCTGGTACATGCCA
47 2541 1340538 N/A N/A 6428 6443 TAATGGTAAACTGTAT 32 2542 1340584
N/A N/A 6748 6763 CCTAGTTGCAATGAGA 77 2543 1340587 N/A N/A 12422
12437 GTGGTAACGGTGATCA 49 2544 1340590 N/A N/A 6711 6726
GGGAATGCTCATATTA 18 2545 1340594 N/A N/A 9057 9072 TGTCAGAGACTCTGTG
39 2546 1340607 N/A N/A 7708 7723 CGTCCTAGGAAACAAA 45 2547 1340619
N/A N/A 8236 8251 CTACATGACCTGGGTC 59 2548 1340630 N/A N/A 4133
4148 GGAGTACTTCACAATT 79 2549 1340646 N/A N/A 5170 5185
GATTGCATAAGAGCCA 82 2550 1340654 N/A N/A 5810 5825 TCAGTATCCCCTCAAA
64 2551 1340677 N/A N/A 8706 8721 GGACCAATATAATCCA 20 2552 1340706
N/A N/A 9323 9338 ACATCCAAGTAATTAC 56 2553 1340731 N/A N/A 5717
5732 TGCCAGATTGCACAAA 54 2554 1340737 N/A N/A 20486 20501
AACTTCATAGTGGACT 68 2555 1340741 N/A N/A 14165 14180
GCAAGCCAACAGAGAG 52 2556 1340748 N/A N/A 11384 11399
TTTAGTCAGGTAGAGT 30 2557 1340751 N/A N/A 9411 9426 TGTATAGCTGCATTTC
37 2558 1340772 N/A N/A 5886 5901 TTTCGCTACTGTAGGC 62 2559 1340780
N/A N/A 5054 5069 CAGCCTTAGAGTGAAT 82 2560 1340782 N/A N/A 4537
4552 GAGATTTGAAGGTTAG 82 2561 1340804 N/A N/A 20005 20020
AGTAATCAGTTTTCCT 65 2562 1340811 1546 1561 21361 21376
ACTTCAGAGTTATACA 35 2563 1340815 N/A N/A 7473 7488 CATTCGGCTAGGCGCG
46 2564 1340816 N/A N/A 9759 9774 CAAGCTACCTCCAAAT 25 2565 1340817
1372 1387 21187 21202 CATTCTGTGTTCTTGT 60 2566 1340820 N/A N/A 3432
3447 GTAGATGGTAAGTCAA 86 2567 1340826 1723 1738 21538 21553
AAATTGTCTAAACATC 24 2568 1340847 N/A N/A 6246 6261 ACTGGATGGATTTCTC
83 2569 1340854 N/A N/A 10201 10216 ATGGTAAGCCCCATGC 22 2570
1340855 N/A N/A 6471 6486 GTAATAGGCAGTAAAG 77 2571 1340866 N/A N/A
12794 12809 AAGAGTCAGTATCCTC 63 2572 1340877 N/A N/A 9521 9536
ATTCTACACTAATATT 0 2573 1340880 N/A N/A 5285 5300 ATAACTGAGCTAGACA
71 2574
TABLE-US-00036 TABLE 36 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO.: 1, and 2 SEQ SEQ SEQ SEQ ID NO: ID
NO: ID NO: ID NO: 1 1 2 2 SEQ Compound Start Stop Start Stop % ID
Number Site Site Site Site Sequence (5' to 3') Inhibition NO
1245927 N/A N/A 3433 3448 AGTAGATGGTAAGTCA 89 121 1246023 N/A N/A
5046 5061 GAGTGAATCATTCAGT 91 1526 1340087 N/A N/A 11578 11593
GTTATTCTCTTGACAA 42 2575 1340089 N/A N/A 11388 11403
AACTTTTAGTCAGGTA 49 2576 1340116 N/A N/A 16381 16396
CCCAACCAAACTTCCA 62 2577 1340124 603 618 10489 10504
ATGGGATGAGGTAAGG 46 2578 1340136 N/A N/A 13782 13797
ACAATCAGGAGTTGCA 62 2579 1340153 N/A N/A 5223 5238 TTAGCTTAAACTCCAA
78 2580 1340162 N/A N/A 12504 12519 CTTGCAGAAATTCACC 40 2581
1340188 N/A N/A 19489 19504 CATCTAGAATTAAGGG 53 2582 1340203 N/A
N/A 18690 18705 CTTTGAGACTCTTGTT 61 2583 1340207 N/A N/A 18002
18017 AGGCTTATGAAGTTAG 57 2584 1340216 N/A N/A 18971 18986
GTTGACTAATGCAAGA 59 2585 1340225 N/A N/A 18096 18111
AAATTGATACACCAAT 14 2586 1340227 N/A N/A 19891 19906
TGCTTACGACAGGTCA 81 2587 1340232 N/A N/A 19656 19671
ATCCATTCTATGCAAG 46 2588 1340240 1397 1412 21212 21227
AAACTTGATCTCTTAG 61 2589 1340248 1726 1741 21541 21556
CTAAAATTGTCTAAAC 35 2590 1340262 N/A N/A 12423 12438
GGTGGTAACGGTGATC 31 2591 1340281 N/A N/A 20122 20137
TGATTACAGCATCAAG 69 2592 1340285 2249 2264 22064 22079
GGATAGTCCATGCAAA 64 2593 1340293 1597 1612 21412 21427
TCTTATAAGACTATAA 17 2594 1340299 N/A N/A 14905 14920
AGCTAAGAGACACTTC 41 2595 1340313 N/A N/A 13568 13583
GAACAGTTCAACTGAA 10 2596 1340326 1054 1069 20869 20884
TATTATCAGGACTGAA 63 2597 1340328 N/A N/A 20382 20397
TAATCACAAGTAAGGT 54 2598 1340331 N/A N/A 8707 8722 GGGACCAATATAATCC
31 2599 1340351 N/A N/A 9194 9209 ACAACCCTTAACAAAC 26 2600 1340371
N/A N/A 6479 6494 CCAACTATGTAATAGG 68 2601 1340378 N/A N/A 9982
9997 TATTAAGACAGTTGAG 44 2602 1340407 N/A N/A 4140 4155
TTCTCAAGGAGTACTT 76 2603 1340417 N/A N/A 9422 9437 TATATGAGGTCTGTAT
42 2604 1340436 N/A N/A 9765 9780 CCAACCCAAGCTACCT 15 2605 1340441
N/A N/A 5812 5827 AGTCAGTATCCCCTCA 82 2606 1340442 N/A N/A 5718
5733 CTGCCAGATTGCACAA 44 2607 1340485 N/A N/A 5058 5073
ATTACAGCCTTAGAGT 56 2608 1340486 N/A N/A 3571 3586 CTATCAACCTGCACAC
39 2609 1340487 N/A N/A 6749 6764 GCCTAGTTGCAATGAG 61 2610 1340509
N/A N/A 7476 7491 TAACATTCGGCTAGGC 52 2611 1340511 N/A N/A 3933
3948 CTGCGCACATATTTTA 92 2612 1340516 N/A N/A 5667 5682
TAGAGAGCATAAGTTA 59 2613 1340523 N/A N/A 9927 9942 TGATTGAATTCACTAT
N.D. 2614 1340536 N/A N/A 11924 11939 CCAAAAATCAGCCACT 0 2615
1340550 N/A N/A 7768 7783 GCAGCTAAAATCCAAT 70 2616 1340557 N/A N/A
17672 17687 AACCTTTGTTGCCTGG 36 2617 1340559 N/A N/A 14462 14477
GAGGTATGTCATACTT 29 2618 1340562 N/A N/A 15510 15525
TATTCCAGGATTTGCT 43 2619 1340564 N/A N/A 3435 3450 TAAGTAGATGGTAAGT
74 2620 1340581 N/A N/A 8613 8628 GGCCAAGGGAACACTG 36 2621 1340589
1200 1215 21015 21030 ATGTTTATGTAAGCAC 70 2622 1340591 N/A N/A 3693
3708 ATCCCGTTCTTGCCCA 30 2623 1340593 N/A N/A 12169 12184
CCTTACCTTGTGCTTG 20 2624 1340595 N/A N/A 8017 8032 ATCTCACAAGGGAAAT
73 2625 1340596 N/A N/A 6435 6450 CTAGTGGTAATGGTAA 62 2626 1340602
N/A N/A 10206 10221 TTGGTATGGTAAGCCC 62 2627 1340605 N/A N/A 5286
5301 TATAACTGAGCTAGAC 53 2628 1340621 N/A N/A 9327 9342
ATATACATCCAAGTAA 18 2629 1340622 N/A N/A 6247 6262 CACTGGATGGATTTCT
72 2630 1340641 N/A N/A 5176 5191 AGTTTAGATTGCATAA 50 2631 1340644
N/A N/A 16282 16297 TAGTCTTCAGCAAAGT 49 2632 1340652 N/A N/A 14168
14183 ATAGCAAGCCAACAGA 37 2633 1340675 N/A N/A 14201 14216
ATTATTATGTGATTGA 39 2634 1340682 N/A N/A 9525 9540 CTAGATTCTACACTAA
17 2635 1340688 N/A N/A 9629 9644 TAGTTTGGTGGGCATG 28 2636 1340699
N/A N/A 20487 20502 TAACTTCATAGTGGAC 76 2637 1340707 N/A N/A 16130
16145 CTCCATAATAATAGCT 59 2638 1340710 N/A N/A 9962 9977
GTAAGCTGAGAGTTCT 49 2639 1340736 N/A N/A 4640 4655 TACGACTTCCTTCTAA
67 2640 1340774 N/A N/A 15212 15227 CCATAAAGCTGGATTG 40 2641
1340779 N/A N/A 5992 6007 AGAGGCAAGGATACCT 78 2642 1340797 N/A N/A
18517 18532 AGTACCAAGACACTAA 66 2643 1340814 N/A N/A 8237 8252
ACTACATGACCTGGGT 54 2644 1340818 N/A N/A 9077 9092 ACTTGAATTCTGTGTC
52 2645 1340849 N/A N/A 6316 6331 GACCATGCTGCTACTC 74 2646 1340853
N/A N/A 10978 10993 CAGCATTGTAATCTTG 43 2647 1340858 N/A N/A 6715
6730 GCCAGGGAATGCTCAT 38 2648 1340860 N/A N/A 12796 12811
GTAAGAGTCAGTATCC 47 2649 1340886 N/A N/A 5888 5903 TATTTCGCTACTGTAG
48 2650 1340887 N/A N/A 20009 20024 AGAGAGTAATCAGTTT 39 2651
TABLE-US-00037 TABLE 37 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO.: 1, and 2 SEQ SEQ SEQ SEQ ID NO: ID
NO: ID NO: ID NO: 1 1 2 2 SEQ Compound Start Stop Start Stop % ID
Number Site Site Site Site Sequence (5' to 3') Inhibition NO
1245927 N/A N/A 3433 3448 AGTAGATGGTAAGTCA 83 121 1246023 N/A N/A
5046 5061 GAGTGAATCATTCAGT 76 1526 1340073 N/A N/A 12797 12812
TGTAAGAGTCAGTATC 43 2652 1340074 1203 1218 21018 21033
AGTATGTTTATGTAAG 48 2653 1340084 N/A N/A 18692 18707
GACTTTGAGACTCTTG 65 2654 1340091 N/A N/A 9333 9348 GATCCTATATACATCC
49 2655 1340101 N/A N/A 11391 11406 TGCAACTTTTAGTCAG 41 2656
1340103 N/A N/A 16383 16398 ATCCCAACCAAACTTC 15 2657 1340140 605
620 10491 10506 ATATGGGATGAGGTAA 37 2658 1340159 N/A N/A 6029 6044
TTCCGTCTCACAATCT 79 2659 1340174 N/A N/A 13571 13586
TCAGAACAGTTCAACT 30 2660 1340178 1598 1613 21413 21428
ATCTTATAAGACTATA 32 2661 1340202 N/A N/A 19658 19673
GAATCCATTCTATGCA 47 2662 1340217 N/A N/A 11579 11594
AGTTATTCTCTTGACA 48 2663 1340236 N/A N/A 20491 20506
GACATAACTTCATAGT 39 2664 1340237 N/A N/A 16131 16146
GCTCCATAATAATAGC 21 2665 1340250 N/A N/A 12170 12185
ACCTTACCTTGTGCTT 0 2666 1340252 N/A N/A 18518 18533
TAGTACCAAGACACTA 27 2667 1340253 N/A N/A 18003 18018
AAGGCTTATGAAGTTA 61 2668 1340317 N/A N/A 18098 18113
TGAAATTGATACACCA 58 2669 1340376 N/A N/A 5304 5319 CGGCCTATTCTTCTGT
25 2670 1340389 N/A N/A 7478 7493 ATTAACATTCGGCTAG 17 2671 1340392
N/A N/A 19498 19513 AATATCAGCCATCTAG 24 2672 1340410 1074 1089
20889 20904 TGCCAAACCAATGTTT 32 2673 1340413 N/A N/A 9195 9210
GACAACCCTTAACAAA 24 2674 1340447 N/A N/A 3436 3451 ATAAGTAGATGGTAAG
58 2675 1340461 N/A N/A 17676 17691 TCAAAACCTTTGTTGC 6 2676 1340463
N/A N/A 6716 6731 TGCCAGGGAATGCTCA 23 2677 1340464 N/A N/A 9647
9662 ATGTATGAGGTCTCCG 63 2678 1340477 N/A N/A 13824 13839
ACCAAGAGGGTTTTTA 7 2679 1340495 N/A N/A 4648 4663 ATTTTTAATACGACTT
35 2680 1340497 N/A N/A 9963 9978 TGTAAGCTGAGAGTTC 45 2681 1340507
N/A N/A 9766 9781 CCCAACCCAAGCTACC 22 2682 1340517 N/A N/A 18983
18998 CACTTTGGTATTGTTG 53 2683 1340528 N/A N/A 8636 8651
GACTGTTGAGCTCAAA 52 2684 1340537 N/A N/A 5669 5684 AGTAGAGAGCATAAGT
52 2685 1340540 N/A N/A 8040 8055 GACTACATTAACACCA 58 2686 1340541
N/A N/A 6438 6453 AAACTAGTGGTAATGG 47 2687 1340568 N/A N/A 20123
20138 CTGATTACAGCATCAA 40 2688 1340573 N/A N/A 6762 6777
CTTGAGAGTGATTGCC 64 2689 1340579 2250 2265 22065 22080
AGGATAGTCCATGCAA 64 2690 1340592 N/A N/A 10218 10233
GATACAAATTTATTGG 33 2691 1340598 N/A N/A 5720 5735 CACTGCCAGATTGCAC
38 2692 1340608 N/A N/A 3575 3590 CTTTCTATCAACCTGC 68 2693 1340615
N/A N/A 14475 14490 AGTATGACAACTGGAG 15 2694 1340616 N/A N/A 20046
20061 CGTAACCATGCATTAA 68 2695 1340618 N/A N/A 6248 6263
CCACTGGATGGATTTC 68 2696 1340624 N/A N/A 7772 7787 GTTAGCAGCTAAAATC
45 2697 1340635 N/A N/A 5814 5829 AAAGTCAGTATCCCCT 77 2698 1340649
N/A N/A 4222 4237 TCAACTAAACATGACA 77 2699 1340660 N/A N/A 9933
9948 GAATCATGATTGAATT 39 2700 1340672 N/A N/A 3695 3710
AGATCCCGTTCTTGCC 68 2701 1340676 N/A N/A 5182 5197 CGCAACAGTTTAGATT
57 2702 1340703 N/A N/A 14911 14926 TTAGCAAGCTAAGAGA 42 2703
1340708 N/A N/A 12424 12439 GGGTGGTAACGGTGAT 46 2704 1340712 N/A
N/A 3952 3967 CAAGGAAAAGCCTGAC 59 2705 1340715 N/A N/A 8256 8271
CTGGTTTCATAACCTA 9 2706 1340718 N/A N/A 9423 9438 TTATATGAGGTCTGTA
32 2707 1340730 N/A N/A 8709 8724 TTGGGACCAATATAAT 18 2708 1340738
N/A N/A 11965 11980 TGTGAGAAGGCGGTAT 20 2709 1340743 N/A N/A 5890
5905 TGTATTTCGCTACTGT 76 2710 1340754 N/A N/A 16284 16299
AATAGTCTTCAGCAAA 48 2711 1340758 N/A N/A 19904 19919
AAGATACCCAGGTTGC 59 2712 1340784 N/A N/A 5226 5241 GCTTTAGCTTAAACTC
72 2713 1340787 N/A N/A 9081 9096 GTCCACTTGAATTCTG 18 2714 1340799
N/A N/A 5066 5081 TGAGTTACATTACAGC 90 2715 1340825 1748 1763 21563
21578 GTGTTAGCTTTAATTT 48 2716 1340844 1398 1413 21213 21228
GAAACTTGATCTCTTA 64 2717 1340851 N/A N/A 9528 9543 GCCCTAGATTCTACAC
15 2718 1340868 N/A N/A 15214 15229 TTCCATAAAGCTGGAT 5 2719 1340869
N/A N/A 11073 11088 TACAACCTGGTTTCAT 25 2720 1340881 N/A N/A 6321
6336 AGGGAGACCATGCTGC 79 2721 1340888 N/A N/A 6480 6495
ACCAACTATGTAATAG 47 2722 1340890 N/A N/A 14204 14219
CAGATTATTATGTGAT 51 2723 1340900 N/A N/A 9989 10004
GTAACTGTATTAAGAC 54 2724 1340906 N/A N/A 12506 12521
TTCTTGCAGAAATTCA 42 2725 1340912 N/A N/A 14169 14184
AATAGCAAGCCAACAG 9 2726 1340914 N/A N/A 20384 20399
AGTAATCACAAGTAAG 54 2727 1340915 794 809 15675 15690
ATCTATCAGACTTCTT 47 2728
TABLE-US-00038 TABLE 38 Inhibition of HSD17B13 RNA by 3-10-3 cEt
gapmers targeting SEQ ID NO.: 1, and 2 SEQ SEQ SEQ SEQ ID NO: ID
NO: ID NO: ID NO: 1 1 2 2 SEQ Compound Start Stop Start Stop % ID
Number Site Site Site Site Sequence (5' to 3') Inhibition NO
1245927 N/A N/A 3433 3448 AGTAGATGGTAAGTCA 84 121 1246023 N/A N/A
5046 5061 GAGTGAATCATTCAGT 91 1526 1340076 N/A N/A 12426 12441
CAGGGTGGTAACGGTG 55 2729 1340079 N/A N/A 12191 12206
ACCCATTCTAACTTGA 0 2730 1340105 N/A N/A 13825 13840
TACCAAGAGGGTTTTT 17 2731 1340107 N/A N/A 12798 12813
CTGTAAGAGTCAGTAT 42 2732 1340112 N/A N/A 20493 20508
TTGACATAACTTCATA 15 2733 1340115 N/A N/A 12003 12018
TGTTAGCTAAGGGAGA 0 2734 1340139 N/A N/A 17768 17783
CAGCATATTCATTTGG 49 2735 1340147 N/A N/A 5831 5846 TGTTAGGACCCAGTCT
51 2736 1340161 N/A N/A 6764 6779 TTCTTGAGAGTGATTG 52 2737 1340167
N/A N/A 4659 4674 GCCCTTAAGTCATTTT 25 2738 1340173 N/A N/A 11075
11090 ATTACAACCTGGTTTC 50 2739 1340184 N/A N/A 14913 14928
CATTAGCAAGCTAAGA 0 2740 1340186 N/A N/A 13576 13591
CACTATCAGAACAGTT 24 2741 1340214 N/A N/A 14173 14188
CTTGAATAGCAAGCCA 25 2742 1340219 N/A N/A 18519 18534
TTAGTACCAAGACACT 41 2743 1340224 N/A N/A 20109 20124
AAGACATTCTAGCCTG 63 2744 1340242 N/A N/A 12616 12631
ATGGCTTAATTTTCGG 33 2745 1340251 N/A N/A 20190 20205
AGTTATTAGAAGTCAG 54 2746 1340257 N/A N/A 20386 20401
ATAGTAATCACAAGTA 56 2747 1340267 1749 1764 21564 21579
TGTGTTAGCTTTAATT 38 2748 1340296 N/A N/A 14476 14491
GAGTATGACAACTGGA 23 2749 1340298 808 823 15689 15704
TTGGTAAGTATTCCAT 20 2750 1340316 1175 1190 20990 21005
TAAGAGGCATGAAAGG 52 2751 1340325 N/A N/A 8713 8728 AGTTTTGGGACCAATA
31 2752 1340343 N/A N/A 11580 11595 GAGTTATTCTCTTGAC 57 2753
1340344 N/A N/A 7479 7494 AATTAACATTCGGCTA 38 2754 1340365 N/A N/A
16384 16399 AATCCCAACCAAACTT 23 2755 1340374 N/A N/A 19673 19688
CAAGAGACACCACCAG 50 2756 1340381 N/A N/A 6439 6454 TAAACTAGTGGTAATG
14 2757 1340383 N/A N/A 5894 5909 CCTTTGTATTTCGCTA 47 2758 1340408
N/A N/A 6326 6341 TTCATAGGGAGACCAT 65 2759 1340421 N/A N/A 9964
9979 GTGTAAGCTGAGAGTT 60 2760 1340424 N/A N/A 10499 10514
ACTTACCAATATGGGA 0 2761 1340457 N/A N/A 15247 15262
ATAGCTAAGTATACTT 0 2762 1340480 N/A N/A 18102 18117
ATACTGAAATTGATAC 11 2763 1340481 N/A N/A 9651 9666 GCTAATGTATGAGGTC
78 2764 1340483 N/A N/A 9112 9127 AGACCAAGTAGCTTAC 42 2765 1340488
N/A N/A 5070 5085 GATCTGAGTTACATTA 69 2766 1340502 N/A N/A 9999
10014 GAAATCTTGTGTAACT 69 2767 1340535 N/A N/A 9198 9213
ACTGACAACCCTTAAC 10 2768 1340551 N/A N/A 16285 16300
GAATAGTCTTCAGCAA 51 2769 1340569 N/A N/A 8050 8065 TTCTACAGAAGACTAC
40 2770 1340583 N/A N/A 9432 9447 ACTAACCAATTATATG 6 2771 1340611
N/A N/A 16132 16147 TGCTCCATAATAATAG 35 2772 1340623 1603 1618
21418 21433 AATGTATCTTATAAGA 10 2773 1340632 N/A N/A 18998 19013
AGTCATATTGAAAATC 39 2774 1340637 N/A N/A 7773 7788 AGTTAGCAGCTAAAAT
33 2775 1340639 N/A N/A 5185 5200 CAACGCAACAGTTTAG 52 2776 1340656
N/A N/A 10258 10273 AGCATTCCATGATTAA 47 2777 1340658 N/A N/A 18005
18020 CCAAGGCTTATGAAGT 27 2778 1340662 N/A N/A 8279 8294
TCTAAAGTGCTGGTTG 34 2779 1340663 N/A N/A 6482 6497 GCACCAACTATGTAAT
53 2780 1340666 N/A N/A 3697 3712 TCAGATCCCGTTCTTG 59 2781 1340702
N/A N/A 3584 3599 CTCCTGAGTCTTTCTA 23 2782 1340714 N/A N/A 5227
5242 TGCTTTAGCTTAAACT 51 2783 1340720 N/A N/A 19531 19546
GCTAAAATGGTCATCT 40 2784 1340721 2356 2371 22171 22186
TTTATAACTACAAGAG 38 2785 1340732 N/A N/A 8639 8654 ACAGACTGTTGAGCTC
53 2786 1340733 1254 1269 21069 21084 TTTTGTCCACCTTTAA 68 2787
1340735 N/A N/A 9334 9349 CGATCCTATATACATC 33 2788 1340745 N/A N/A
9767 9782 TCCCAACCCAAGCTAC 8 2789 1340760 N/A N/A 19905 19920
TAAGATACCCAGGTTG 39 2790 1340764 N/A N/A 3478 3493 GACCAGGGAATTTATC
41 2791 1340766 N/A N/A 9934 9949 TGAATCATGATTGAAT 38 2792 1340793
N/A N/A 5646 5661 GCATTCATCAGATGTT 89 2793 1340794 N/A N/A 6717
6732 CTGCCAGGGAATGCTC 23 2794 1340796 N/A N/A 6033 6048
ACTTTTCCGTCTCACA 89 2795 1340806 N/A N/A 5671 5686 TCAGTAGAGAGCATAA
52 2796 1340809 1417 1432 21232 21247 TGAGATAAAGCTGCCT 63 2797
1340827 N/A N/A 5732 5747 TGGTAGCTTGCTCACT 71 2798 1340829 N/A N/A
6249 6264 GCCACTGGATGGATTT 36 2799 1340856 N/A N/A 11392 11407
CTGCAACTTTTAGTCA 21 2800 1340862 N/A N/A 9530 9545 CTGCCCTAGATTCTAC
33 2801 1340867 N/A N/A 14263 14278 GAGTTAGGGAGCCAGC 39 2802
1340882 N/A N/A 4223 4238 TTCAACTAAACATGAC 55 2803 1340897 N/A N/A
18693 18708 AGACTTTGAGACTCTT 57 2804 1340911 N/A N/A 3988 4003
GTTTACAAGTAAGAAC 42 2805
[0523] Modified oligonucleotides complementary to an HSD17B13
nucleic acid with other chemistry modifications were synthesized
and tested for their effect on HSD17B13 RNA levels in vitro, as
described above. The Chemistry Notation column in the Tables below
specifies the chemistry of each modified oligonucleotide; wherein
subscript `d` represents a 2'-.beta.-D-deoxyribosyl sugar moiety,
subscript `e` represents a 2'-MOE sugar moiety, subscript `y`
represents a 2'-O-methyl sugar moiety, subscript `k` represents a
cEt modified sugar moiety, subscript `s` represents a
phosphorothioate internucleoside linkage, and superscript `m`
before the cytosine residue represents a 5-methyl cytosine.
TABLE-US-00039 TABLE 39 Inhibition of HSD17B13 RNA by modified
oligonucleotides targeting SEQ ID NO.: 1, and 2 SEQ ID SEQ ID SEQ
ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ Compound Start Stop Start
Stop Sequence Chemistry Notation % ID Number Site Site Site Site
(5' to 3') (5' to 3') Inhibition NO 1245927 N/A N/A 3433 3448
AGTAGATGGTAAGTCA
A.sub.ksG.sub.ksT.sub.ksA.sub.dsG.sub.dsA.sub.dsT.sub.dsG.sub.dsG.sub.ds
78 121
T.sub.dsA.sub.dsA.sub.dsG.sub.dsT.sub.ks.sup.mC.sub.ksA.sub.k
1246023 N/A N/A 5046 5061 GAGTGAATCATTCAGT
G.sub.ksA.sub.ksG.sub.ksT.sub.dsG.sub.dsA.sub.dsA.sub.dsT.sub.ds.sup.m
78 1526
C.sub.dsA.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ksG.sub.ksT.sub.-
k 1341171 700 715 12118 12133 CAGAGACATGAGGTTT
.sup.mC.sub.ksA.sub.ksG.sub.dsA.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.dsA.sub-
.ds 61 2319
T.sub.dsG.sub.dsA.sub.dsG.sub.ksG.sub.esT.sub.ksT.sub.esT.sub.k
1341175 794 809 15675 15690 ATCTATCAGACTTCTT
A.sub.ksT.sub.ks.sup.mC.sub.dsT.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.dsA.sub-
.ds 37 2728
G.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.ksT.sub.es.sup.mC.sub.ksT.sub.es-
T.sub.k 1341179 606 621 10492 10507 AATATGGGATGAGGTA
A.sub.ksA.sub.ksT.sub.dsA.sub.dsT.sub.dsG.sub.dsG.sub.dsG.sub.dsA.sub.ds
52 1424 T.sub.dsG.sub.dsA.sub.ksG.sub.esG.sub.ksT.sub.esA.sub.k
1341180 1080 1095 20895 20910 TGCTAGTGCCAAACCA
T.sub.ksG.sub.ks.sup.mC.sub.dsT.sub.dsA.sub.dsG.sub.dsT.sub.dsG.sub.ds.su-
p.m 58 1432
C.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.ksA.sub.es.sup.mC.sub.ks.sup.mC.-
sub.esA.sub.k 1341189 1019 1034 20834 20849 TGCAGCATTGATTCGA
T.sub.ksG.sub.ks.sup.mC.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.dsT.sub-
.ds 42 419
T.sub.dsG.sub.dsA.sub.dsT.sub.ksT.sub.es.sup.mC.sub.ksG.sub.esA.sub.-
k 1341190 1258 1273 21073 21088 TAGCTTTTGTCCACCT
T.sub.ksA.sub.ksG.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsT.sub.dsT.sub.dsG.s-
ub.ds 71 1900
T.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksA.sub.es.sup.mC.sub.ks.sup.mC.su-
b.esT.sub.k 1341193 1202 1217 21017 21032 GTATGTTTATGTAAGC
G.sub.ksT.sub.ksA.sub.dsT.sub.dsG.sub.dsT.sub.dsT.sub.dsT.sub.dsA.sub.ds
72 1511
T.sub.dsG.sub.dsT.sub.ksA.sub.esA.sub.ksG.sub.es.sup.mC.sub.k
1341198 1084 1099 20899 20914 CTGCTGCTAGTGCCAA
.sup.mC.sub.ksT.sub.ksG.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.d-
sT.sub.ds 44 1743
A.sub.dsG.sub.dsT.sub.dsG.sub.ks.sup.mC.sub.es.sup.mC.sub.ksA.sub.es-
A.sub.k 1341200 1316 1331 21131 21146 AACAGTCTTAAACCTT
A.sub.ksA.sub.ks.sup.mC.sub.dsA.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.dsT.sub-
.ds 37 188
T.sub.dsA.sub.dsA.sub.dsA.sub.ks.sup.mC.sub.es.sup.mC.sub.ksT.sub.es-
T.sub.k 1341213 1324 1339 21139 21154 GCTACTTGAACAGTCT
G.sub.ks.sup.mC.sub.ksT.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsG.sub-
.ds 64 811
A.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.ksG.sub.esT.sub.ks.sup.mC.sub.es-
T.sub.k 1341217 1312 1327 21127 21142 GTCTTAAACCTTCCCT
G.sub.ksT.sub.ks.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.dsA.sub.dsA.sub.ds.su-
p.m 28 1901
C.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ks.sup.mC.sub.es.sup.mC.sub.ks.s-
up.mC.sub.esT.sub.k 1341228 1333 1348 21148 21163 GATTGGAATGCTACTT
G.sub.ksA.sub.ksT.sub.dsT.sub.dsG.sub.dsG.sub.dsA.sub.dsA.sub.dsT.sub.ds
53 1435
G.sub.ds.sup.mC.sub.dsT.sub.ksA.sub.es.sup.mC.sub.ksT.sub.esT.sub.k
1341234 1356 1371 21171 21186 TGATATTCTGTGGCAT
T.sub.ksG.sub.ksA.sub.dsT.sub.dsA.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsT.s-
ub.ds 46 1124
G.sub.dsT.sub.dsG.sub.ksG.sub.es.sup.mC.sub.ksA.sub.esT.sub.k
1341236 1352 1367 21167 21182 ATTCTGTGGCATGGCT
A.sub.ksT.sub.ksT.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.dsT.sub.dsG.sub.dsG.s-
ub.ds 55 2328
.sup.mC.sub.dsA.sub.dsT.sub.ksG.sub.esG.sub.ks.sup.mC.sub.esT.sub.k
1341239 1340 1355 21155 21170 GGCTACAGATTGGAAT
G.sub.ksG.sub.ks.sup.mC.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.dsG.sub-
.ds 73 1980
A.sub.dsT.sub.dsT.sub.dsG.sub.ksG.sub.esA.sub.ksA.sub.esT.sub.k
1341241 1387 1402 21202 21217 TCTTAGCTGTGCACTC
T.sub.ks.sup.mC.sub.ksT.sub.dsT.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.dsT.sub-
.dsG 50 190
.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.ksA.sub.es.sup.mC.sub.ksT.sub.es.-
sup.mC.sub.k 1341247 1364 1379 21179 21194 GTTCTTGTTGATATTC
G.sub.ksT.sub.ksT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsG.sub.dsT.sub.dsT.s-
ub.ds 66 1436
G.sub.dsA.sub.dsT.sub.ksA.sub.esT.sub.ksT.sub.es.sup.mC.sub.k
1341250 1393 1408 21208 21223 TTGATCTCTTAGCTGT
T.sub.ksT.sub.ksG.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.ds.sup.mC.sub-
.ds 38 658
T.sub.dsT.sub.dsA.sub.dsG.sub.ks.sup.mC.sub.esT.sub.ksG.sub.esT.sub.-
k 1341258 1420 1435 21235 21250 GGTTGAGATAAAGCTG
G.sub.ksG.sub.ksT.sub.dsT.sub.dsG.sub.dsA.sub.dsG.sub.dsA.sub.dsT.sub.ds
60 1826
A.sub.dsA.sub.dsA.sub.ksG.sub.es.sup.mC.sub.ksT.sub.esG.sub.k
1341263 1489 1504 21304 21319 CGTTTTGGGCTAATGA
.sup.mC.sub.ksG.sub.ksT.sub.dsT.sub.dsT.sub.dsT.sub.dsG.sub.dsG.sub.dsG.s-
ub.ds 37 1282
.sup.mC.sub.dsT.sub.dsA.sub.ksA.sub.esT.sub.ksG.sub.esA.sub.k
1341267 1493 1508 21308 21323 GCACCGTTTTGGGCTA
G.sub.ks.sup.mC.sub.ksA.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsG.sub.dsT.sub.d-
sT.sub.ds 49 1593
T.sub.dsT.sub.dsG.sub.dsG.sub.ksG.sub.es.sup.mC.sub.ksT.sub.esA.sub.-
k 1341274 1497 1512 21312 21327 AGTTGCACCGTTTTGG
A.sub.ksG.sub.ksT.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub-
.ds.sup.m 41 1905
C.sub.dsG.sub.dsT.sub.dsT.sub.ksT.sub.esT.sub.ksG.sub.esG.sub.k
1341280 1622 1637 21437 21452 AGAGTCGGTCACCTTT
A.sub.ksG.sub.ksA.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.dsG.sub.dsG.sub.ds
61 428
T.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ks.sup.mC.sub.esT.sub.ksT.-
sub.esT.sub.k 1341281 1630 1645 21445 21460 TTTAAAATAGAGTCGG
T.sub.ksT.sub.ksT.sub.dsA.sub.dsA.sub.dsA.sub.dsA.sub.dsT.sub.dsA.sub.ds
43 1051
G.sub.dsA.sub.dsG.sub.ksT.sub.es.sup.mC.sub.ksG.sub.esG.sub.k
1341287 1618 1633 21433 21448 TCGGTCACCTTTCATA
T.sub.ks.sup.mC.sub.ksG.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ds.sup.-
mC.sub.ds 63 116
.sup.mC.sub.dsT.sub.dsT.sub.dsT.sub.ks.sup.mC.sub.esA.sub.ksT.sub.es-
A.sub.k 1341290 1626 1641 21441 21456 AAATAGAGTCGGTCAC
A.sub.ksA.sub.ksA.sub.dsT.sub.dsA.sub.dsG.sub.dsA.sub.dsG.sub.dsT.sub.ds
50 740
.sup.mC.sub.dsG.sub.dsG.sub.ksT.sub.es.sup.mC.sub.ksA.sub.es.sup.mC.-
sub.k 1341296 1714 1729 21529 21544 AAACATCTCTGGGACC
A.sub.ksA.sub.ksA.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.dsT.sub-
.ds.sup.m 36 2129
C.sub.dsT.sub.dsG.sub.dsG.sub.ksG.sub.esA.sub.ks.sup.mC.sub.es.sup.m-
C.sub.k 1341297 1710 1725 21525 21540 ATCTCTGGGACCAAGG
A.sub.ksT.sub.ks.sup.mC.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.dsG.sub-
.dsG 65 37
.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksA.sub.esA.sub.ksG.sub.esG-
.sub.k 1341303 1768 1783 21583 21598 CCAGTACAGTTCCTTT
.sup.mC.sub.ks.sup.mC.sub.ksA.sub.dsG.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.d-
sA.sub.ds 75 1753
G.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ks.sup.mC.sub.esT.sub.ksT.sub.es-
T.sub.k 1341305 1750 1765 21565 21580 CTGTGTTAGCTTTAAT
.sup.mC.sub.ksT.sub.ksG.sub.dsT.sub.dsG.sub.dsT.sub.dsT.sub.dsA.sub.dsG.s-
ub.ds 47 1286
.sup.mC.sub.dsT.sub.dsT.sub.ksT.sub.esA.sub.ksA.sub.esT.sub.k
1341313 1778 1793 21593 21608 TATGTAATAGCCAGTA
T.sub.ksA.sub.ksT.sub.dsG.sub.dsT.sub.dsA.sub.dsA.sub.dsT.sub.dsA.sub.ds
78 508
G.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksA.sub.esG.sub.ksT.sub.esA.sub.k
1341315 1782 1797 21597 21612 TTCTTATGTAATAGCC
T.sub.ksT.sub.ks.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.dsT.sub.dsG.sub.dsT.s-
ub.ds 78 819
A.sub.dsA.sub.dsT.sub.ksA.sub.esG.sub.ks.sup.mC.sub.es.sup.mC.sub.k
1341325 2247 2262 22062 22077 ATAGTCCATGCAAAAG
A.sub.ksT.sub.ksA.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub-
.ds 31 2436
T.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.ksA.sub.esA.sub.ksA.sub.esG.sub.-
k 1341328 2193 2208 22008 22023 TAGTCTTGATGTAGTG
T.sub.ksA.sub.ksG.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsG.sub.dsA.s-
ub.ds 43 1288
T.sub.dsG.sub.dsT.sub.ksA.sub.esG.sub.ksT.sub.esG.sub.k 1341339 N/A
N/A 9330 9345 CCTATATACATCCAAG
.sup.mC.sub.ks.sup.mC.sub.ksT.sub.dsA.sub.dsT.sub.dsA.sub.dsT.sub.dsA.sub-
.ds.sup.m 61 1771
C.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.ks.sup.mC.sub.esA.sub.ksA.sub.es-
G.sub.k 1341343 N/A N/A 11571 11586 TCTTGACAATGGTTGA
T.sub.ks.sup.mC.sub.ksT.sub.dsT.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.dsA.sub-
.ds 40 2440
A.sub.dsT.sub.dsG.sub.dsG.sub.ksT.sub.esT.sub.ksG.sub.esA.sub.k
1341344 N/A N/A 11855 11870 TAAGCAGAATTGTGAA
T.sub.ksA.sub.ksA.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.dsA.sub.ds
29 2361
A.sub.dsT.sub.dsT.sub.dsG.sub.ksT.sub.esG.sub.ksA.sub.esA.sub.k
1341347 N/A N/A 9964 9979 GTGTAAGCTGAGAGTT
G.sub.ksT.sub.ksG.sub.dsT.sub.dsA.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.ds
57 2760
T.sub.dsG.sub.dsA.sub.dsG.sub.ksA.sub.esG.sub.ksT.sub.esT.sub.k
1341351 N/A N/A 12423 12438 GGTGGTAACGGTGATC
G.sub.ksG.sub.ksT.sub.dsG.sub.dsG.sub.dsT.sub.dsA.sub.dsA.sub.ds.sup.m
39 2591
C.sub.dsG.sub.dsG.sub.dsT.sub.ksG.sub.esA.sub.ksT.sub.es.sup.mC.sub.-
k 1341354 N/A N/A 14914 14929 ACATTAGCAAGCTAAG
A.sub.ks.sup.mC.sub.ksA.sub.dsT.sub.dsT.sub.dsA.sub.dsG.sub.ds.sup.mC.sub-
.ds 23 2065
A.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.ksT.sub.esA.sub.ksA.sub.esG.sub.-
k 1341360 N/A N/A 15494 15509 GCATTAATGCCACCCT
G.sub.ks.sup.mC.sub.ksA.sub.dsT.sub.dsT.sub.dsA.sub.dsA.sub.dsT.sub.dsG.s-
ub.ds 24 1012
.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ks.sup.mC.sub.es.sup.mC.sub.ks.sup-
.mC.sub.esT.sub.k
1341361 N/A N/A 16287 16302 TAGAATAGTCTTCAGC
T.sub.ksA.sub.ksG.sub.dsA.sub.dsA.sub.dsT.sub.dsA.sub.dsG.sub.dsT.sub.ds
50 1403
.sup.mC.sub.dsT.sub.dsT.sub.ks.sup.mC.sub.esA.sub.ksG.sub.es.sup.mC.-
sub.k 1341375 N/A N/A 17992 18007 AGTTAGTATAGTTATC
A.sub.ksG.sub.ksT.sub.dsT.sub.dsA.sub.dsG.sub.dsT.sub.dsA.sub.dsT.sub.ds
47 1249
A.sub.dsG.sub.dsT.sub.ksT.sub.esA.sub.ksT.sub.es.sup.mC.sub.k
1341377 N/A N/A 16380 16395 CCAACCAAACTTCCAG
.sup.mC.sub.ks.sup.mC.sub.ksA.sub.dsA.sub.ds.sup.mc.sub.ds.sup.mC.sub.dsA-
.sub.ds 15 2539
A.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ks.sup.mC.sub.es.sup.mC.-
sub.ksA.sub.esG.sub.k 1341382 N/A N/A 19908 19923 TCTTAAGATACCCAGG
T.sub.ks.sup.mC.sub.ksT.sub.dsT.sub.dsA.sub.dsA.sub.dsG.sub.dsA.sub.dsT.s-
ub.ds 35 319
A.sub.ds.sup.mC.sub.ds.sup.mC.sub.ks.sup.mC.sub.esA.sub.ksG.sub.esG.-
sub.k 1341387 N/A N/A 18693 18708 AGACTTTGAGACTCTT
A.sub.ksG.sub.ksA.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsT.sub.dsG.sub.dsA.s-
ub.ds 55 2804
G.sub.dsA.sub.ds.sup.mC.sub.ksT.sub.es.sup.mC.sub.ksT.sub.esT.sub.k
1341389 N/A N/A 19912 19927 TGCATCTTAAGATACC
T.sub.ksG.sub.ks.sup.mC.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub-
.ds 24 2050
A.sub.dsA.sub.dsG.sub.dsA.sub.ksT.sub.esA.sub.ks.sup.mC.sub.es.sup.m-
C.sub.k 1341393 N/A N/A 20381 20396 AATCACAAGTAAGGTA
A.sub.ksA.sub.ksT.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.dsA.sub-
.ds 59 1333
G.sub.dsT.sub.dsA.sub.dsA.sub.ksG.sub.esG.sub.ksT.sub.esA.sub.k
1341396 N/A N/A 20116 20131 CAGCATCAAGACATTC
.sup.mC.sub.ksA.sub.ksG.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.d-
sA.sub.ds 62 2191
A.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.ksA.sub.esT.sub.ksT.sub.es.sup.m-
C.sub.k 1341406 N/A N/A 12503 12518 TTGCAGAAATTCACCT
T.sub.ksT.sub.ksG.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.dsA.sub.dsA.sub.ds
46 2528
A.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ksA.sub.es.sup.mC.sub.ks.sup.mC.-
sub.esT.sub.k 1341407 N/A N/A 20482 20497 TCATAGTGGACTTCAT
T.sub.ks.sup.mC.sub.ksA.sub.dsT.sub.dsA.sub.dsG.sub.dsT.sub.dsG.sub.ds
48 633
G.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.ksT.sub.es.sup.mC.sub.ksA.sub.es-
T.sub.k 1341412 N/A N/A 14196 14211 TATGTGATTGAGTTCT
T.sub.ksA.sub.ksT.sub.dsG.sub.dsT.sub.dsG.sub.dsA.sub.dsT.sub.dsT.sub.ds
23 2367
G.sub.dsA.sub.dsG.sub.ksT.sub.esT.sub.ks.sup.mC.sub.esT.sub.k
1341415 N/A N/A 13952 13967 TCTAAGTTAGCCCCCA
T.sub.ks.sup.mC.sub.ksT.sub.dsA.sub.dsA.sub.dsG.sub.dsT.sub.dsT.sub.dsA.s-
ub.ds 19 928
G.sub.ds.sup.mC.sub.ds.sup.mC.sub.ks.sup.mC.sub.es.sup.mC.sub.ks.sup-
.mC.sub.esA.sub.k 1341417 N/A N/A 14170 14185 GAATAGCAAGCCAACA
G.sub.ksA.sub.ksA.sub.dsT.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.ds
27 1708
A.sub.dsG.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksA.sub.esA.sub.ks.sup.mC.-
sub.esA.sub.k 1341532 805 820 15686 15701 GTAAGTATTCCATCTA
G.sub.ksT.sub.ksA.sub.dsA.sub.dsG.sub.dsT.sub.dsA.sub.dsT.sub.dsT.sub.ds
53 1038
.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ksT.sub.es.sup.mC.sub.ksT.sub.esA.-
sub.k 1341534 613 628 N/A N/A CTGGAACAATATGGGA
.sup.mC.sub.ksT.sub.ksG.sub.dsG.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.dsA.sub-
.ds 33 1969
A.sub.dsT.sub.dsA.sub.dsT.sub.ksG.sub.esG.sub.ksG.sub.esA.sub.k
1341538 1091 1106 20906 20921 CGTTTGACTGCTGCTA
.sup.mC.sub.ksG.sub.ksT.sub.dsT.sub.dsT.sub.dsG.sub.dsA.sub.ds.sup.mC.sub-
.ds 48 264
T.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.ksG.sub.es.sup.mC.sub.ksT.sub.es-
A.sub.k 1341541 1320 1335 21135 21150 CTTGAACAGTCTTAAA
.sup.mC.sub.ksT.sub.ksT.sub.dsG.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.dsA.sub-
.ds 38 500
G.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.ksT.sub.esA.sub.ksA.sub.esA.sub.-
k 1341543 1308 1323 21123 21138 TAAACCTTCCCTGTGT
T.sub.ksA.sub.ksA.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub.dsT.sub-
.ds.sup.m 9 1745
C.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub.ksG.sub.esT.sub.ksG.sub.es-
T.sub.k 1341547 1076 1091 20891 20906 AGTGCCAAACCAATGT
A.sub.ksG.sub.ksT.sub.dsG.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsA.sub-
.ds 71 1120
A.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ksA.sub.esT.sub.ksG.sub.es-
T.sub.k 1341551 1347 1362 21162 21177 GTGGCATGGCTACAGA
G.sub.ksT.sub.ksG.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.dsG.sub.ds
59 501
G.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.ks.sup.mC.sub.esA.sub.ksG.sub.es-
A.sub.k 1341555 1328 1343 21143 21158 GAATGCTACTTGAACA
G.sub.ksA.sub.ksA.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.ds.su-
p.m 48 1123
C.sub.dsT.sub.dsT.sub.dsG.sub.ksA.sub.esA.sub.ks.sup.mC.sub.esA.sub.-
k 1341564 1425 1440 21240 21255 GTCCAGGTTGAGATAA
G.sub.ksT.sub.ks.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.dsG.sub.dsT.sub-
.ds 36 113
T.sub.dsG.sub.dsA.sub.dsG.sub.ksA.sub.esT.sub.ksA.sub.esA.sub.k
1341565 1461 1476 21276 21291 CTAGGGAAATCTTTCA
.sup.mC.sub.ksT.sub.ksA.sub.dsG.sub.dsG.sub.dsG.sub.dsA.sub.dsA.sub.ds
46 659
A.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.ksT.sub.esT.sub.ks.sup.mC.sub.es-
A.sub.k 1341567 1415 1430 21230 21245 AGATAAAGCTGCCTGC
A.sub.ksG.sub.ksA.sub.dsT.sub.dsA.sub.dsA.sub.dsA.sub.dsG.sub.ds.sup.m
30 1515
C.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.ks.sup.mC.sub.esT.sub.ksG.sub.es-
.sup.mC.sub.k 1341568 1718 1733 21533 21548 GTCTAAACATCTCTGG
G.sub.ksT.sub.ks.sup.mC.sub.dsT.sub.dsA.sub.dsA.sub.dsA.sub.ds.sup.mC.sub-
.ds 50 429
A.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.ks.sup.mC.sub.esT.sub.ksG.sub.es-
G.sub.k 1341569 1504 1519 21319 21334 AGAATAGAGTTGCACC
A.sub.ksG.sub.ksA.sub.dsA.sub.dsT.sub.dsA.sub.dsG.sub.dsA.sub.dsG.sub.ds
59 426
T.sub.dsT.sub.dsG.sub.ks.sup.mC.sub.esA.sub.ks.sup.mC.sub.es.sup.mC.-
sub.k 1341575 1614 1629 21429 21444 TCACCTTTCATAATGT
T.sub.ks.sup.mC.sub.ksA.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.d-
sT.sub.ds 31 2109
.sup.mC.sub.dsA.sub.dsT.sub.dsA.sub.ksA.sub.esT.sub.ksG.sub.esT.sub.-
k 1341578 2186 2201 22001 22016 GATGTAGTGGGAGTCG
G.sub.ksA.sub.ksT.sub.dsG.sub.dsT.sub.dsA.sub.dsG.sub.dsT.sub.dsG.sub.ds
38 743
G.sub.dsG.sub.dsA.sub.ksG.sub.esT.sub.ks.sup.mC.sub.esG.sub.k
1341580 2257 2272 22072 22087 AAACAAGAGGATAGTC
A.sub.ksA.sub.ksA.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsG.sub.dsA.sub.ds
52 744
G.sub.dsG.sub.dsA.sub.dsT.sub.ksA.sub.esG.sub.ksT.sub.es.sup.mC.sub.-
k 1341585 1774 1789 21589 21604 TAATAGCCAGTACAGT
T.sub.ksA.sub.ksA.sub.dsT.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.ds.sup.mC.sub-
.ds 44 196
A.sub.dsG.sub.dsT.sub.dsA.sub.ks.sup.mC.sub.esA.sub.ksG.sub.esT.sub.-
k 1341588 N/A N/A 9511 9526 AATATTGAGGCACTGG
A.sub.ksA.sub.ksT.sub.dsA.sub.dsT.sub.dsT.sub.dsG.sub.dsA.sub.dsG.sub.ds
29 1538
G.sub.ds.sup.mC.sub.dsA.sub.ks.sup.mC.sub.esT.sub.ksG.sub.esG.sub.k
1341596 N/A N/A 9598 9613 ATGTGAAGAGCTGGTA
A.sub.ksT.sub.ksG.sub.dsT.sub.dsG.sub.dsA.sub.dsA.sub.dsG.sub.dsA.sub.ds
54 527
G.sub.ds.sup.mC.sub.dsT.sub.ksG.sub.esG.sub.ksT.sub.esA.sub.k
1341603 N/A N/A 16134 16149 GATGCTCCATAATAAT
G.sub.ksA.sub.ksT.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.ds.sup.mC.sub.ds.sup.-
mC.sub.ds 17 2049
A.sub.dsT.sub.dsA.sub.dsA.sub.ksT.sub.esA.sub.ksA.sub.esT.sub.k
1341604 N/A N/A 16124 16139 AATAATAGCTCTATTG
A.sub.ksA.sub.ksT.sub.dsA.sub.dsA.sub.dsT.sub.dsA.sub.dsG.sub.ds.sup.m
2 2410
C.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.ksA.sub.esT.sub.ksT.sub.esG.sub.-
k 1341614 N/A N/A 17987 18002 GTATAGTTATCTTCTC
G.sub.ksT.sub.ksA.sub.dsT.sub.dsA.sub.dsG.sub.dsT.sub.dsT.sub.dsA.sub.ds
49 937
T.sub.ds.sup.mC.sub.dsT.sub.ksT.sub.es.sup.mC.sub.ksT.sub.es.sup.mC.-
sub.k 1341615 N/A N/A 17997 18012 TATGAAGTTAGTATAG
T.sub.ksA.sub.ksT.sub.dsG.sub.dsA.sub.dsA.sub.dsG.sub.dsT.sub.dsT.sub.ds
47 1560 A.sub.dsG.sub.dsT.sub.ksA.sub.esT.sub.ksA.sub.esG.sub.k
TABLE-US-00040 TABLE 40 Inhibition of HSD17B13 RNA by modified
oligonucleotides targeting SEQ ID NO.: 1, and 2 SEQ SEQ SEQ SEQ ID
NO: ID NO: ID NO: ID NO: % SEQ Compound 1 Start 1 Stop 2 Start 2
Stop Sequence Chemistry Notation in- ID Number Site Site Site Site
(5' to 3') (5' to 3') hibition NO 1245927 N/A N/A 3433 3448
AGTAGATGGTAAGTCA
A.sub.ksG.sub.ksT.sub.ksA.sub.dsG.sub.dsA.sub.dsT.sub.dsG.sub.dsG.sub.ds
76 121 T.sub.dsA.sub.dsG.sub.dsT.sub.ks.sup.mC.sub.ksA.sub.k
1246023 N/A N/A 5046 5061 GAGTGAATCATTCAGT
G.sub.ksA.sub.ksG.sub.ksT.sub.dsG.sub.dsA.sub.dsA.sub.dsT.sub.ds.sup.mC.s-
ub.ds 84 1526
A.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ksG.sub.ksT.sub.k
1341176 796 811 15677 15692 CCATCTATCAGACTTC
.sup.mC.sub.ks.sup.mC.sub.ksA.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.d-
sT.sub.ds 52 415
.sup.mC.sub.dsA.sub.dsG.sub.dsA.sub.ks.sup.mC.sub.esT.sub.ksT.sub.es-
.sup.mC.sub.k 1341182 808 823 15689 15704 TTGGTAAGTATTCCAT
T.sub.ksT.sub.ksG.sub.dsG.sub.dsT.sub.dsA.sub.dsA.sub.dsG.sub.dsT.sub.ds
13 2750
A.sub.dsT.sub.dsT.sub.ks.sup.mC.sub.es.sup.mC.sub.ksA.sub.esT.sub.k
1341183 1077 1092 20892 20907 TAGTGCCAAACCAATG
T.sub.ksA.sub.ksG.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub-
.ds 66 1198
A.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksA.sub.esA.sub.ksT.sub.es-
G.sub.k 1341187 1081 1096 20896 20911 CTGCTAGTGCCAAACC
.sup.mC.sub.ksT.sub.ksG.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.dsG.sub.dsT.sub-
.dsG.sub.ds 51 1510
.sup.m.sub.kCA.sub.s.sup.m.sub.kCA.sub.sA.sub.ksA.sub.esA.sub.ks.sup-
.mC.sub.es.sup.mC.sub.k 1341191 1085 1100 20900 20915
ACTGCTGCTAGTGCCA
A.sub.ks.sup.mC.sub.ksT.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.ds.sup.-
mC.sub.ds 39 1821
T.sub.dsA.sub.dsG.sub.dsT.sub.ksG.sub.es.sup.mC.sub.ks.sup.mC.sub.es-
A.sub.k 1341202 1259 1274 21074 21089 GTAGCTTTTGTCCACC
G.sub.ksT.sub.ksA.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsT.sub.dsT.s-
ub.ds 34 1978
G.sub.dsT.sub.ds.sup.mC.sub.ks.sup.mC.sub.esA.sub.ks.sup.mC.sub.es.s-
up.mC.sub.k 1341204 1313 1328 21128 21143 AGTCTTAAACCTTCCC
A.sub.ksG.sub.ksT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.dsA.sub.dsA.s-
ub.ds 43 1979
.sup.mC.sub.ds.sup.mC.sub.dsT.sub.ksT.sub.es.sup.mC.sub.ks.sup.mC.su-
b.es.sup.mC.sub.k 1341211 1325 1340 21140 21155 TGCTACTTGAACAGTC
T.sub.ksG.sub.ks.sup.mC.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.dsT.sub-
.dsG.sub.ds 64 889
A.sub.dsA.sub.ds.sup.mC.sub.ksA.sub.esG.sub.ksT.sub.es.sup.mC.sub.k
1341214 1321 1336 21136 21151 ACTTGAACAGTCTTAA
A.sub.ks.sup.mC.sub.ksT.sub.dsT.sub.dsG.sub.dsA.sub.dsA.sub.ds.sup.mC.sub-
.ds 60 578
A.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.ksT.sub.esT.sub.ksA.sub.esA.sub.-
k 1341218 1317 1332 21132 21147 GAACAGTCTTAAACCT
G.sub.ksA.sub.ksA.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.dsT.sub.ds.sup.mC.sub-
.ds 63 266
T.sub.dsT.sub.dsA.sub.dsA.sub.ksA.sub.es.sup.mC.sub.ks.sup.mC.sub.es-
T.sub.k 1341222 1342 1357 21157 21172 ATGGCTACAGATTGGA
A.sub.ksT.sub.ksG.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.ds.sup.mC.sub-
.ds 57 111
A.sub.dsG.sub.dsA.sub.dsT.sub.ksT.sub.esG.sub.ksG.sub.esA.sub.k
1341226 1329 1344 21144 21159 GGAATGCTACTTGAAC
G.sub.ksG.sub.ksA.sub.dsA.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsA.s-
ub.d 49 1201
.sub.s.sup.mC.sub.dsT.sub.dsT.sub.ksG.sub.esA.sub.ksA.sub.es.sup.mC.-
sub.k 1341227 1335 1350 21150 21165 CAGATTGGAATGCTAC
.sup.mC.sub.ksA.sub.ksG.sub.dsA.sub.dsT.sub.dsT.sub.dsG.sub.dsG.sub.dsA.s-
ub.d 57 1590
.sub.sA.sub.dsT.sub.dsG.sub.ks.sup.mC.sub.esT.sub.ksA.sub.es.sup.mC.-
sub.k 1341237 1353 1368 21168 21183 TATTCTGTGGCATGGC
T.sub.ksA.sub.ksT.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.dsT.sub.dsG.s-
ub.ds 57 890
G.sub.ds.sup.mC.sub.dsA.sub.ksT.sub.esG.sub.ksG.sub.es.sup.mC.sub.k
1341242 1366 1381 21181 21196 GTGTTCTTGTTGATAT
G.sub.ksT.sub.ksG.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsG.s-
ub.ds 63 1514
T.sub.dsT.sub.dsCT.sub.ksA.sub.esT.sub.ksA.sub.eT.sub.k 1341248
1357 1372 21172 21187 TTGATATTCTGTGGCA
T.sub.ksT.sub.ksG.sub.dsA.sub.dsT.sub.dsA.sub.dsT.sub.dsT.sub.ds.sup.MC.s-
ub.ds 55 1202
T.sub.dsG.sub.dsT.sub.ksG.sub.esG.sub.ks.sup.mC.sub.esA.sub.k
1341254 1421 1436 21236 21251 AGGTTGAGATAAAGCT
A.sub.ksG.sub.ksG.sub.dsT.sub.dsT.sub.dsG.sub.dsA.sub.dsG.sub.dsA.sub.ds
60 1904
T.sub.dsA.sub.dsA.sub.ksA.sub.esG.sub.ks.sup.mC.sub.esT.sub.k
1341262 1490 1505 21305 21320 CCGTTTTGGGCTAATG
.sup.mC.sub.ks.sup.mC.sub.ksG.sub.dsT.sub.dsT.sub.dsT.sub.dsT.sub.dsG.sub-
.dsG 72 1360
.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.ksA.sub.esA.sub.ksT.sub.esG.sub.k
1341265 1494 1509 21309 21324 TGCACCGTTTTGGGCT
T.sub.ksG.sub.ks.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsG.sub.d-
sT.sub.ds 29 1671
T.sub.dsT.sub.dsT.sub.dsG.sub.ksG.sub.esG.sub.ks.sup.mC.sub.esT.sub.-
k 1341269 1464 1479 21279 21294 AGGCTAGGGAAATCTT
A.sub.ksG.sub.ksG.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.dsG.sub.dsG.sub.dsG.s-
ub.d 45 892
.sub.sA.sub.dsA.sub.dsA.sub.ksT.sub.es.sup.mC.sub.ksT.sub.esT.sub.k
1341275 1619 1634 21434 21449 GTCGGTCACCTTTCAT
G.sub.ksT.sub.ks.sup.mC.sub.dsG.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.dsA.sub-
.ds.sup.m 57 194
C.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ksT.sub.es.sup.mC.sub.ksA.sub.es-
T.sub.k 1341277 1598 1613 21413 21428 ATCTTATAAGACTATA
A.sub.ksT.sub.ks.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.dsT.sub.dsA.sub.dsA.s-
ub.ds 30 2661
G.sub.dsA.sub.ds.sup.mC.sub.ksT.sub.esA.sub.ksT.sub.esA.sub.k
1341284 1627 1642 21442 21457 AAAATAGAGTCGGTCA
A.sub.ksA.sub.ksA.sub.dsA.sub.dsT.sub.dsA.sub.dsG.sub.dsA.sub.dsG.sub.ds
53 817
T.sub.ds.sup.mC.sub.dsG.sub.ksG.sub.esT.sub.ks.sup.mC.sub.esA.sub.k
1341286 1623 1638 21438 21453 TAGAGTCGGTCACCTT
T.sub.ksA.sub.ksG.sub.dsA.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.dsG.sub.dsG.s-
ub.ds 48 506
T.sub.ds.sup.mC.sub.dsA.sub.ks.sup.mC.sub.es.sup.mC.sub.ksT.sub.esT.-
sub.k 1341291 1711 1726 21526 21541 CATCTCTGGGACCAAG
.sup.mC.sub.ksA.sub.ksT.sub.ds.sup.mC.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.d-
sG.sub.ds 44 117
G.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.ks.sup.mC.sub.esA.sub.ksA.sub.es-
G.sub.k 1341292 1715 1730 21530 21545 TAAACATCTCTGGGAC
T.sub.ksA.sub.ksA.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.ds.sup.mC.sub-
.dsT 39 351
.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.ksG.sub.esG.sub.ksA.sub.es.sup.mC-
.sub.k 1341300 1719 1734 21534 21549 TGTCTAAACATCTCTG
T.sub.ksG.sub.ksT.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.dsA.sub.dsA.sub.ds.su-
p.mC 59 507
.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.ksT.sub.es.sup.mC.sub.ksT.sub.esG-
.sub.k 1341302 1770 1785 21585 21600 AGCCAGTACAGTTCCT
A.sub.ksG.sub.ks.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.dsT.sub.dsA.sub-
.ds.sup.m 49 1909
C.sub.dsA.sub.dsG.sub.dsT.sub.ksT.sub.es.sup.mC.sub.ks.sup.mC.sub.es-
T.sub.k 1341307 1751 1766 21566 21581 CCTGTGTTAGCTTTAA
.sup.mC.sub.ks.sup.mC.sub.ksT.sub.dsG.sub.dsT.sub.dsG.sub.dsT.sub.dsT.sub-
.dsA 62 1364
.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.ksT.sub.esT.sub.ksA.sub.esA.sub.k
1341310 1783 1798 21598 21613 TTTCTTATGTAATAGC
T.sub.ksT.sub.ksT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.dsT.sub.dsG.s-
ub.ds 60 2128
T.sub.dsA.sub.dsA.sub.ksT.sub.esA.sub.ksG.sub.es.sup.mC.sub.k
1341314 1779 1794 21594 21609 TTATGTAATAGCCAGT
T.sub.ksT.sub.ksA.sub.dsT.sub.dsG.sub.dsT.sub.dsA.sub.dsA.sub.dsT.sub.ds
63 586
A.sub.dsG.sub.ds.sup.mC.sub.ks.sup.mC.sub.esA.sub.ksG.sub.esT.sub.k
1341316 1775 1790 21590 21605 GTAATAGCCAGTACAG
G.sub.ksT.sub.ksA.sub.dsA.sub.dsT.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.ds.su-
p.m 47 274
C.sub.dsA.sub.dsG.sub.dsT.sub.ksA.sub.es.sup.mC.sub.ksA.sub.esG.sub.-
k 1341329 2187 2202 22002 22017 TGATGTAGTGGGAGTC
T.sub.ksG.sub.ksA.sub.dsT.sub.dsG.sub.dsT.sub.dsA.sub.dsG.sub.dsT.sub.ds
46 820
G.sub.dsG.sub.dsG.sub.ksA.sub.esG.sub.ksT.sub.es.sup.mC.sub.k
1341332 N/A N/A 9514 9529 ACTAATATTGAGGCAC
A.sub.ks.sup.mC.sub.ksT.sub.dsA.sub.dsA.sub.dsT.sub.dsA.sub.dsT.sub.dsT.s-
ub.ds 27 1772
G.sub.dsA.sub.dsG.sub.ksG.sub.es.sup.mC.sub.ksA.sub.es.sup.mC.sub.k
1341334 2250 2265 22065 22080 AGGATAGTCCATGCAA
A.sub.ksG.sub.ksG.sub.dsA.sub.dsT.sub.dsA.sub.dsG.sub.dsT.sub.ds.sup.mC.s-
ub.d 46 2690
.sub.s.sup.mC.sub.dsA.sub.dsT.sub.ksG.sub.es.sup.mC.sub.ksA.sub.esA.-
sub.k 1341337 N/A N/A 9332 9347 ATCCTATATACATCCA
A.sub.ksT.sub.ks.sup.mC.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.dsT.sub.dsA.sub-
.dsT 65 1927
.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.ksT.sub.es.sup.mC.sub.ks.sup.mC.s-
ub.esA.sub.k 1341342 N/A N/A 9966 9981 TAGTGTAAGCTGAGAG
T.sub.ksA.sub.ksG.sub.dsT.sub.dsG.sub.dsT.sub.dsA.sub.dsA.sub.dsG.sub.ds
68 1852
.sup.mC.sub.dsT.sub.dsG.sub.ksA.sub.esG.sub.ksA.sub.esG.sub.k
1341346 N/A N/A 9601 9616 CATATGTGAAGAGCTG
.sup.mC.sub.ksA.sub.ksT.sub.dsA.sub.dsT.sub.dsG.sub.dsT.sub.dsG.sub.dsA.s-
ub.d 35 683
.sub.sA.sub.dsG.sub.dsA.sub.ksG.sub.es.sup.mC.sub.ksT.sub.esG.sub.k
1341348 N/A N/A 11548 11563 TCTCTTGACAATGGTT
T.sub.ks.sup.mC.sub.ksT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsG.sub.dsA.sub-
.ds.sup.m 70 1389 11573 11588
C.sub.dsA.sub.dsA.sub.dsT.sub.ksG.sub.esG.sub.ksT.sub.esT.sub.k 100
1341350 N/A N/A 14916 14931 ATACATTAGCAAGCTA
A.sub.ksT.sub.ksA.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.dsT.sub.dsA.sub.dsG.s-
ub.d 22 309
.sub.s.sup.mC.sub.dsA.sub.dsA.sub.ksG.sub.es.sup.mC.sub.ksT.sub.esA.-
sub.k
1341358 N/A N/A 14197 14212 TTATGTGATTGAGTTC
T.sub.ksT.sub.ksA.sub.dsT.sub.dsG.sub.dsT.sub.dsG.sub.dsA.sub.dsT.sub.dsT
21 2431
.sub.dsG.sub.dsA.sub.ksG.sub.esT.sub.ksT.sub.es.sup.mC.sub.k
1341363 N/A N/A 15496 15511 CTGCATTAATGCCACC
.sup.mC.sub.ksT.sub.ksG.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.dsT.sub.dsA.sub-
.dsA 6 1168
.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.ks.sup.mC.sub.esA.sub.ks.sup.mC.s-
ub.es.sup.mC.sub.k 1341364 N/A N/A 16127 16142 CATAATAATAGCTCTA
.sup.mC.sub.ksA.sub.ksT.sub.dsA.sub.dsA.sub.dsT.sub.dsA.sub.dsA.sub.dsT.s-
ub.ds 13 2511
A.sub.dsG.sub.ds.sup.mC.sub.ksT.sub.esT.sub.ks.sup.mC.sub.esA.sub.k
1341365 N/A N/A 16289 16304 GTTAGAATAGTCTTCA
G.sub.ksT.sub.ksT.sub.dsA.sub.dsG.sub.dsA.sub.dsA.sub.dsT.sub.dsA.sub.ds
45 1481
G.sub.dsT.sub.ds.sup.mC.sub.ksT.sub.esT.sub.ks.sup.mC.sub.esA.sub.k
1341370 N/A N/A 16382 16397 TCCCAACCAAACTTCC
T.sub.ks.sup.mC.sub.ks.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.ds.sup.mC-
.sub.ds.sup.m 27 2026
C.sub.dsA.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.ksT.sub.esT.sub.ks.sup.m-
C.sub.es.sup.m C.sub.k 1341371 N/A N/A 18095 18110 AATTGATACACCAATG
A.sub.ksA.sub.ksT.sub.dsTa.sub.sG.sub.dsA.sub.dsT.sub.dsA.sub.ds.sup.mC.s-
ub.ds 50 2525
A.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksA.sub.esA.sub.ksT.sub.esG.sub.k
1341376 N/A N/A 17994 18009 GAAGTTAGTATAGTTA
G.sub.ksA.sub.ksA.sub.dsG.sub.dsT.sub.dsT.sub.dsA.sub.dsG.sub.dsT.sub.ds
56 1327 A.sub.dsT.sub.dsA.sub.ksG.sub.esT.sub.ksT.sub.esA.sub.k
1341379 N/A N/A 17989 18004 TAGTATAGTTATCTTC
T.sub.ksA.sub.ksG.sub.dsT.sub.dsA.sub.dsT.sub.dsA.sub.dsG.sub.dsT.sub.ds
34 1093
T.sub.dsA.sub.dsT.sub.ks.sup.mC.sub.esT.sub.ksT.sub.es.sup.mC.sub.k
1341380 N/A N/A 19909 19924 ATCTTAAGATACCCAG
A.sub.ksT.sub.ks.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.dsA.sub.dsG.sub.dsA.s-
ub.d 45 397
.sub.sT.sub.dsA.sub.ds.sup.mC.sub.ks.sup.mC.sub.es.sup.mC.sub.ksA.su-
b.esG.sub.k 1341384 N/A N/A 19913 19928 GTGCATCTTAAGATAC
G.sub.ksT.sub.ksG.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.dsT.sub-
.dsT 20 2806
.sub.dsA.sub.dsA.sub.dsG.sub.ksA.sub.esT.sub.ksA.sub.es.sup.mC.sub.k
1341388 N/A N/A 18695 18710 AAAGACTTTGAGACTC
A.sub.ksA.sub.ksA.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsT.s-
ub.d 45 1250
.sub.sG.sub.dsA.sub.dsG.sub.ksA.sub.es.sup.mC.sub.ksT.sub.es.sup.mC.-
sub.k 1341391 N/A N/A 20383 20398 GTAATCACAAGTAAGG
G.sub.ksT.sub.ksA.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub-
.ds 72 1411
A.sub.dsA.sub.dsG.sub.dsT.sub.ksA.sub.esA.sub.ksG.sub.esG.sub.k
1341399 N/A N/A 20190 20205 AGTTATTAGAAGTCAG
A.sub.ksG.sub.ksT.sub.dsT.sub.dsA.sub.dsT.sub.dsT.sub.dsA.sub.dsG.sub.ds
42 2746
A.sub.dsA.sub.dsG.sub.ksT.sub.es.sup.mC.sub.ksA.sub.esG.sub.k
1341401 N/A N/A 20484 20499 CTTCATAGTGGACTTC
.sup.mC.sub.ksT.sub.ksT.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.dsA.sub.dsG.sub-
.dsT 45 711
.sub.dsG.sub.dsG.sub.dsA.sub.ks.sup.mC.sub.esT.sub.ksT.sub.es.sup.mC-
.sub.k 1341410 N/A N/A 13954 13969 CCTCTAAGTTAGCCCC
.sup.mC.sub.ks.sup.mC.sub.ksT.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.dsA.sub.d-
sG.sub.ds 20 1084
T.sub.dsT.sub.dsA.sub.dsG.sub.ks.sup.mC.sub.es.sup.mC.sub.ks.sup.mC.-
sub.es.sup.mC.sub.k 1341418 N/A N/A 12797 12812 TGTAAGAGTCAGTATC
T.sub.ksG.sub.ksT.sub.dsA.sub.dsA.sub.dsG.sub.dsA.sub.dsG.sub.dsT.sub.ds
35 2652
.sup.mC.sub.dsA.sub.dsG.sub.ksT.sub.esA.sub.ksT.sub.es.sup.mC.sub.k
1341419 N/A N/A 14172 14187 TTGAATAGCAAGCCAA
T.sub.ksT.sub.ksG.sub.dsA.sub.dsA.sub.dsT.sub.dsA.sub.dsG.sub.ds.sup.mC.s-
ub.ds 27 1864
A.sub.dsA.sub.dsG.sub.ks.sup.mC.sub.es.sup.mC.sub.ksA.sub.esA.sub.k
1341529 693 708 12111 12126 ATGAGGTTTTGATACC
A.sub.ksT.sub.ksG.sub.dsA.sub.dsG.sub.dsG.sub.dsT.sub.dsT.sub.dsT.sub.ds
51 569
T.sub.dsG.sub.dsA.sub.ksT.sub.esA.sub.ks.sup.mC.sub.es.sup.mC.sub.k
1341533 1022 1037 20837 20852 CTTTGCAGCATTGATT
.sup.mC.sub.ksT.sub.ksT.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.dsG.sub-
.ds.sup.m 49 2463
C.sub.dsA.sub.dsT.sub.dsT.sub.ksG.sub.esA.sub.ksT.sub.esT.sub.k
1341540 1309 1324 21124 21139 TTAAACCTTCCCTGTG
T.sub.ksT.sub.ksA.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub-
.dsT.sub.ds 0 2807
.sup.mC.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksT.sub.esG.sub.ksT.sub.esG.-
sub.k 1341545 1175 1190 20990 21005 TAAGAGGCATGAAAGG
T.sub.ksA.sub.ksA.sub.dsG.sub.dsA.sub.dsG.sub.dsG.sub.ds.sup.mC.sub.dsA.s-
ub.d 54 2751
.sub.sT.sub.dsG.sub.dsA.sub.ksA.sub.esA.sub.ksG.sub.esG.sub.k
1341546 1251 1266 21066 21081 TGTCCACCTTTAAATG
T.sub.ksG.sub.ksT.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.d-
s.sup.mC.sub.d 27 1666
.sub.sT.sub.dsT.sub.dsT.sub.dsA.sub.ksA.sub.esA.sub.ksT.sub.esG.sub.-
k 1341552 1348 1363 21163 21178 TGTGGCATGGCTACAG
T.sub.ksG.sub.ksT.sub.dsG.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.dsG.s-
ub.d 22 579
.sub.sG.sub.ds.sup.mC.sub.dsT.sub.ksA.sub.es.sup.mC.sub.ksA.sub.esG.-
sub.k 1341554 1394 1409 21209 21224 CTTGATCTCTTAGCTG
.sup.mC.sub.ksT.sub.ksT.sub.dsG.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.dsT.sub-
.ds.sup.m 49 736
C.sub.dsT.sub.dsT.sub.dsA.sub.ksG.sub.es.sup.mC.sub.ksT.sub.esG.sub.-
k 1341558 1388 1403 21203 21218 CTCTTAGCTGTGCACT
.sup.mC.sub.ksT.sub.ks.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.dsG.sub.ds.sup.-
mC.sub.ds 56 268
T.sub.dsG.sub.dsT.sub.dsG.sub.ks.sup.mC.sub.esA.sub.ks.sup.mC.sub.es-
T.sub.k 1341560 1498 1513 21313 21328 GAGTTGCACCGTTTTG
G.sub.ksA.sub.ksG.sub.dsT.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.ds.su-
p.m 61 1983
C.sub.ds.sup.mC.sub.dsG.sub.dsT.sub.ksT.sub.esT.sub.ksT.sub.esG.sub.-
k 1341563 1416 1431 21231 21246 GAGATAAAGCTGCCTG
G.sub.ksA.sub.ksG.sub.dsA.sub.dsT.sub.dsA.sub.dsA.sub.dsA.sub.dsG.sub.ds.-
sup.m 40 1592
C.sub.dsT.sub.dsG.sub.ks.sup.mC.sub.es.sup.mC.sub.ksT.sub.esG.sub.k
1341566 1426 1441 21241 21256 TGTCCAGGTTGAGATA
T.sub.ksG.sub.ksT.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.dsG.sub-
.dsT 48 191
.sub.dsT.sub.dsG.sub.dsA.sub.ksG.sub.esA.sub.ksT.sub.esA.sub.k
1341574 1615 1630 21430 21445 GTCACCTTTCATAATG
G.sub.ksT.sub.ks.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub.d-
sT.sub.ds 4 1907
T.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.ksA.sub.esA.sub.ksT.sub.esG.sub.-
k 1341577 1705 1720 21520 21535 TGGGACCAAGGATATA
T.sub.ksG.sub.ksG.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub-
.ds 30 1674
A.sub.dsG.sub.dsG.sub.dsA.sub.ksT.sub.esA.sub.ksT.sub.esA.sub.k
1341583 2194 2209 22009 22024 TTAGTCTTGATGTAGT
T.sub.ksT.sub.ksA.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsG.s-
ub.ds 36 1366
A.sub.dsT.sub.dsG.sub.ksT.sub.esA.sub.ksG.sub.esT.sub.k 1341589 N/A
N/A 11858 11873 GATTAAGCAGAATTGT
G.sub.ksA.sub.ksT.sub.dsT.sub.dsA.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.dsA.s-
ub.d 31 1156
.sub.sG.sub.dsA.sub.dsA.sub.ksT.sub.esT.sub.ksG.sub.esT.sub.k
1341591 N/A N/A 11543 11558 TGACAATGGTTGCCAC
T.sub.ksG.sub.ksA.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsT.sub.dsG.sub.dsG.s-
ub.ds 38 1233
T.sub.dsT.sub.dsG.sub.ks.sup.mC.sub.es.sup.mC.sub.ksA.sub.es.sup.mC.-
sub.k 1341595 2350 2365 22165 22180 ACTACAAGAGGTTATT
A.sub.ks.sup.mC.sub.ksT.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsG.sub-
.ds 42 899
A.sub.dsG.sub.dsG.sub.dsT.sub.ksT.sub.esA.sub.ksT.sub.esT.sub.k
1341600 N/A N/A 12416 12431 ACGGTGATCAAATGTA
A.sub.ks.sup.mC.sub.ksG.sub.dsG.sub.dsT.sub.dsG.sub.dsA.sub.dsT.sub.ds.su-
p.m 33 2205
C.sub.dsA.sub.dsA.sub.dsA.sub.ksT.sub.esG.sub.ksT.sub.esA.sub.k
1341601 N/A N/A 16218 16233 TATAGACTGGGTAGGA
T.sub.ksA.sub.ksT.sub.dsA.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.dsG.s-
ub.d 38 2808
.sub.sG.sub.dsG.sub.dsT.sub.ksA.sub.esG.sub.ksG.sub.esA.sub.k
1341607 N/A N/A 12426 12441 CAGGGTGGTAACGGTG
.sup.mC.sub.ksA.sub.ksG.sub.dsG.sub.dsG.sub.dsT.sub.dsG.sub.dsG.sub.dsT.s-
ub.d 49 2729
.sub.sA.sub.dsA.sub.ds.sup.mC.sub.ksG.sub.esG.sub.ksT.sub.esG.sub.k
TABLE-US-00041 TABLE 41 Inhibition of HSD17B13 RNA by modified
oligonucleotides targeting SEQ ID NO.: 1, and 2 SEQ SEQ SEQ SEQ ID
NO: ID NO: ID NO: ID NO: % SEQ Compound 1 Start 1 Stop 2 Start 2
Stop Sequence Chemistry Notation in- ID Number Site Site Site Site
(5' to 3') (5' to 3') hibition NO 1245927 N/A N/A 3433 3448
AGTAGATGGTAAGTCA
A.sub.ksG.sub.ksT.sub.ksA.sub.dsG.sub.dsA.sub.dsT.sub.dsG.sub.dsG.sub.dsT-
.sub.d 93 121
.sub.sA.sub.dsA.sub.dsG.sub.dsT.sub.ks.sup.mC.sub.ksA.sub.k 1246023
N/A N/A 5046 5061 GAGTGAATCATTCAGT
G.sub.ksA.sub.ksG.sub.ksT.sub.dsG.sub.dsA.sub.dsA.sub.dsT.sub.ds.sup.mC.s-
ub.ds 88 1526
A.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ksG.sub.ksT.sub.k
1341165 608 623 N/A N/A ACAATATGGGATGAGG
A.sub.ks.sup.mC.sub.ksA.sub.dsA.sub.dsT.sub.dsA.sub.dsT.sub.dsG.sub.dsG.s-
ub.ds 51 1579
G.sub.dsA.sub.dsT.sub.ksG.sub.esA.sub.ksG.sub.esG.sub.k 1341170 810
825 15691 15706 TATTGGTAAGTATTCC
T.sub.ksA.sub.ksT.sub.dsT.sub.dsG.sub.dsG.sub.dsT.sub.dsA.sub.dsA.sub.dsG-
.sub.d 36 1272
.sub.sT.sub.dsA.sub.ksT.sub.esT.sub.ks.sup.mC.sub.es.sup.mC.sub.k
1341174 798 813 15679 15694 TTCCATCTATCAGACT
T.sub.ksT.sub.ks.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.d-
sT.sub.dsA.sub.d 33 571
.sub.sT.sub.ds.sup.mC.sub.dsA.sub.ksG.sub.esA.sub.ks.sup.mC.sub.esT.-
sub.k 1341177 696 711 12114 12129 GACATGAGGTTTTGAT
G.sub.ksA.sub.ks.sup.mC.sub.dsA.sub.dsT.sub.dsG.sub.dsA.sub.dsG.sub.dsG.s-
ub.ds 55 647
T.sub.dsT.sub.dsT.sub.ksT.sub.esG.sub.ksA.sub.esT.sub.k 1341181
1078 1093 20893 20908 CTAGTGCCAAACCAAT
.sup.mC.sub.ksT.sub.ksA.sub.dsG.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.ds.sup.-
mC.sub.dsA 47 1276
.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.ks.sup.mC.sub.esA.sub.ksA.sub.esT-
.sub.k 1341185 1082 1097 20897 20912 GCTGCTAGTGCCAAAC
G.sub.ks.sup.mC.sub.ksT.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.dsG.sub-
.dsT.sub.ds 62 1587
G.sub.ds.sup.mC.sub.ds.sup.mC.sub.kSA.sub.eSA.sub.kSA.sub.es.sup.mC.-
sub.k 1341195 1180 1195 20995 21010 GTTTTTAAGAGGCATG
G.sub.ksT.sub.ksT.sub.dsT.sub.dsT.sub.dsT.sub.dsA.sub.dsA.sub.dsG.sub.dsA-
.sub.ds 79 1199
G.sub.dsGr.sub.ks.sup.mC.sub.esA.sub.ksT.sub.esG.sub.k 1341197 1086
1101 20901 20916 GACTGCTGCTAGTGCC
G.sub.ksA.sub.ks.sup.mC.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsG.sub-
.ds.sup.mC 35 1899
.sub.dsT.sub.dsA.sub.dsG.sub.ksT.sub.esG.sub.ks.sup.mC.sub.es.sup.mC-
.sub.k 1341201 1314 1329 21129 21144 CAGTCTTAAACCTTCC
.sup.mC.sub.ksA.sub.ksG.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub-
.dsA.sub.ds 51 30
A.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksT.sub.esT.sub.ks.sup.mC.sub.es.s-
up.mC.sub.k 1341206 1256 1271 21071 21086 GCTTTTGTCCACCTTT
G.sub.ks.sup.mC.sub.ksT.sub.dsT.sub.dsT.sub.dsT.sub.dsG.sub.dsT.sub.ds.su-
p.mC.sub.ds 75 1744
.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ks.sup.mC.sub.esT.sub.ksT.sub.esT.-
sub.k 1341207 1261 1276 21076 21091 AGGTAGCTTTTGTCCA
A.sub.ksG.sub.ksG.sub.dsT.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsT.s-
ub.dsT 26 109
.sub.dsT.sub.dsG.sub.ksT.sub.es.sup.mC.sub.ks.sup.mC.sub.esA.sub.k
1341210 1326 1341 21141 21156 ATGCTACTTGAACAGT
A.sub.ksT.sub.ksG.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.dsT.sub-
.dsT.sub.ds 54 967
G.sub.dsA.sub.dsA.sub.ks.sup.mC.sub.esA.sub.ksG.sub.esT.sub.k
1341212 1322 1337 21137 21152 TACTTGAACAGTCTTA
T.sub.ksA.sub.ks.sup.mC.sub.dsT.sub.dsT.sub.dsG.sub.dsA.sub.dsA.sub.ds.su-
p.mC.sub.ds 60 656
A.sub.dsG.sub.dsT.sub.ks.sup.mC.sub.esT.sub.ksT.sub.esA.sub.k
1341219 1318 1333 21133 21148 TGAACAGTCTTAAACC
T.sub.ksG.sub.ksA.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.dsT.sub.ds.su-
p.mC.sub.ds 34 344
T.sub.dsT.sub.dsA.sub.ksA.sub.esA.sub.ks.sup.mC.sub.es.sup.mC.sub.k
1341225 1344 1359 21159 21174 GCATGGCTACAGATTG
G.sub.ks.sup.mC.sub.ksA.sub.dsT.sub.dsG.sub.dsG.sub.ds.sup.mC.sub.dsT.sub-
.dsA.sub.ds 41 267
.sup.mC.sub.dsA.sub.dsG.sub.ksA.sub.esT.sub.ksT.sub.esG.sub.k
1341231 1354 1369 21169 21184 ATATTCTGTGGCATGG
A.sub.ksT.sub.ksA.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.dsT.s-
ub.dsG 43 968
.sub.dsG.sub.ds.sup.mC.sub.ksA.sub.esT.sub.ksG.sub.esG.sub.k
1341233 1358 1373 21173 21188 GTTGATATTCTGTGGC
G.sub.ksT.sub.ksT.sub.dsG.sub.dsA.sub.dsT.sub.dsA.sub.dsT.sub.dsT.sub.ds.-
sup.mC 69 1280
.sub.dsT.sub.dsG.sub.ksT.sub.esG.sub.ksG.sub.es.sup.mC.sub.k
1341238 1349 1364 21164 21179 CTGTGGCATGGCTACA
.sup.mC.sub.ksT.sub.ksG.sub.dsT.sub.dsG.sub.dsG.sub.ds.sup.mC.sub.dsA.sub-
.dsT.sub.ds 33 657
G.sub.dsG.sub.ds.sup.mC.sub.ksT.sub.esA.sub.ks.sup.mC.sub.esA.sub.k
1341240 1395 1410 21210 21225 ACTTGATCTCTTAGCT
A.sub.ks.sup.mC.sub.ksT.sub.dsT.sub.dsG.sub.dsA.sub.dsT.sub.ds.sup.mC.sub-
.dsT.sub.ds 62 813
.sup.mC.sub.dsT.sub.dsT.sub.ksA.sub.esG.sub.ks.sup.mC.sub.esT.sub.k
1341243 1389 1404 21204 21219 TCTCTTAGCTGTGCAC
T.sub.ks.sup.mC.sub.ksT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.dsG.sub-
.ds.sup.mC.sub.d 36 346
.sub.sT.sub.dsG.sub.dsT.sub.ksG.sub.es.sup.mC.sub.ksA.sub.es.sup.mC.-
sub.k 1341246 1367 1382 21182 21197 TGTGTTCTTGTTGATA
T.sub.ksG.sub.ksT.sub.dsG.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsT.s-
ub.dsG 64 1591
.sub.dsT.sub.dsT.sub.ksG.sub.esA.sub.ksT.sub.esA.sub.k 1341251 1429
1444 21244 21259 ATATGTCCAGGTTGAG
A.sub.ksT.sub.ksA.sub.dsT.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.ds.sup.mC.sub-
.dsA.sub.ds 28 425
G.sub.dsG.sub.dsT.sub.ksT.sub.esG.sub.ksA.sub.esG.sub.k 1341257
1418 1433 21233 21248 TTGAGATAAAGCTGCC
T.sub.ksT.sub.ksG.sub.dsA.sub.dsG.sub.dsA.sub.dsT.sub.dsA.sub.dsA.sub.dsA-
.sub.d 2 1670
.sub.sG.sub.ds.sup.mC.sub.ksT.sub.esG.sub.ks.sup.mC.sub.es.sup.mC.su-
b.k 1341259 1422 1437 21237 21252 CAGGTTGAGATAAAGC
.sup.mC.sub.ksA.sub.ksG.sub.dsG.sub.dsT.sub.dsT.sub.dsG.sub.dsA.sub.dsG.s-
ub.ds 53 1982
A.sub.dsT.sub.dsA.sub.ksA.sub.esA.sub.ksG.sub.es.sup.mC.sub.k
1341260 1491 1506 21306 21321 ACCGTTTTGGGCTAAT
A.sub.ks.sup.mC.sub.ks.sup.mC.sub.dsG.sub.dsT.sub.dsT.sub.dsT.sub.dsT.sub-
.dsG.sub.ds 76 1438
G.sub.dsG.sub.ds.sup.mC.sub.ksT.sub.esA.sub.ksA.sub.esT.sub.k
1341261 1495 1510 21310 21325 TTGCACCGTTTTGGGC
T.sub.ksT.sub.ksG.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.d-
sG.sub.dsT.sub.d 26 1749
.sub.sT.sub.dsT.sub.dsT.sub.ksG.sub.esG.sub.ksG.sub.es.sup.mC.sub.k
1341268 1466 1481 21281 21296 AGAGGCTAGGGAAATC
A.sub.ksG.sub.ksA.sub.dsG.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.dsG.s-
ub.ds 59 1048
G.sub.dsG.sub.dsA.sub.ksA.sub.esA.sub.ksT.sub.es.sup.mC.sub.k
1341273 1499 1514 21314 21329 AGAGTTGCACCGTTTT
A.sub.ksG.sub.ksA.sub.dsG.sub.dsT.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.dsA.s-
ub.ds.sup.m 80 34
C.sub.ds.sup.mC.sub.dsG.sub.ksT.sub.esT.sub.ksT.sub.esT.sub.k
1341279 1600 1615 21415 21430 GTATCTTATAAGACTA
G.sub.ksT.sub.ksA.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.dsT.s-
ub.dsA 61 1595
.sub.dsA.sub.dsG.sub.ksA.sub.es.sup.mC.sub.ksT.sub.esA.sub.k
1341285 1624 1639 21439 21454 ATAGAGTCGGTCACCT
A.sub.ksT.sub.ksA.sub.dsG.sub.dsA.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.dsG.s-
ub.ds 56 584
G.sub.dsT.sub.ds.sup.mC.sub.ksA.sub.es.sup.mC.sub.ks.sup.mC.sub.esT.-
sub.k 1341288 1620 1635 21435 21450 AGTCGGTCACCTTTCA
A.sub.ksG.sub.ksT.sub.ds.sup.mC.sub.dsG.sub.dsG.sub.dsT.sub.ds.sup.mC.sub-
.dsA.sub.ds 55 272
.sup.mC.sub.ds.sup.mC.sub.dsT.sub.ksT.sub.esT.sub.ks.sup.mC.sub.esA.-
sub.k 1341298 1712 1727 21527 21542 ACATCTCTGGGACCAA
A.sub.ks.sup.mC.sub.ksA.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.ds.sup.mC.sub.d-
sT.sub.dsG.sub.d 67 195
.sub.sG.sub.dsG.sub.dsA.sub.ks.sup.mC.sub.es.sup.mC.sub.ksA.sub.esA.-
sub.k 1341299 1628 1643 21443 21458 TAAAATAGAGTCGGTC
T.sub.ksA.sub.ksA.sub.dsA.sub.dsA.sub.dsT.sub.dsA.sub.dsG.sub.dsA.sub.dsG
68 895
.sub.dsT.sub.ds.sup.mC.sub.ksG.sub.esG.sub.ksT.sub.es.sup.mC.sub.k
1341306 1721 1736 21536 21551 ATTGTCTAAACATCTC
A.sub.ksT.sub.ksT.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.dsA.s-
ub.dsA 62 585
.sub.ds.sup.mC.sub.dsA.sub.ksT.sub.es.sup.mC.sub.ksT.sub.es.sup.mC.s-
ub.k 1341308 1752 1767 21567 21582 TCCTGTGTTAGCTTTA
T.sub.ks.sup.mC.sub.ks.sup.mC.sub.dsT.sub.dsG.sub.dsT.sub.dsG.sub.dsT.sub-
.dsT.sub.ds 79 1442
A.sub.dsG.sub.ds.sup.mC.sub.ksT.sub.esT.sub.ksT.sub.esA.sub.k
1341312 1784 1799 21599 21614 GTTTCTTATGTAATAG
G.sub.ksT.sub.ksT.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.dsT.s-
ub.dsG 21 897
.sub.dsT.sub.dsA.sub.ksA.sub.esT.sub.ksA.sub.esG.sub.k 1341317 1780
1795 21595 21610 CTTATGTAATAGCCAG
.sup.mC.sub.ksT.sub.ksT.sub.dsA.sub.dsT.sub.dsG.sub.dsT.sub.dsA.sub.dsA.s-
ub.dsT 61 664
.sub.dsA.sub.dsG.sub.ks.sup.mC.sub.es.sup.mC.sub.ksA.sub.esG.sub.k
1341320 2189 2204 22004 22019 CTTGATGTAGTGGGAG
.sup.mC.sub.ksT.sub.ksT.sub.dsG.sub.dsA.sub.dsT.sub.dsG.sub.dsT.sub.dsA.s-
ub.dsG 20 976
.sub.dsT.sub.dsG.sub.ksG.sub.esG.sub.ksA.sub.esG.sub.k 1341324 2252
2267 22067 22082 AGAGGATAGTCCATGC
A.sub.ksG.sub.ksA.sub.dsG.sub.dsG.sub.dsA.sub.dsT.sub.dsA.sub.dsG.sub.dsT
70 354
.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksA.sub.esT.sub.ksG.sub.es.sup.mC.s-
ub.k 1341330 N/A N/A 9334 9349 CGATCCTATATACATC
.sup.mC.sub.ksG.sub.ksA.sub.dsT.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub.d-
sA.sub.dsT.sub.d 29 2788
.sub.sA.sub.dsT.sub.dsA.sub.ks.sup.mC.sub.esA.sub.ksT.sub.es.sup.mC.-
sub.k 1341331 N/A N/A 9516 9531 ACACTAATATTGAGGC
A.sub.ks.sup.mC.sub.ksA.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.dsA.sub.dsT.sub-
.dsA.sub.ds 55 1928
T.sub.dsT.sub.dsG.sub.ksA.sub.esG.sub.ksG.sub.es.sup.mC.sub.k
1341336 2353 2368 22168 22183 ATAACTACAAGAGGTT
A.sub.ksT.sub.ksA.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.ds.sup.mC.sub-
.dsA.sub.ds 46 1133
A.sub.dsG.sub.dsA.sub.ksG.sub.esG.sub.ksT.sub.esT.sub.k
1341340 N/A N/A 11546 11561 TCTTGACAATGGTTGC
T.sub.ks.sup.mC.sub.ksT.sub.dsT.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.dsA.sub-
.dsA.sub.ds 37 2199
T.sub.dsG.sub.dsG.sub.ksT.sub.esT.sub.ksG.sub.es.sup.mC.sub.k
1341341 N/A N/A 9968 9983 AGTAGTGTAAGCTGAG
A.sub.ksG.sub.ksT.sub.dsA.sub.dsG.sub.dsT.sub.dsG.sub.dsT.sub.dsA.sub.dsA-
.sub.d 52 2155
.sub.sG.sub.ds.sup.mC.sub.ksT.sub.esG.sub.ksA.sub.esG.sub.k 1341349
N/A N/A 9603 9618 CACATATGTGAAGAGC
.sup.mC.sub.ksA.sub.ks.sup.mC.sub.dsA.sub.dsT.sub.dsA.sub.dsT.sub.dsG.sub-
.dsT.sub.ds 53 760
G.sub.dsA.sub.dsA.sub.ksG.sub.esA.sub.ksG.sub.es.sup.mC.sub.k
1341352 N/A N/A 15498 15513 TGCTGCATTAATGCCA
T.sub.ksG.sub.ks.sup.mC.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.dsT.sub-
.dsT.sub.ds 30 2485
A.sub.dsA.sub.dsT.sub.ksG.sub.es.sup.mC.sub.ks.sup.mC.sub.esA.sub.k
1341355 N/A N/A 14918 14933 TAATACATTAGCAAGC
T.sub.ksA.sub.ksA.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.dsT.s-
ub.dsA 34 2266
.sub.dsG.sub.ds.sup.mC.sub.ksA.sub.esA.sub.ksG.sub.es.sup.mC.sub.k
1341356 N/A N/A 12419 12434 GTAACGGTGATCAAAT
G.sub.ksT.sub.ksA.sub.dsA.sub.ds.sup.mC.sub.dsG.sub.dsG.sub.dsT.sub.dsG.s-
ub.ds 34 2345
A.sub.dsT.sub.ds.sup.mC.sub.ksA.sub.esA.sub.ksA.sub.esT.sub.k
1341359 N/A N/A 14199 14214 TATTATGTGATTGAGT
T.sub.ksA.sub.ksT.sub.dsT.sub.dsA.sub.dsT.sub.dsG.sub.dsT.sub.dsG.sub.dsA-
.sub.ds 65 73 T.sub.dsT.sub.ksG.sub.esA.sub.ksG.sub.esT.sub.k
1341362 N/A N/A 16384 16399 AATCCCAACCAAACTT
A.sub.ksA.sub.ksT.sub.ds.sup.mC.sub.ds.sup.m.sub.ksC.sub.ds.sup.mC.sub.ds-
A.sub.dsA.sub.ds.sup.m 17 2755
C.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.ksA.sub.es.sup.mC.sub.ksT.sub.es-
T.sub.k 1341367 N/A N/A 16129 16144 TCCATAATAATAGCTC
T.sub.ks.sup.mC.sub.ks.sup.mC.sub.dsA.sub.dsT.sub.dsA.sub.dsA.sub.dsT.sub-
.dsA.sub.ds 41 546
A.sub.dsT.sub.dsA.sub.ksG.sub.es.sup.mC.sub.ksT.sub.es.sup.mC.sub.k
1341369 N/A N/A 16223 16238 CTTTTTATAGACTGGG
.sup.mC.sub.ksT.sub.ksT.sub.dsT.sub.dsT.sub.dsT.sub.dsA.sub.dsT.sub.dsA.s-
ub.dsG 37 857
.sub.dsA.sub.ds.sup.mC.sub.ksT.sub.esG.sub.ksG.sub.esG.sub.k
1341372 N/A N/A 18097 18112 GAAATTGATACACCAA
G.sub.ksA.sub.ksA.sub.dsA.sub.dsT.sub.dsT.sub.dsG.sub.dsA.sub.dsT.sub.dsA-
.sub.d 68 315
.sub.s.sup.mC.sub.dsA.sub.ks.sup.mC.sub.es.sup.mC.sub.ksA.sub.esA.su-
b.k 1341373 N/A N/A 17990 18005 TTAGTATAGTTATCTT
T.sub.ksT.sub.ksA.sub.dsG.sub.dsT.sub.dsA.sub.dsT.sub.dsA.sub.dsG.sub.dsT-
.sub.ds 33 2366
T.sub.dsA.sub.ksT.sub.es.sup.mC.sub.ksT.sub.esT.sub.k 1341383 N/A
N/A 18697 18712 CAAAAGACTTTGAGAC
.sup.mC.sub.ksA.sub.ksA.sub.dsA.sub.dsA.sub.dsG.sub.dsA.sub.ds.sup.mC.sub-
.dsT.sub.d 32 2186
.sub.sT.sub.dsT.sub.dsG.sub.ksA.sub.esG.sub.ksA.sub.es.sup.mC.sub.k
1341386 N/A N/A 19910 19925 CATCTTAAGATACCCA
.sup.mC.sub.ksA.sub.ksT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.dsA.sub-
.dsG.sub.ds 59 475
A.sub.dsT.sub.dsA.sub.ks.sup.mC.sub.es.sup.mC.sub.ks.sup.mC.sub.esA.-
sub.k 1341394 N/A N/A 20385 20400 TAGTAATCACAAGTAA
T.sub.ksA.sub.ksG.sub.dsT.sub.dsA.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.dsA.s-
ub.ds.sup.m 55 1489
C.sub.dsA.sub.dsA.sub.ksG.sub.esT.sub.ksA.sub.esA.sub.k 1341395 N/A
N/A 20112 20127 ATCAAGACATTCTAGC
A.sub.ksT.sub.ks.sup.mC.sub.dsA.sub.dsA.sub.dsG.sub.dsA.sub.ds.sup.mC.sub-
.dsA.sub.d 30 1488
.sub.sT.sub.dsT.sub.ds.sup.mC.sub.ksT.sub.esA.sub.ksG.sub.es.sup.mC.-
sub.k 1341397 N/A N/A 20192 20207 GCAGTTATTAGAAGTC
G.sub.ks.sup.mC.sub.ksA.sub.dsG.sub.dsT.sub.dsT.sub.dsA.sub.dsT.sub.dsT.s-
ub.dsA 68 398
.sub.dsG.sub.dsA.sub.ksA.sub.esG.sub.ksT.sub.es.sup.mC.sub.k
1341402 N/A N/A 12799 12814 GCTGTAAGAGTCAGTA
G.sub.ks.sup.mC.sub.ksT.sub.dsG.sub.dsT.sub.dsA.sub.dsA.sub.dsG.sub.dsA.s-
ub.ds 42 693
G.sub.dsT.sub.ds.sup.mC.sub.ksA.sub.esG.sub.ksT.sub.esA.sub.k
1341404 N/A N/A 12499 12514 AGAAATTCACCTTGAC
A.sub.ksG.sub.ksA.sub.dsA.sub.dsA.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsA.s-
ub.ds.sup.m 33 2284
C.sub.ds.sup.mC.sub.dsT.sub.ksT.sub.esG.sub.ksA.sub.es.sup.mC.sub.k
1341408 N/A N/A 20486 20501 AACTTCATAGTGGACT
A.sub.ksA.sub.ks.sup.mC.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.dsT.sub-
.dsA.sub.ds 68 2555
G.sub.dsT.sub.dsG.sub.ksG.sub.esA.sub.ks.sup.mC.sub.esT.sub.k
1341416 N/A N/A 13956 13971 TACCTCTAAGTTAGCC
T.sub.ksA.sub.ks.sup.mC.sub.ds.sup.mC.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.d-
sA.sub.dsA.sub.d 20 2249
.sub.sG.sub.dsT.sub.dsT.sub.ksA.sub.esG.sub.ks.sup.mC.sub.es.sup.mC.-
sub.k 1341429 N/A N/A 14192 14207 TGATTGAGTTCTCCAC
T.sub.ksG.sub.ksA.sub.dsT.sub.dsT.sub.dsG.sub.dsA.sub.dsG.sub.dsT.sub.dsT-
.sub.ds 32 2116
.sup.mC.sub.dsT.sub.ks.sup.mC.sub.es.sup.mC.sub.ksA.sub.es.sup.mC.su-
b.k 1341535 1074 1089 20889 20904 TGCCAAACCAATGTTT
T.sub.ksG.sub.ks.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsA.sub.ds.sup.-
mC.sub.ds.sup.m 61 2673
C.sub.dsA.sub.dsA.sub.dsT.sub.ksG.sub.esT.sub.ksT.sub.esT.sub.k
1341539 1310 1325 21125 21140 CTTAAACCTTCCCTGT
.sup.mC.sub.ksT.sub.ksT.sub.dsA.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.ds.sup.-
mC.sub.dsT.sub.d 36 1823
.sub.sT.sub.ds.sup.mC.sub.ds.sup.mC.sub.ks.sup.mC.sub.esT.sub.ksG.su-
b.esT.sub.k 1341549 1330 1345 21145 21160 TGGAATGCTACTTGAA
T.sub.ksG.sub.ksG.sub.dsA.sub.dsA.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.dsT.s-
ub.ds 68 2203
A.sub.ds.sup.mC.sub.dsT.sub.ksT.sub.esG.sub.ksA.sub.esA.sub.k
1341556 1336 1351 21151 21166 ACAGATTGGAATGCTA
A.sub.ks.sup.mC.sub.ksA.sub.dsG.sub.dsA.sub.dsT.sub.dsT.sub.dsG.sub.dsG.s-
ub.ds 49 1668
A.sub.dsA.sub.dsT.sub.ksG.sub.es.sup.mC.sub.ksT.sub.esA.sub.k
1341570 1707 1722 21522 21537 TCTGGGACCAAGGATA
T.sub.ks.sup.mC.sub.ksT.sub.dsG.sub.dsG.sub.dsG.sub.dsA.sub.ds.sup.mC.sub-
.ds.sup.mC 56 1830
.sub.dsA.sub.dsA.sub.dsG.sub.ksG.sub.esA.sub.ksT.sub.esA.sub.k
1341572 1616 1631 21431 21446 GGTCACCTTTCATAAT
G.sub.ksG.sub.ksT.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.d-
sT.sub.dsT.sub.d 52 1985
.sub.sT.sub.ds.sup.mC.sub.dsA.sub.ksT.sub.esA.sub.ksA.sub.esT.sub.k
1341579 1771 1786 21586 21601 TAGCCAGTACAGTTCC
T.sub.ksA.sub.ksG.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.dsT.sub-
.dsA.sub.ds 57 1987
.sup.mC.sub.dsA.sub.dsG.sub.ksT.sub.esT.sub.ks.sup.mc.sub.es.sup.mC.-
sub.k 1341581 1716 1731 21531 21546 CTAAACATCTCTGGGA
.sup.mC.sub.ksT.sub.ksA.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.dsT.sub-
.ds.sup.mC 29 2259
.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.ksG.sub.esG.sub.ksG.sub.esA.sub.k
1341582 2196 2211 22011 22026 GATTAGTCTTGATGTA
G.sub.ksA.sub.ksT.sub.dsT.sub.dsA.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.dsT.s-
ub.dsT 56 1521
.sub.dsG.sub.dsA.sub.ksT.sub.esG.sub.ksT.sub.esA.sub.k 1341584 1776
1791 21591 21606 TGTAATAGCCAGTACA
T.sub.ksG.sub.ksT.sub.dsA.sub.dsA.sub.dsT.sub.dsA.sub.dsG.sub.ds.sup.mC.s-
ub.ds.sup.m 45 352
C.sub.dsA.sub.dsG.sub.ksT.sub.esA.sub.ks.sup.mC.sub.esA.sub.k
1341592 N/A N/A 11578 11593 GTTATTCTCTTGACAA
G.sub.ksT.sub.ksT.sub.dsA.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.ds.su-
p.mC.sub.ds 27 2575
T.sub.dsT.sub.dsG.sub.ksA.sub.es.sup.mC.sub.ksA.sub.esA.sub.k
1341602 N/A N/A 16292 16307 TTAGTTAGAATAGTCT
T.sub.ksT.sub.ksA.sub.dsG.sub.dsT.sub.dsT.sub.dsA.sub.dsG.sub.dsA.sub.dsA-
.sub.d 53 1714
.sub.sT.sub.dsA.sub.ksG.sub.esT.sub.ks.sup.mC.sub.esT.sub.k 1341617
N/A N/A 17995 18010 TGAAGTTAGTATAGTT
T.sub.ksG.sub.ksA.sub.dsA.sub.dsG.sub.dsT.sub.dsT.sub.dsA.sub.dsG.sub.dsT-
.sub.d 46 1405
.sub.sA.sub.dsT.sub.ksA.sub.esG.sub.ksT.sub.esT.sub.k
TABLE-US-00042 TABLE 42 Inhibition of HSD17B13 RNA by modified
oligonucleotides targeting SEQ ID NO.: 1, and 2 SEQ SEQ SEQ SEQ ID
NO: ID NO: ID NO: ID NO: % SEQ Compound 1 Start 1 Stop 2 Start 2
Stop Sequence Chemistry Notation in- ID Number Site Site Site Site
(5' to 3') (5' to 3') hibition NO 1245927 N/A N/A 3433 3448
AGTAGATGGTAAGTCA
A.sub.ksG.sub.ksT.sub.ksA.sub.dsG.sub.dsA.sub.dsT.sub.dsG.sub.dsG.sub.dsT-
.sub.d 84 121
.sub.sA.sub.dsA.sub.dsG.sub.dsT.sub.ks.sup.mC.sub.ksA.sub.k 1246023
N/A N/A 5046 5061 GAGTGAATCATTCAGT
G.sub.ksA.sub.ksG.sub.ksT.sub.dsG.sub.dsA.sub.dsA.sub.dsT.sub.ds.sup.mC.s-
ub.ds 83 1526
A.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ksG.sub.ksT.sub.k
1340984 1497 1512 21312 21327 AGTTGCACCGTTTTGG
A.sub.ksG.sub.ksT.sub.ksT.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub-
.ds.sup.mC 43 1905
.sub.dsG.sub.dsT.sub.dsT.sub.dsT.sub.ksT.sub.ksG.sub.ksG.sub.e
1340987 1489 1504 21304 21319 CGTTTTGGGCTAATGA
.sup.mC.sub.ksG.sub.ksT.sub.dsT.sub.dsT.sub.dsG.sub.dsG.sub.dsG.sub.ds.su-
p.m 52 1282 C.sub.dsT.sub.dsA.sub.dsA.sub.ksT.sub.ksG.sub.ksA.sub.e
1340990 1618 1633 21433 21448 TCGGTCACCTTTCATA
T.sub.ks.sup.mC.sub.ksG.sub.ksG.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ds.sup.-
mC.sub.ds.sup.m 72 116
C.sub.dsT.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ksA.sub.ksT.sub.ksA.sub.-
e 1340997 1622 1637 21437 21452 AGAGTCGGTCACCTTT
A.sub.ksG.sub.ksA.sub.ksG.sub.dsT.sub.ds.sup.mC.sub.dsG.sub.dsG.sub.dsT.s-
ub.ds.sup.m 66 428
C.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksT.sub.ksT.sub.ksT.sub.e
1341001 1626 1641 21441 21456 AAATAGAGTCGGTCAC
A.sub.ksA.sub.ksA.sub.ksT.sub.dsA.sub.dsG.sub.dsA.sub.dsG.sub.dsT.sub.ds.-
sup.m 48 740
C.sub.dsG.sub.dsG.sub.dsT.sub.ks.sup.mC.sub.ksA.sub.ks.sup.mC.sub.e
1341005 1630 1645 21445 21460 TTTAAAATAGAGTCGG
T.sub.ksT.sub.ksT.sub.ksA.sub.dsA.sub.dsA.sub.dsA.sub.dsT.sub.dsA.sub.dsG-
.sub.d 58 1051
.sub.sA.sub.dsG.sub.dsT.sub.ks.sup.mC.sub.ksG.sub.ksG.sub.e 1341018
1710 1725 21525 21540 ATCTCTGGGACCAAGG
A.sub.ksT.sub.ks.sup.mC.sub.ksT.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.dsG.sub-
.dsG.sub.ds 53 37
A.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ksA.sub.ksG.sub.ksG.sub.e
1341019 1714 1729 21529 21544 AAACATCTCTGGGACC
A.sub.ksA.sub.ksA.sub.ks.sup.mC.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.dsT.sub-
.ds.sup.mC 48 2129
.sub.dsT.sub.dsG.sub.dsG.sub.dsG.sub.ksA.sub.ks.sup.mC.sub.ks.sup.mC-
.sub.e 1341026 1768 1783 21583 21598 CCAGTACAGTTCCTTT
.sup.mC.sub.ks.sup.mC.sub.ksA.sub.ksG.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.d-
sA.sub.dsG 76 1753
.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksT.sub.ksT.sub.ksT-
.sub.e 1341029 1750 1765 21565 21580 CTGTGTTAGCTTTAAT
.sup.mC.sub.ksT.sub.ksG.sub.ksT.sub.dsG.sub.dsT.sub.dsT.sub.dsA.sub.dsG.s-
ub.ds.sup.m 50 1286
C.sub.dsT.sub.dsT.sub.dsT.sub.ksA.sub.ksA.sub.ksT.sub.e 1341031
2193 2208 22008 22023 TAGTCTTGATGTAGTG
T.sub.ksA.sub.ksG.sub.ksT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsG.sub.dsA.s-
ub.dsT 61 1288
.sub.dsG.sub.dsT.sub.dsA.sub.ksG.sub.ksT.sub.ksG.sub.e 1341036 1778
1793 21593 21608 TATGTAATAGCCAGTA
T.sub.ksA.sub.ksT.sub.ksG.sub.dsT.sub.dsA.sub.dsA.sub.dsT.sub.dsA.sub.dsG-
.sub.d 82 508
.sub.s.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ksG.sub.ksT.sub.ksA.sub.e
1341038 1782 1797 21597 21612 TTCTTATGTAATAGCC
T.sub.ksT.sub.ks.sup.mC.sub.ksT.sub.dsT.sub.dsA.sub.dsT.sub.dsG.sub.dsT.s-
ub.dsA 73 819
.sub.dsA.sub.dsT.sub.dsA.sub.ksG.sub.ks.sup.mC.sub.ks.sup.mC.sub.e
1341047 2247 2262 22062 22077 ATAGTCCATGCAAAAG
A.sub.ksT.sub.ksA.sub.ksG.sub.dsT.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub-
.dsT.sub.ds 29 2436
G.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.ksA.sub.ksA.sub.ksG.sub.e
1341058 N/A N/A 9330 9345 CCTATATACATCCAAG
.sup.mC.sub.ks.sup.mC.sub.ksT.sub.ksA.sub.dsT.sub.dsA.sub.dsT.sub.dsA.sub-
.ds.sup.mC.sub.d 63 1771
.sub.sA.sub.dsT.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksA.sub.ksA.sub.ksG.-
sub.e 1341063 1082 1097 20897 20912 GCTGCTAGTGCCAAAC
G.sub.ks.sup.mC.sub.ksT.sub.ksG.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.dsG.sub-
.dsT.sub.ds 62 1587
G.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ksA.sub.ksA.sub.ks.sup.mC.-
sub.e 1341064 N/A N/A 11855 11870 TAAGCAGAATTGTGAA
T.sub.ksA.sub.ksA.sub.ksG.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.dsA.sub.dsA.s-
ub.ds 52 2361
T.sub.dsT.sub.dsG.sub.dsT.sub.ksG.sub.ksA.sub.ksA.sub.e 1341067 N/A
N/A 11571 11586 TCTTGACAATGGTTGA
T.sub.ks.sup.mC.sub.ksT.sub.ksT.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.dsA.sub-
.dsA.sub.ds 61 2440
T.sub.dsG.sub.dsG.sub.dsT.sub.ksT.sub.ksG.sub.ksA.sub.e 1341069 N/A
N/A 9964 9979 GTGTAAGCTGAGAGTT
G.sub.ksT.sub.ksG.sub.ksT.sub.dsA.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.dsT.s-
ub.ds 45 2760
G.sub.dsA.sub.dsG.sub.dsA.sub.ksG.sub.ksT.sub.ksT.sub.e 1341070 N/A
N/A 14199 14214 TATTATGTGATTGAGT
T.sub.ksA.sub.ksT.sub.ksT.sub.dsA.sub.dsT.sub.dsG.sub.dsT.sub.dsG.sub.dsA-
.sub.ds 51 73 T.sub.dsT.sub.dsG.sub.ksA.sub.ksG.sub.ksT.sub.e
1341073 N/A N/A 15498 15513 TGCTGCATTAATGCCA
T.sub.ksG.sub.ks.sup.mC.sub.ksT.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.dsT.sub-
.dsT.sub.ds 6 2485
A.sub.dsA.sub.dsT.sub.dsG.sub.ks.sup.mC.sub.ks.sup.mC.sub.ksA.sub.e
1341079 N/A N/A 14918 14933 TAATACATTAGCAAGC
T.sub.ksA.sub.ksA.sub.ksT.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.dsT.s-
ub.dsA 35 2266
.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.ksA.sub.ksG.sub.ks.sup.mC.sub.e
1341082 N/A N/A 16380 16395 CCAACCAAACTTCCAG
.sup.mC.sub.ks.sup.mC.sub.ksA.sub.ksA.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA-
.sub.dsA.sub.ds 47 2539
A.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ks.sup.mC.sub.ksA.-
sub.ksG.sub.e 1341083 1078 1093 20893 20908 CTAGTGCCAAACCAAT
.sup.mC.sub.ksT.sub.ksA.sub.ksG.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.ds.sup.-
mC.sub.dsA 61 1276
.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksA.sub.ksA.sub.ksT-
.sub.e 1341085 N/A N/A 16287 16302 TAGAATAGTCTTCAGC
T.sub.ksA.sub.ksG.sub.ksA.sub.dsA.sub.dsT.sub.dsA.sub.dsG.sub.dsT.sub.ds.-
sup.m 50 1403
C.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ksA.sub.ksG.sub.ks.sup.mC.sub.e
1341090 N/A N/A 18697 18712 CAAAAGACTTTGAGAC
.sup.mC.sub.ksA.sub.ksA.sub.ksA.sub.dsA.sub.dsG.sub.dsA.sub.ds.sup.mC.sub-
.dsT.sub.d 13 2186
.sub.sT.sub.dsT.sub.dsG.sub.dsA.sub.ksG.sub.ksA.sub.ks.sup.mC.sub.e
1341095 N/A N/A 18099 18114 CTGAAATTGATACACC
.sup.mC.sub.ksT.sub.ksG.sub.ksA.sub.dsA.sub.dsA.sub.dsT.sub.dsT.sub.dsG.s-
ub.ds 75 393
A.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.ksA.sub.ks.sup.mC.sub.ks.sup.mC.-
sub.e 1341098 N/A N/A 17992 18007 AGTTAGTATAGTTATC
A.sub.ksG.sub.ksT.sub.ksT.sub.dsA.sub.dsG.sub.dsT.sub.dsA.sub.dsT.sub.dsA-
.sub.d 47 1249
.sub.sG.sub.dsT.sub.dsT.sub.ksA.sub.ksT.sub.ks.sup.mC.sub.e 1341107
N/A N/A 19907 19922 CTTAAGATACCCAGGT
.sup.mC.sub.ksT.sub.ksT.sub.ksA.sub.dsA.sub.dsG.sub.dsA.sub.dsT.sub.dsAci-
.sub.s.sup.m 45 241
C.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ksG.sub.ksG.sub.ksT.sub.e
1341108 N/A N/A 19911 19926 GCATCTTAAGATACCC
G.sub.ks.sup.mC.sub.ksA.sub.ksT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub-
.dsA.sub.ds 84 553
G.sub.dsA.sub.dsT.sub.dsA.sub.ks.sup.mC.sub.ks.sup.mC.sub.ks.sup.mC.-
sub.e 1341110 N/A N/A 20383 20398 GTAATCACAAGTAAGG
G.sub.ksT.sub.ksA.sub.ksA.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub-
.dsA.sub.ds 56 1411
A.sub.dsG.sub.dsT.sub.dsA.sub.ksA.sub.ksG.sub.ksG.sub.e 1341116 N/A
N/A 20194 20209 TTGCAGTTATTAGAAG
T.sub.ksT.sub.ksG.sub.ks.sup.mC.sub.dsA.sub.dsG.sub.dsT.sub.dsT.sub.dsA.s-
ub.dsT 10 2123
.sub.dsT.sub.dsA.sub.dsG.sub.ksA.sub.ksA.sub.ksG.sub.e 1341122 1086
1101 20901 20916 GACTGCTGCTAGTGCC
G.sub.ksA.sub.ks.sup.mC.sub.ksT.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsG.sub-
.ds.sup.mC 49 1899
.sub.dsT.sub.dsA.sub.dsG.sub.dsT.sub.ksG.sub.ks.sup.mC.sub.ks.sup.mC-
.sub.e 1341123 N/A N/A 12801 12816 AGGCTGTAAGAGTCAG
A.sub.ksG.sub.ksG.sub.ks.sup.mC.sub.dsT.sub.dsG.sub.dsT.sub.dsA.sub.dsA.s-
ub.ds 49 2809
G.sub.dsA.sub.dsG.sub.dsT.sub.ks.sup.mC.sub.ksA.sub.ksG.sub.e
1341125 N/A N/A 12503 12518 TTGCAGAAATTCACCT
T.sub.ksT.sub.ksG.sub.ks.sup.mC.sub.dsA.sub.dsG.sub.dsA.sub.dsA.sub.dsA.s-
ub.ds 29 2528
T.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ks.sup.mC.sub.ks.sup.mC.sub.ksT.-
sub.e 1341134 N/A N/A 13954 13969 CCTCTAAGTTAGCCCC
.sup.mC.sub.ks.sup.mC.sub.ksT.sub.ks.sup.mC.sub.dsT.sub.dsA.sub.dsA.sub.d-
sG.sub.dsT.sub.d 16 1084
.sub.sT.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.ks.sup.mC.sub.ks.sup.mC.su-
b.ks.sup.mC.sub.e 1341136 N/A N/A 14168 14183 ATAGCAAGCCAACAGA
A.sub.ksT.sub.ksA.sub.ksG.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsG.sub.ds.su-
p.mC.sub.d 30 2633
.sub.s.sup.mC.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.ksA.sub.ksG.sub.ksA.-
sub.e 1341144 1258 1273 21073 21088 TAGCTTTTGTCCACCT
T.sub.ksA.sub.ksG.sub.ks.sup.mC.sub.dsT.sub.dsT.sub.dsT.sub.dsT.sub.dsG.s-
ub.dsT 65 1900
.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ks.sup.mC.sub.ks.sup.mC.sub-
.ksT.sub.e 1341146 1200 1215 21015 21030 ATGTTTATGTAAGCAC
A.sub.ksT.sub.ksG.sub.ksT.sub.dsT.sub.dsT.sub.dsA.sub.dsT.sub.dsG.sub.dsT-
.sub.ds 73 2622
A.sub.dsA.sub.dsG.sub.ks.sup.mC.sub.ksA.sub.ks.sup.mC.sub.e 1341148
N/A N/A 14192 14207 TGATTGAGTTCTCCAC
T.sub.ksG.sub.ksA.sub.ksT.sub.dsT.sub.dsG.sub.dsA.sub.dsG.sub.dsT.sub.dsT-
.sub.ds 30 2116
.sup.mC.sub.dsT.sub.ds.sup.mC.sub.ks.sup.mC.sub.ksA.sub.ks.sup.mC.su-
b.e 1341149 606 621 10492 10507 AATATGGGATGAGGTA
A.sub.ksA.sub.ksT.sub.ksA.sub.dsT.sub.dsG.sub.dsG.sub.dsG.sub.dsA.sub.dsT-
.sub.d 47 1424
.sub.sG.sub.dsA.sub.dsG.sub.ksG.sub.ksT.sub.ksA.sub.e 1341155 1312
1327 21127 21142 GTCTTAAACCTTCCCT
G.sub.ksT.sub.ks.sup.mC.sub.ksT.sub.dsT.sub.dsA.sub.dsA.sub.dsA.sub.ds.su-
p.mC.sub.ds 50 1901
.sup.mC.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ks.sup.mC.sub.ks.sup.mC.su-
b.ksT.sub.e 1341157 1316 1331 21131 21146 AACAGTCTTAAACCTT
A.sub.ksA.sub.ks.sup.mC.sub.ksA.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.dsT.sub-
.dsT.sub.ds 57 188
A.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.ks.sup.mC.sub.ksT.sub.ksT.sub.e
1341161 1322 1337 21137 21152 TACTTGAACAGTCTTA
T.sub.ksA.sub.ks.sup.mC.sub.ksT.sub.dsT.sub.dsG.sub.dsA.sub.dsA.sub.ds.su-
p.mC.sub.ds 65 656
A.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.ksT.sub.ksT.sub.ksA.sub.e
1341162 1333 1348 21148 21163 GATTGGAATGCTACTT
G.sub.ksA.sub.ksT.sub.ksT.sub.dsG.sub.dsG.sub.dsA.sub.dsA.sub.ksT.sub.dsG-
.sub.d 59 1435
.sub.s.sup.mC.sub.dsT.sub.dsA.sub.ks.sup.mC.sub.ksT.sub.ksT.sub.e
1341169 1326 1341 21141 21156 ATGCTACTTGAACAGT
A.sub.ksT.sub.ksG.sub.ks.sup.mC.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.dsT.sub-
.dsT.sub.ds 50 967
G.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.ksA.sub.ksG.sub.ksT.sub.e
1341220 1342 1357 21157 21172 ATGGCTACAGATTGGA
A.sub.ksT.sub.ksG.sub.ksG.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.ds.sup.mC.sub-
.dsA.sub.ds 65 111
G.sub.dsA.sub.dsT.sub.dsT.sub.ksG.sub.ksG.sub.ksA.sub.e 1341283
1356 1371 21171 21186 TGATATTCTGTGGCAT
T.sub.ksG.sub.ksA.sub.ksT.sub.dsA.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsT.s-
ub.dsG 74 1124
.sub.dsT.sub.dsG.sub.dsG.sub.ks.sup.mC.sub.ksA.sub.ksT.sub.e
1341309 1352 1367 21167 21182 ATTCTGTGGCATGGCT
A.sub.ksT.sub.ks.sup.mC.sub.dsT.sub.dsG.sub.dsT.sub.dsG.sub.dsG.sub.ds.su-
p.m 68 2328
C.sub.dsA.sub.dsT.sub.dsG.sub.ksG.sub.ks.sup.mC.sub.ksT.sub.e
1341366 1364 1379 21179 21194 GTTCTTGTTGATATTC
G.sub.ksT.sub.ksT.sub.ks.sup.mC.sub.dsT.sub.dsT.sub.dsG.sub.dsT.sub.dsT.s-
ub.dsG 69 1436
.sub.dsA.sub.dsT.sub.dsA.sub.ksT.sub.ksT.sub.ks.sup.mC.sub.e
1341420 1418 1433 21233 21248 TTGAGATAAAGCTGCC
T.sub.ksT.sub.ksG.sub.ksA.sub.dsG.sub.dsA.sub.dsT.sub.dsA.sub.dsA.sub.ksA-
.sub.d 43 1670
.sub.sG.sub.ds.sup.mC.sub.dsT.sub.ksG.sub.ks.sup.mC.sub.ks.sup.mC.su-
b.e 1341422 1389 1404 21204 21219 TCTCTTAGCTGTGCAC
T.sub.ks.sup.mC.sub.ksT.sub.ks.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.dsG.sub-
.ds.sup.mC.sub.d 69 346
.sub.sT.sub.dsG.sub.dsT.sub.dsG.sub.ks.sup.mC.sub.ksA.sub.ks.sup.mC.-
sub.e 1341423 1422 1437 21237 21252 CAGGTTGAGATAAAGC
.sup.mC.sub.ksA.sub.ksG.sub.ksG.sub.dsT.sub.dsT.sub.dsG.sub.dsA.sub.dsG.s-
ub.ds 63 1982
A.sub.dsT.sub.dsA.sub.dsA.sub.ksA.sub.ksG.sub.ks.sup.mC.sub.e
1341430 1493 1508 21308 21323 GCACCGTTTTGGGCTA
G.sub.ks.sup.mC.sub.ksA.sub.ks.sup.mC.sub.ds.sup.mC.sub.dsG.sub.dsT.sub.d-
sT.sub.dsT.sub.d 45 1593
.sub.sT.sub.dsG.sub.dsG.sub.dsG.sub.ks.sup.mC.sub.ksT.sub.ksA.sub.e
1341438 1504 1519 21319 21334 AGAATAGAGTTGCACC
A.sub.ksG.sub.ksA.sub.ksA.sub.dsT.sub.dsA.sub.dsG.sub.dsA.sub.dsG.sub.dsT
58 426
.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.ksA.sub.ks.sup.mC.sub.ks.sup.mC.s-
ub.e 1341440 1461 1476 21276 21291 CTAGGGAAATCTTTCA
.sup.mC.sub.ksT.sub.ksA.sub.ksG.sub.dsG.sub.dsG.sub.dsA.sub.dsA.sub.dsA.s-
ub.ds 55 659
T.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ksT.sub.ks.sup.mC.sub.ksA.sub.e
1341443 1614 1629 21429 21444 TCACCTTTCATAATGT
T.sub.ks.sup.mC.sub.ksA.sub.ks.sup.mC.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.d-
sT.sub.ds.sup.m 41 2109
C.sub.dsA.sub.dsT.sub.dsA.sub.dsA.sub.ksT.sub.ksG.sub.ksT.sub.e
1341444 805 820 15686 15701 GTAAGTATTCCATCTA
G.sub.ksT.sub.ksA.sub.ksA.sub.dsG.sub.dsT.sub.dsA.sub.dsT.sub.dsT.sub.ds.-
sup.mC 39 1038
.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.ks.sup.mC.sub.ksT.sub.ksA.sub.e
1341445 613 628 N/A N/A CTGGAACAATATGGGA
.sup.mC.sub.ksT.sub.ksG.sub.ksG.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.dsA.sub-
.dsA.sub.d 36 1969
.sub.sT.sub.dsA.sub.dsT.sub.dsG.sub.ksG.sub.ksG.sub.ksA.sub.e
1341452 1718 1733 21533 21548 GTCTAAACATCTCTGG
G.sub.ksT.sub.ks.sup.mC.sub.ksT.sub.dsA.sub.dsA.sub.dsA.sub.ds.sup.mC.sub-
.dsA.sub.ds 49 429
G.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.ksA.sub.ksG.sub.ksT.sub.e
1341453 1774 1789 21589 21604 TAATAGCCAGTACAGT
T.sub.ksA.sub.ksA.sub.ksT.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.ds.sup.mC.sub-
.dsA.sub.ds 64 196
G.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.ksA.sub.ksG.sub.ksT.sub.e
1341459 1074 1089 20889 20904 TGCCAAACCAATGTTT
T.sub.ksG.sub.ks.sup.mC.sub.ks.sup.mC.sub.dsA.sub.dsA.sub.dsA.sub.ds.sup.-
mC.sub.ds.sup.m 43 2673
C.sub.dsA.sub.dsA.sub.dsT.sub.dsG.sub.ksT.sub.ksT.sub.ksT.sub.e
1341461 N/A N/A 9511 9526 AATATTGAGGCACTGG
A.sub.ksA.sub.ksT.sub.ksA.sub.dsT.sub.dsT.sub.dsG.sub.dsA.sub.dsG.sub.dsG-
.sub.d 36 1538
.sub.s.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ksT.sub.ksG.sub.ksG.sub.e
1341462 N/A N/A 9598 9613 ATGTGAAGAGCTGGTA
A.sub.ksT.sub.ksG.sub.ksT.sub.dsG.sub.dsA.sub.ksA.sub.dsG.sub.dsA.sub.dsG
56 527 .sub.ds.sup.mC.sub.dsT.sub.dsG.sub.ksG.sub.ksT.sub.ksA.sub.e
1341464 2257 2272 22072 22087 AAACAAGAGGATAGTC
A.sub.ksA.sub.ksA.sub.ks.sup.mC.sub.dsA.sub.dsA.sub.dsG.sub.dsA.sub.dsG.s-
ub.ds 45 744
G.sub.dsA.sub.ksT.sub.dsA.sub.ksG.sub.ksT.sub.ks.sup.mC.sub.e
1341465 2186 2201 22001 22016 GATGTAGTGGGAGTCG
G.sub.ksA.sub.ksT.sub.ksG.sub.dsT.sub.dsA.sub.dsG.sub.dsT.sub.dsG.sub.dsG-
.sub.d 42 743
.sub.sG.sub.dsA.sub.dsG.sub.ksT.sub.ks.sup.mC.sub.ksG.sub.e 1341470
N/A N/A 12416 12431 ACGGTGATCAAATGTA
A.sub.ks.sup.mC.sub.ksG.sub.ksG.sub.dsT.sub.dsG.sub.dsA.sub.dsT.sub.ds.su-
p.mC.sub.ds 41 2205
A.sub.dsA.sub.dsA.sub.dsT.sub.ksG.sub.ksT.sub.ksA.sub.e 1341472 N/A
N/A 12426 12441 CAGGGTGGTAACGGTG
.sup.mC.sub.ksA.sub.ksG.sub.ksG.sub.dsG.sub.dsT.sub.dsG.sub.dsG.sub.dsT.s-
ub.ds 39 2729
A.sub.dsA.sub.ds.sup.mC.sub.dsG.sub.ksG.sub.ksT.sub.ksG.sub.e
1341478 N/A N/A 17997 18012 TATGAAGTTAGTATAG
T.sub.ksA.sub.ksT.sub.ksG.sub.dsA.sub.dsA.sub.dsG.sub.dsT.sub.dsT.sub.dsA-
.sub.d 13 1560
.sub.sG.sub.dsT.sub.dsA.sub.ksT.sub.ksA.sub.ksG.sub.e 1341480 N/A
N/A 16134 16149 GATGCTCCATAATAAT
G.sub.ksA.sub.ksT.sub.ksG.sub.ds.sup.mC.sub.dsT.sub.ds.sup.mC.sub.ds.sup.-
mC.sub.dsA 15 2049
.sub.dsT.sub.dsA.sub.dsA.sub.dsT.sub.ksA.sub.ksA.sub.ksT.sub.e
1341486 N/A N/A 16124 16139 AATAATAGCTCTATTG
A.sub.ksA.sub.ksT.sub.ksA.sub.dsA.sub.dsT.sub.dsA.sub.dsG.sub.ds.sup.mC.s-
ub.ds 3 2410
T.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.ksT.sub.ksT.sub.ksG.sub.e
1341494 N/A N/A 19915 19930 GAGTGCATCTTAAGAT
G.sub.ksA.sub.ksG.sub.ksT.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.ds.su-
p.mC.sub.ds 34 2256
T.sub.dsT.sub.dsA.sub.dsA.sub.ksG.sub.ksA.sub.ksT.sub.e 1341496 N/A
N/A 17987 18002 GTATAGTTATCTTCTC
G.sub.ksT.sub.ksA.sub.ksT.sub.dsA.sub.dsG.sub.dsT.sub.dsT.sub.dsA.sub.ksT-
.sub.ds 68 937
.sup.mC.sub.dsT.sub.dsT.sub.ks.sup.mC.sub.ksT.sub.ks.sup.mC.sub.e
1341499 N/A N/A 20489 20504 CATAACTTCATAGTGG
.sup.mC.sub.ksA.sub.ksT.sub.ksA.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.dsT.sub-
.ds.sup.mC.sub.d 16 866
.sub.sA.sub.dsT.sub.dsA.sub.dsG.sub.ksT.sub.ksG.sub.ksG.sub.e
1341501 N/A N/A 20109 20124 AAGACATTCTAGCCTG
A.sub.ksA.sub.ksG.sub.ksA.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.dsT.sub.ds.su-
p.mC.sub.ds 40 2744
T.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.ks.sup.mC.sub.ksT.sub.ksG.sub.e
1341506 N/A N/A 20119 20134 TTACAGCATCAAGACA
T.sub.ksksA.sub.ks.sup.mC.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.dsT.s-
ub.ds 44 2409
.sup.mC.sub.dsA.sub.dsA.sub.dsG.sub.ksA.sub.ks.sup.mC.sub.ksA.sub.e
1341517 N/A N/A 20479 20494 TAGTGGACTTCATTAG
T.sub.ksA.sub.ksG.sub.ksT.sub.dsG.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.dsT.s-
ub.dsT 22 2351
.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.ksT.sub.ksA.sub.ksG.sub.e
TABLE-US-00043 TABLE 43 Inhibition of HSD17B13 RNA by modified
oligonucleotides targeting SEQ ID NO.: 1, and 2 SEQ SEQ SEQ SEQ ID
NO: ID NO: ID NO: ID NO: % SEQ Compound 1 Start 1 Stop 2 Start 2
Stop Sequence Chemistry Notation in- ID Number Site Site Site Site
(5' to 3') (5' to 3') hibition NO 1245927 N/A N/A 3433 3448
AGTAGATGGTAAGTCA
A.sub.ksG.sub.ksT.sub.ksA.sub.dsG.sub.dsA.sub.dsT.sub.dsG.sub.dsG
88 121 .sub.dsT.sub.dsA.sub.dsG.sub.dsT.sub.ks.sup.mC.sub.ksA.sub.k
1246023 N/A N/A 5046 5061 GAGTGAATCATTCAGT
G.sub.ksA.sub.ksG.sub.ksT.sub.dsG.sub.dsA.sub.dsA.sub.ksdsT.sub.ds.sup.m
84 1526
C.sub.dsA.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ksG.sub.ksT.sub.-
k 1340982 1490 1505 21305 21320 CCGTTTTGGGCTAATG
.sup.mC.sub.ks.sup.mC.sub.ksG.sub.ksT.sub.dsT.sub.dsT.sub.dsT.sub.dsG.sub-
.ds 69 1360
G.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.ksA.sub.ksT.sub.ksG.sub.-
e 1340988 1494 1509 21309 21324 TGCACCGTTTTGGGCT
T.sub.ksG.sub.ks.sup.mC.sub.kA.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsG.sub.ds-
T 43 1671
.sub.dsT.sub.dsT.sub.dsT.sub.dsG.sub.dsG.sub.ksG.sub.ks.sup.mC.sub.k-
sT.sub.e 1340993 1619 1634 21434 21449 GTCGGTCACCTTTCAT
G.sub.ksT.sub.ks.sup.mC.sub.ksG.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.dsA.sub-
.d 68 194
.sub.s.sup.mC.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsT.sub.ks.sup.mC.su-
b.ksA.sub.ksT.sub.e 1340994 1598 1613 21413 21428 ATCTTATAAGACTATA
A.sub.ksT.sub.ks.sup.mC.sub.ksT.sub.dsT.sub.dsA.sub.dsT.sub.dsA.sub.ds
53 2661
A.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.ksA.sub.ksT.sub.ksA.sub.-
e 1341006 1627 1642 21442 21457 AAAATAGAGTCGGTCA
A.sub.ksA.sub.ksA.sub.ksA.sub.dsT.sub.dsA.sub.dsG.sub.dsA.sub.dsG
65 817
.sub.dsT.sub.ds.sup.mC.sub.dsG.sub.DsG.sub.ksT.sub.ks.sup.mC.sub.ksA-
.sub.e 1341008 808 823 15689 15704 TTGGTAAGTATTCCAT
T.sub.ksT.sub.ksG.sub.ksG.sub.dsT.sub.dsA.sub.dsA.sub.dsG.sub.dsT.sub.d
28 2750
.sub.sA.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ks.sup.mC.sub.ksA.sub.ksT.-
sub.e 1341009 1623 1638 21438 21453 TAGAGTCGGTCACCTT
T.sub.ksA.sub.ksCr.sub.ksA.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.dsG.sub.ds
59 506
G.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ks.sup.mC.sub.ksT.-
sub.ksT.sub.e 1341012 1719 1734 21534 21549 TGTCTAAACATCTCTG
T.sub.ksG.sub.ksT.sub.ks.sup.mC.sub.dsT.sub.dsA.sub.dsA.sub.dsA.sub.ds.su-
p.m 69 507
C.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.ks.sup.mC.sub.ksT.sub.ks-
G.sub.e 1341014 1711 1726 21526 21541 CATCTCTGGGACCAAG
.sup.mC.sub.ksA.sub.ksT.sub.ks.sup.mC.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.d-
sG 42 117
.sub.dsG.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksA.sub.ksA-
.sub.ksG.sub.e 1341016 1715 1730 21530 21545 TAAACATCTCTGGGAC
T.sub.ksA.sub.ksA.sub.ksA.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.ds.sup.mC.sub-
.d 32 351
.sub.sT.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.dsG.sub.ksG.sub.ksA.sub.ks-
.sup.mC.sub.e 1341020 1017 1032 20832 20847 CAGCATTGATTCGAAA
.sup.mC.sub.ksA.sub.ksG.sub.ks.sup.mC.sub.dsA.sub.dsT.sub.dsT.sub.dsG.sub-
.d 53 263
.sub.sA.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsG.sub.ksA.sub.ksA.sub.ks-
A.sub.e 1341025 1775 1790 21590 21605 GTAATAGCCAGTACAG
G.sub.ksT.sub.ksA.sub.ksA.sub.dsT.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.ds
62 274
.sup.mC.sub.dsA.sub.dsG.sub.dsT.sub.dsA.sub.ks.sup.mC.sub.ksA.sub.ks-
G.sub.e 1341027 1751 1766 21566 21581 CCTGTGTTAGCTTTAA
.sup.mC.sub.ks.sup.mC.sub.ksT.sub.ksG.sub.dsT.sub.dsG.sub.dsT.sub.dsT.sub-
.ds 66 1364
A.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ksT.sub.ksA.sub.ksA.sub.-
e 1341028 1770 1785 21585 21600 AGCCAGTACAGTTCCT
A.sub.ksG.sub.ks.sup.mC.sub.ks.sup.mC.sub.dsA.sub.dsG.sub.dsT.sub.dsA.sub-
.d 59 1909
.sub.s.sup.mC.sub.dsA.sub.dsG.sub.dsT.sub.dsT.sub.ks.sup.mC.sub.ks.s-
up.mC.sub.ksT.sub.e 1341032 1779 1794 21594 21609 TTATGTAATAGCCAGT
T.sub.ksT.sub.ksA.sub.ksT.sub.dsG.sub.dsT.sub.dsA.sub.dsA.sub.dsT.sub.d
77 586
.sub.sA.sub.dsG.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksA.sub.ksG.sub.ksT.-
sub.e 1341035 2187 2202 22002 22017 TGATGTAGTGGGAGTC
T.sub.ksG.sub.ksA.sub.ksT.sub.dsG.sub.dsT.sub.dsA.sub.dsG.sub.dsT.sub.d
77 820
.sub.sG.sub.dsG.sub.dsG.sub.dsA.sub.ksG.sub.ksT.sub.ks.sup.mC.sub.e
1341037 1783 1798 21598 21613 TTTCTTATGTAATAGC
T.sub.ksT.sub.ksT.sub.ks.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.dsT.sub.dsG
60 2128
.sub.dsT.sub.dsA.sub.dsA.sub.dsT.sub.ksA.sub.ksG.sub.ks.sup.mC.sub.e
1341041 1079 1094 20894 20909 GCTAGTGCCAAACCAA
G.sub.ks.sup.mC.sub.ksT.sub.ksA.sub.dsG.sub.dsT.sub.dsG.sub.ds.sup.mC.sub-
.d 70 1354
.sub.s.sup.mC.sub.dsA.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.ks.sup.mC.su-
b.ksA.sub.ksA.sub.e 1341046 2250 2265 22065 22080 AGGATAGTCCATGCAA
A.sub.ksG.sub.ksG.sub.ksA.sub.dsT.sub.dsA.sub.dsG.sub.dsT.sub.ds.sup.m
61 2690
C.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.dsG.sub.ks.sup.mC.sub.ksA.sub.ks-
A.sub.e 1341050 N/A N/A 9332 9347 ATCCTATATACATCCA
A.sub.ksT.sub.ks.sup.mC.sub.ks.sup.mC.sub.dsT.sub.dsA.sub.dsT.sub.dsA.sub-
.ds 75 1927
T.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.ks.sup.mC.sub.ks.sup.mC.-
sub.ksA.sub.e 1341052 N/A N/A 9966 9981 TAGTGTAAGCTGAGAG
T.sub.ksA.sub.ksG.sub.ksT.sub.dsG.sub.dsT.sub.dsA.sub.dsA.sub.dsG
82 1852
.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.dsA.sub.ksG.sub.ksSksG.sub.e
1341054 N/A N/A 9601 9616 CATATGTGAAGAGCTG
.sup.mC.sub.ksA.sub.ksT.sub.ksA.sub.dsT.sub.dsG.sub.dsT.sub.dsG.sub.ds
50 683
A.sub.dsA.sub.dsG.sub.dsA.sub.dsG.sub.ks.sup.mC.sub.ksT.sub.ksG.sub.-
e 1341055 N/A N/A 9514 9529 ACTAATATTGAGGCAC
A.sub.ks.sup.mC.sub.ksT.sub.ksA.sub.dsA.sub.dsT.sub.dsA.sub.dsT.sub.ds
62 1772
T.sub.dsG.sub.dsA.sub.dsG.sub.dsG.sub.ks.sup.mC.sub.ksA.sub.ks.sup.m-
C.sub.e 1341061 N/A N/A 12419 12434 GTAACGGTGATCAAAT
G.sub.ksT.sub.ksA.sub.ksA.sub.ds.sup.mC.sub.dsG.sub.dsG.sub.dsT.sub.ds
32 2345
G.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ksA.sub.ksA.sub.ksT.sub.-
e 1341062 N/A N/A 11548 11563 TCTCTTGACAATGGTT
T.sub.ks.sup.mC.sub.ksT.sub.ks.sup.mC.sub.dsT.sub.dsT.sub.dsG.sub.dsA.sub-
.ds 84 1389 11573 11588
.sup.mC.sub.dsA.sub.dsA.sub.dsT.sub.dsG.sub.ksG.sub.ksT.sub.ksT.sub.e
100 1341080 N/A N/A 16289 16304 GTTAGAATAGTCTTCA
G.sub.ksT.sub.ksT.sub.ksA.sub.dsG.sub.dsA.sub.dsA.sub.dsT.sub.dsA
71 1481
.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.ksT.sub.ks.sup.mC.sub.ksA-
.sub.e 1341087 N/A N/A 16382 16397 TCCCAACCAAACTTCC
T.sub.ks.sup.mC.sub.ks.sup.mC.sub.ks.sup.mC.sub.dsA.sub.dsA.sub.ds.sup.mC-
.sub.ds 24 2026
.sup.mC.sub.dsA.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.ksT.sub.ks-
.sup.mC.sub.ks.sup.mC.sub.e 1341088 N/A N/A 16127 16142
CATAATAATAGCTCTA
.sup.mC.sub.ksA.sub.ksT.sub.ksA.sub.dsA.sub.dsT.sub.dsA.sub.dsA.sub.ds
55 2511
T.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.ks.sup.mC.sub.ksT.sub.ks-
A.sub.e 1341093 1083 1098 20898 20913 TGCTGCTAGTGCCAAA
T.sub.ksG.sub.ks.sup.mC.sub.ksT.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsA.sub-
.ds 56 1665
G.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksA.sub.ksA.sub.ks-
A.sub.e 1341097 N/A N/A 17989 18004 TAGTATAGTTATCTTC
T.sub.ksA.sub.ksG.sub.ksT.sub.dsA.sub.dsT.sub.dsA.sub.dsG.sub.dsT.sub.d
28 1093
.sub.sT.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.ksT.sub.ksT.sub.ks.sup.mC.-
sub.e 1341099 N/A N/A 17994 18009 GAAGTTAGTATAGTTA
G.sub.ksA.sub.ksA.sub.ksG.sub.dsT.sub.dsT.sub.dsA.sub.dsG.sub.dsT
75 1327
.sub.dsA.sub.dsT.sub.dsA.sub.dsG.sub.ksT.sub.ksT.sub.ksA.sub.e
1341100 N/A N/A 19908 19923 TCTTAAGATACCCAGG
T.sub.ks.sup.mC.sub.ksT.sub.ksT.sub.dsA.sub.dsA.sub.dsG.sub.dsA.sub.ds
48 319
T.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksA.sub.ksG.-
sub.ksG.sub.e 1341105 N/A N/A 19912 19927 TGCATCTTAAGATACC
T.sub.ksG.sub.ks.sup.mC.sub.ksA.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub-
.ds 37 2050
A.sub.dsA.sub.dsG.sub.dsA.sub.dsT.sub.ksA.sub.ks.sup.mC.sub.ks.sup.m-
C.sub.e 1341113 N/A N/A 20385 20400 TAGTAATCACAAGTAA
T.sub.ksA.sub.ksG.sub.ksT.sub.dsA.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.ds
65 1489
A.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsG.sub.ksT.sub.ksA.sub.ksA.sub.-
e 1341114 N/A N/A 20112 20127 ATCAAGACATTCTAGC
AT.sub.ks.sup.mC.sub.ksA.sub.dsA.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.d
52 1488
.sub.sA.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.ksA.sub.ksG.sub.ks-
.sup.mC.sub.e 1341119 1088 1103 20903 20918 TTGACTGCTGCTAGTG
T.sub.ksT.sub.ksG.sub.ksA.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.ds.sup.mC.sub-
.ds 50 28
T.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.ksG.sub.ksT.sub.ksG.sub.-
e 1341127 N/A N/A 20482 20497 TCATAGTGGACTTCAT
T.sub.ks.sup.mC.sub.ksA.sub.ksT.sub.dsA.sub.dsG.sub.dsT.sub.dsG.sub.ds
54 633
G.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ks.sup.mC.sub.ksA.sub.ks-
T.sub.e 1341130 N/A N/A 13956 13971 TACCTCTAAGTTAGCC
T.sub.ksA.sub.ks.sup.mC.sub.ks.sup.mC.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.d-
sA 30 2249
.sub.dsA.sub.dsG.sub.dsT.sub.dsT.sub.dsA.sub.ksG.sub.ks.sup.mC.sub.k-
s.sup.mC.sub.e 1341132 N/A N/A 14194 14209 TGTGATTGAGTTCTCC
T.sub.ksG.sub.ksT.sub.ksG.sub.dsA.sub.dsT.sub.dsT.sub.dsG.sub.dsA.sub.d
52 2020
.sub.sG.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ksT.sub.ks.sup.mC.sub.ks.s-
up.mC.sub.e
1341133 N/A N/A 14170 14185 GAATAGCAAGCCAACA
G.sub.ksA.sub.ksA.sub.ksT.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.ds
30 1708
A.sub.dsG.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ksA.sub.ks.sup.mC.-
sub.ksA.sub.e 1341141 1259 1274 21074 21089 GTAGCTTTTGTCCACC
G.sub.ksT.sub.ksA.sub.ksG.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsT.sub.dsT
67 1978
.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksA.sub.ks.sup.mC.s-
ub.ks.sup.mC.sub.e 1341147 1202 1217 21017 21032 GTATGTTTATGTAAGC
G.sub.ksT.sub.ksA.sub.ksT.sub.dsG.sub.dsT.sub.dsT.sub.dsT.sub.dsA.sub.d
71 1511
.sub.sT.sub.dsG.sub.dsT.sub.dsA.sub.ksA.sub.ksG.sub.ks.sup.mC.sub.e
1341152 1317 1332 21132 21147 GAACAGTCTTAAACCT
G.sub.ksA.sub.ksA.sub.ks.sup.mC.sub.dsA.sub.dsG.sub.dsT.sub.ds.sup.mC.sub-
.d 64 266
.sub.sT.sub.dsT.sub.dsA.sub.dsA.sub.dsA.sub.ksA.sub.ks.sup.mC.sub.ks-
.sup.mC.sub.ksT.sub.e 1341159 1313 1328 21128 21143
AGTCTTAAACCTTCCC
A.sub.ksG.sub.ksT.sub.ks.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.dsA.sub.ds
61 1979
A.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ks.sup.mC.sub.ks.s-
up.mC.sub.ks.sup.mC.sub.e 1341163 1327 1342 21142 21157
AATGCTACTTGAACAG
A.sub.ksA.sub.ksT.sub.ksG.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.ds.sup.mC.sub-
.d 50 1045
.sub.sT.sub.dsT.sub.dsG.sub.dsA.sub.dsA.sub.ks.sup.mC.sub.ksA.sub.ks-
G.sub.e 1341168 1323 1338 21138 21153 CTACTTGAACAGTCTT
.sup.mC.sub.ksT.sub.ksA.sub.ks.sup.mC.sub.dsT.sub.dsT.sub.dsG.sub.dsA.sub-
.ds 71 734
A.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.dsT.sub.ks.sup.mC.sub.ksT.sub.ks-
T.sub.e 1341205 1335 1350 21150 21165 CAGATTGGAATGCTAC
.sup.mC.sub.ksA.sub.ksG.sub.ksA.sub.dsT.sub.dsT.sub.dsG.sub.dsG.sub.ds
61 1590
A.sub.dsA.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.ksT.sub.ksA.sub.ks.sup.m-
C.sub.e 1341216 1344 1359 21159 21174 GCATGGCTACAGATTG
G.sub.ks.sup.mC.sub.ksA.sub.ksT.sub.dsG.sub.dsG.sub.ds.sup.mC.sub.dsT.sub-
.d 67 267
.sub.sA.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.dsA.sub.ksT.sub.ksT.sub.ks-
G.sub.e 1341223 696 711 12114 12129 GACATGAGGTTTTGAT
G.sub.ksA.sub.ks.sup.mC.sub.ksA.sub.dsT.sub.dsG.sub.dsA.sub.dsG.sub.ds
55 647
G.sub.dsT.sub.dsT.sub.dsT.sub.dsTIc.sub.sG.sub.ksA.sub.ksT.sub.e
1341244 1353 1368 21168 21183 TATTCTGTGGCATGGC
T.sub.ksA.sub.ksT.sub.ksT.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.dsT.sub.dsG
74 890
.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.ksG.sub.ksG.sub.ks.sup.mC-
.sub.e 1341335 1357 1372 21172 21187 TTGATATTCTGTGGCA
T.sub.ksT.sub.ksG.sub.ksA.sub.dsT.sub.dsA.sub.dsT.sub.dsT.sub.ds.sup.mC
76 1202
.sub.dsT.sub.dsG.sub.dsT.sub.dsG.sub.ksG.sub.ks.sup.mC.sub.ksA.sub.e
1341353 1366 1381 21181 21196 GTGTTCTTGTTGATAT
G.sub.ksT.sub.ksG.sub.ksT.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsG
66 1514
.sub.dsT.sub.dsT.sub.dsG.sub.dsA.sub.ksT.sub.ksA.sub.ksT.sub.e
1341413 1391 1406 21206 21221 GATCTCTTAGCTGTGC
G.sub.ksA.sub.ksT.sub.ks.sup.mC.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub-
.ds 70 502
A.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.ksT.sub.ksG.sub.ks.sup.m-
C.sub.e 1341424 794 809 15675 15690 ATCTATCAGACTTCTT
A.sub.ksT.sub.ks.sup.mC.sub.ksT.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.dsA.sub-
.ds 51 2728
G.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ks.sup.mC.sub.ksT.sub.ks-
T.sub.e 1341425 1423 1438 21238 21253 CCAGGTTGAGATAAAG
.sup.mC.sub.ks.sup.mC.sub.ksA.sub.ksG.sub.dsG.sub.dsT.sub.dsT.sub.dsG.sub-
.d 51 33
.sub.sA.sub.dsG.sub.dsA.sub.dsT.sub.dsA.sub.ksA.sub.ksA.sub.ksG.sub.-
e 1341433 1464 1479 21279 21294 AGGCTAGGGAAATCTT
A.sub.ksG.sub.ksG.sub.ks.sup.mC.sub.dsT.sub.dsA.sub.dsG.sub.dsG.sub.ds
55 892
G.sub.dsA.sub.dsA.sub.dsA.sub.dsT.sub.ks.sup.mC.sub.ksT.sub.ksT.sub.-
e 1341434 1419 1434 21234 21249 GTTGAGATAAAGCTGC
G.sub.ksT.sub.ksT.sub.ksG.sub.dsA.sub.dsG.sub.dsAci.sub.sT.sub.dsA
59 1748
.sub.dsA.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.ksT.sub.ksG.sub.ks.sup.mC-
.sub.e 1341439 1615 1630 21430 21445 GTCACCTTTCATAATG
G.sub.ksT.sub.ks.sup.mC.sub.ksA.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub.d-
sT 21 1907
.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.dsA.sub.ksA.sub.ksT.sub.k-
sG.sub.e 1341442 1498 1513 21313 21328 GAGTTGCACCGTTTTG
G.sub.ksA.sub.ksG.sub.ksT.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.ds
62 1983
.sup.mC.sub.ds.sup.mC.sub.dsG.sub.dsT.sub.dsT.sub.ksT.sub.ksT.sub.ks-
G.sub.e 1341448 1705 1720 21520 21535 TGGGACCAAGGATATA
T.sub.ksG.sub.ksG.sub.ksG.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub-
.d 55 1674
.sub.sA.sub.dsG.sub.dsG.sub.dsA.sub.dsT.sub.ksA.sub.ksT.sub.ksA.sub.-
e 1341458 2194 2209 22009 22024 TTAGTCTTGATGTAGT
T.sub.ksT.sub.ksA.sub.ksG.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsG
61 1366
.sub.dsA.sub.dsT.sub.dsG.sub.dsT.sub.ksA.sub.ksG.sub.ksT.sub.e
1341463 2350 2365 22165 22180 ACTACAAGAGGTTATT
A.sub.ks.sup.mC.sub.ksT.sub.ksA.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsG.sub-
.d 58 899
.sub.sA.sub.dsG.sub.dsG.sub.dsT.sub.dsT.sub.ksA.sub.ksT.sub.ksT.sub.-
e 1341468 N/A N/A 14204 14219 CAGATTATTATGTGAT
.sup.mC.sub.ksA.sub.ksG.sub.ksA.sub.dsT.sub.dsT.sub.dsA.sub.dsT.sub.ds
38 2723
T.sub.dsA.sub.dsT.sub.dsG.sub.dsT.sub.ksG.sub.ksA.sub.ksT.sub.e
1341471 1075 1090 20890 20905 GTGCCAAACCAATGTT
G.sub.ksT.sub.ksG.sub.ks.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsA.sub-
.d 56 1042
.sub.s.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsT.sub.ksG.sub.ksT.-
sub.ksT.sub.e 1341473 N/A N/A 11858 11873 GATTAAGCAGAATTGT
G.sub.ksA.sub.ksT.sub.ksT.sub.dsA.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.ds
28 1156
A.sub.dsG.sub.dsA.sub.dsA.sub.dsT.sub.ksT.sub.ksG.sub.ksT.sub.e
1341475 N/A N/A 11543 11558 TGACAATGGTTGCCAC
T.sub.ksG.sub.ksA.sub.ks.sup.mC.sub.dsA.sub.dsA.sub.dsT.sub.dsG.sub.ds
45 1233
G.sub.dsT.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.ks.sup.mC.sub.ksA.sub.ks-
.sup.mC.sub.e 1341485 N/A N/A 16218 16233 TATAGACTGGGTAGGA
T.sub.ksA.sub.ksT.sub.ksA.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.ds
55 2808
G.sub.dsG.sub.dsG.sub.dsT.sub.dsA.sub.ksG.sub.ksG.sub.ksA.sub.e
1341487 N/A N/A 15491 15506 TTAATGCCACCCTACC
T.sub.ksT.sub.ksA.sub.ksA.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.ds.sup.mC.sub-
.ds 20 2304
A.sub.ds.sup.mC.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub.ksA.sub.ks.s-
up.mC.sub.ks.sup.mC.sub.e 1341489 N/A N/A 18092 18107
TGATACACCAATGCAG
T.sub.ksG.sub.ksA.sub.ksT.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub-
.d 58 2370
.sub.s.sup.mC.sub.dsA.sub.dsA.sub.dsT.sub.dsG.sub.ks.sup.mC.sub.ksA.-
sub.ksG.sub.e 1341490 N/A N/A 19916 19931 GGAGTGCATCTTAAGA
G.sub.ksG.sub.ksA.sub.ksG.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.ds
40 2810
T.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.ksA.sub.ksG.sub.ksA.sub.-
e 1341491 N/A N/A 19904 19919 AAGATACCCAGGTTGC
A.sub.ksA.sub.ksG.sub.ksA.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub-
.d 69 2712
.sub.s.sup.mC.sub.dsA.sub.dsG.sub.dsG.sub.dsT.sub.ksT.sub.ksG.sub.ks-
.sup.mC.sub.e 1341497 N/A N/A 18690 18705 CTTTGAGACTCTTGTT
.sup.mC.sub.ksT.sub.ksT.sub.ksT.sub.dsG.sub.dsA.sub.dsG.sub.dsA.sub.ds.su-
p.m 57 2583
C.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ksksT.sub.ksT.sub.e
1341502 N/A N/A 20187 20202 TATTAGAAGTCAGCCC
T.sub.ksA.sub.ksT.sub.ksT.sub.dsA.sub.dsG.sub.dsA.sub.dsA.sub.dsG
32 164
.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.ks.sup.mC.sub.ks.sup.mC.s-
ub.ks.sup.mC.sub.e 1341504 N/A N/A 20197 20212 ACATTGCAGTTATTAG
A.sub.ks.sup.mC.sub.ksA.sub.ksT.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.dsA.sub-
.d 52 2309
.sub.sG.sub.dsT.sub.dsT.sub.dsA.sub.dsT.sub.ksT.sub.ksA.sub.ksG.sub.-
e 1341512 N/A N/A 12794 12809 AAGAGTCAGTATCCTC
A.sub.ksA.sub.ksG.sub.ksA.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ds
67 2572
G.sub.dsT.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.ks.sup.mC.sub.ksT.sub.ks-
.sup.mC.sub.e 1341514 N/A N/A 12496 12511 AATTCACCTTGACTAA
A.sub.ksA.sub.ksT.sub.ksT.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ds.sup.-
mC 16 2144
.sub.dsT.sub.dsT.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.ksA.sub.ksA.sub.e
1341515 N/A N/A 12804 12819 CTCAGGCTGTAAGAGT
.sup.mC.sub.ksT.sub.ks.sup.mC.sub.ksA.sub.dsG.sub.dsG.sub.ds.sup.mC.sub.d-
sT 21 2240
.sub.dsG.sub.dsT.sub.dsA.sub.dsA.sub.dsG.sub.ksA.sub.ksG.sub.ksT.sub-
.e
TABLE-US-00044 TABLE 44 Inhibition of HSD17B13 RNA by modified
oligonucleotides targeting SEQ ID NO.: 1, and 2 SEQ SEQ SEQ SEQ ID
NO: ID NO: ID NO: ID NO: % SEQ Compound 1 Start 1 Stop 2 Start 2
Stop Sequence Chemistry Notation in- ID Number Site Site Site Site
(5' to 3') (5' to 3') hibition NO 1245927 N/A N/A 3433 3448
AGTAGATGGTAAGTCA
A.sub.ksG.sub.ksT.sub.ksA.sub.dsG.sub.dsA.sub.dsT.sub.dsG.sub.dsG.sub.ds
79 121
T.sub.dsA.sub.dsA.sub.dsG.sub.dsT.sub.ks.sup.mC.sub.ksA.sub.k
1246023 N/A N/A 5046 5061 GAGTGAATCATTCAGT
G.sub.ksA.sub.ksG.sub.ksT.sub.dsG.sub.dsA.sub.dsA.sub.dsT.sub.ds.sup.mC.s-
ub.d 83 1526
.sub.sA.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ksG.sub.ksT.sub.k
1340981 1495 1510 21310 21325 TTGCACCGTTTTGGGC
T.sub.ksT.sub.ksG.sub.ks.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.d-
sG.sub.ds 50 1749
T.sub.dsT.sub.dsT.sub.dsT.sub.dsG.sub.ksG.sub.ksG.sub.ks.sup.mC.sub.-
e 1340983 1499 1514 21314 21329 AGAGTTGCACCGTTTT
A.sub.ksG.sub.ksA.sub.ksG.sub.dsT.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.dsA.s-
ub.d 78 34
.sub.s.sup.mC.sub.ds.sup.mC.sub.dsG.sub.dsT.sub.ksT.sub.ksT.sub.ksT.-
sub.e 1340991 810 825 15691 15706 TATTGGTAAGTATTCC
T.sub.ksA.sub.ksT.sub.ksT.sub.dsG.sub.dsG.sub.dsT.sub.dsA.sub.dsA.sub.ds
48 1272
G.sub.dsT.sub.dsA.sub.dsT.sub.ksT.sub.ks.sup.mC.sub.ks.sup.mC.sub.e
1340995 1620 1635 21435 21450 AGTCGGTCACCTTTCA
A.sub.ksG.sub.ksT.sub.ks.sup.mC.sub.dsG.sub.dsG.sub.dsT.sub.ds.sup.mC.sub-
.ds 75 272
A.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ksT.sub.ks.sup.mC.-
sub.ksA.sub.e 1340998 1600 1615 21415 21430 GTATCTTATAAGACTA
G.sub.ksT.sub.ksA.sub.ksT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.dsT.s-
ub.ds 72 1595
A.sub.dsA.sub.dsG.sub.dsA.sub.ks.sup.mC.sub.ksT.sub.ksA.sub.e
1341000 1624 1639 21439 21454 ATAGAGTCGGTCACCT
A.sub.ksT.sub.ksA.sub.ksG.sub.dsA.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.dsG.s-
ub.d 67 584
.sub.sG.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ks.sup.mC.sub.ks.sup.mC.su-
b.ksT.sub.e 1341002 1712 1727 21527 21542 ACATCTCTGGGACCAA
A.sub.ks.sup.mC.sub.ksA.sub.ksT.sub.ds.sup.mC.sub.dsT.sub.ds.sup.mC.sub.d-
sT.sub.ds 65 195
G.sub.dsG.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.ks.sup.mC.sub.ksA.sub.ks-
A.sub.e 1341004 1628 1643 21443 21458 TAAAATAGAGTCGGTC
T.sub.ksA.sub.ksA.sub.ksA.sub.dsA.sub.dsT.sub.dsA.sub.dsG.sub.dsA.sub.ds
74 895
G.sub.dsT.sub.ds.sup.mC.sub.dsG.sub.ksG.sub.ksT.sub.ks.sup.mC.sub.e
1341011 1752 1767 21567 21582 TCCTGTGTTAGCTTTA
T.sub.ks.sup.mC.sub.ks.sup.mC.sub.ksT.sub.dsG.sub.dsT.sub.dsG.sub.dsT.sub-
.dsT 75 1442
.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.ksT.sub.ksT.sub.ksA.sub.e
1341013 1721 1736 21536 21551 ATTGTCTAAACATCTC
A.sub.ksT.sub.ksT.sub.ksG.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.dsA.s-
ub.ds 71 585
A.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.ks.sup.mC.sub.ksT.sub.ks.sup.mC.-
sub.e 1341017 1019 1034 20834 20849 TGCAGCATTGATTCGA
T.sub.ksG.sub.ks.sup.mC.sub.ksA.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.dsT.sub-
.dsT 52 419
.sub.dsG.sub.dsA.sub.dsT.sub.dsT.sub.kss.sup.mC.sub.ksG.sub.ksA.sub.-
e 1341030 1784 1799 21599 21614 GTTTCTTATGTAATAG
G.sub.ksT.sub.ksT.sub.ksT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.ksT.s-
ub.ds 44 897
G.sub.dsT.sub.dsA.sub.dsA.sub.ksT.sub.ksA.sub.ksG.sub.e 1341033
2189 2204 22004 22019 CTTGATGTAGTGGGAG
.sup.mC.sub.ksT.sub.ksT.sub.ksG.sub.dsA.sub.dsT.sub.dsG.sub.dsT.sub.dsA.s-
ub.ds 62 976
G.sub.dsT.sub.dsG.sub.dsG.sub.ksG.sub.ksA.sub.ksG.sub.e 1341039
1780 1795 21595 21610 CTTATGTAATAGCCAG
.sup.mC.sub.ksT.sub.ksTd.sub.sA.sub.dsT.sub.dsG.sub.dsT.sub.dsA.sub.dsA.s-
ub.ds 70 664
T.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.ks.sup.mC.sub.ksA.sub.ksG.sub.e
1341042 N/A N/A 9334 9349 CGATCCTATATACATC
.sup.mC.sub.ksG.sub.ksA.sub.ksT.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub.d-
sA.sub.ds 29 2788
T.sub.dsA.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.ksA.sub.ksT.sub.ks.sup.m-
C.sub.e 1341043 2252 2267 22067 22082 AGAGGATAGTCCATGC
A.sub.ksG.sub.ksA.sub.ksG.sub.dsG.sub.dsA.sub.dsT.sub.dsA.sub.dsG.sub.ds
78 354
T.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ksT.sub.ksG.sub.ks.sup.mC.-
sub.e 1341044 2353 2368 22168 22183 ATAACTACAAGAGGTT
A.sub.ksT.sub.ksA.sub.ksA.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.ds.sup.mC.sub-
.ds 67 1133
A.sub.dsA.sub.dsG.sub.dsA.sub.dsG.sub.ksG.sub.ksT.sub.ksT.sub.e
1341053 N/A N/A 9968 9983 AGTAGTGTAAGCTGAG
A.sub.ksG.sub.ksT.sub.ksA.sub.dsG.sub.dsT.sub.dsG.sub.dsT.sub.dsA.sub.ds
71 2155
A.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.ksG.sub.ksA.sub.ksG.sub.e
1341056 N/A N/A 9516 9531 ACACTAATATTGAGGC
A.sub.ks.sup.mC.sub.ksA.sub.ks.sup.mC.sub.dsT.sub.dsA.sub.dsA.sub.dsT.sub-
.ds 68 1928
A.sub.dsT.sub.dsT.sub.dsG.sub.dsA.sub.ksG.sub.ksG.sub.ks.sup.mC.sub.-
e 1341057 N/A N/A 9603 9618 CACATATGTGAAGAGC
.sup.mC.sub.ksA.sub.ks.sup.mC.sub.ksA.sub.dsT.sub.dsA.sub.dsT.sub.dsG.sub-
.dsT 74 760
.sub.dsG.sub.dsA.sub.dsA.sub.dsG.sub.ksA.sub.ksG.sub.ks.sup.mC.sub.e
1341060 N/A N/A 12421 12436 TGGTAACGGTGATCAA
T.sub.ksG.sub.ksG.sub.ksT.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.dsG.sub.dsG.s-
ub.d 35 67
.sub.sT.sub.dsG.sub.dsA.sub.dsT.sub.ks.sup.mC.sub.ksA.sub.ksA.sub.e
1341068 N/A N/A 11546 11561 TCTTGACAATGGTTGC
T.sub.ks.sup.mC.sub.ksT.sub.ksT.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.dsA.sub-
.dsA 77 2199
.sub.dsT.sub.dsG.sub.dsG.sub.dsT.sub.ksT.sub.ksG.sub.ks.sup.mC.sub.e
1341071 N/A N/A 15494 15509 GCATTAATGCCACCCT
G.sub.ks.sup.mC.sub.ksA.sub.ksT.sub.dsT.sub.dsA.sub.dsA.sub.dsT.sub.dsG.s-
ub.d 51 1012
.sub.s.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ks.sup.mC.sub.-
ks.sup.mC.sub.ksT.sub.e 1341075 608 623 N/A N/A ACAATATGGGATGAGG
A.sub.ks.sup.mC.sub.ksA.sub.ksA.sub.dsT.sub.dsA.sub.dsT.sub.dsG.sub.dsG.s-
ub.d 76 1579
.sub.sG.sub.dsA.sub.dsT.sub.dsG.sub.ksA.sub.ksG.sub.ksG.sub.e
1341076 N/A N/A 14914 14929 ACATTAGCAAGCTAAG
A.sub.ks.sup.mC.sub.ksA.sub.ksT.sub.dsT.sub.dsA.sub.dsG.sub.ds.sup.mC.sub-
.ds 41 2065
A.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.ksA.sub.ksA.sub.ksG.sub.-
e 1341077 1080 1095 20895 20910 TGCTAGTGCCAAACCA
T.sub.ksG.sub.ks.sup.mC.sub.ksT.sub.dsA.sub.dsG.sub.dsT.sub.dsG.sub.ds.su-
p.mC 73 1432
.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsA.sub.ks.sup.mC.sub.ks.sup.mC.s-
ub.ksA.sub.e 1341081 N/A N/A 16223 16238 CTTTTTATAGACTGGG
.sup.mC.sub.ksT.sub.ksT.sub.ksT.sub.dsT.sub.dsT.sub.dsA.sub.dsT.sub.dsA.s-
ub.ds 44 857
G.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.ksG.sub.ksG.sub.ksG.sub.e
1341084 N/A N/A 16384 16399 AATCCCAACCAAACTT
A.sub.ksA.sub.ksT.sub.ks.sup.mC.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.d-
sA.sub.ds 13 2755
.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsA.sub.ks.sup.mC.sub.ksT.-
sub.ksT.sub.e 1341089 N/A N/A 16129 16144 TCCATAATAATAGCTC
T.sub.ks.sup.mC.sub.ks.sup.mC.sub.ksA.sub.dsT.sub.dsA.sub.dsA.sub.dsT.sub-
.dsA 66 546
.sub.dsA.sub.dsT.sub.dsA.sub.dsG.sub.ks.sup.mC.sub.ksT.sub.ks.sup.mC-
.sub.e 1341092 N/A N/A 18095 18110 AATTGATACACCAATG
A.sub.ksA.sub.ksT.sub.ksT.sub.dsG.sub.dsA.sub.dsT.sub.dsA.sub.ds.sup.mC.s-
ub.d 53 2525
.sub.sA.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ksA.sub.ksT.sub.ksG.-
sub.e 1341096 N/A N/A 17990 18005 TTAGTATAGTTATCTT
T.sub.ksT.sub.ksA.sub.ksG.sub.dsT.sub.dsA.sub.dsT.sub.dsA.sub.dsG.sub.ds
45 2366
T.sub.dsT.sub.dsA.sub.dsT.sub.ks.sup.mC.sub.ksT.sub.ksT.sub.e
1341101 N/A N/A 19909 19924 ATCTTAAGATACCCAG
A.sub.ksT.sub.ks.sup.mC.sub.ksT.sub.dsT.sub.dsA.sub.dsA.sub.dsG.sub.dsA.s-
ub.d 71 397
.sub.sT.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.ks.sup.mC.sub.ksA.su-
b.ksG.sub.e 1341102 N/A N/A 18693 18708 AGACTTTGAGACTCTT
A.sub.ksG.sub.ksA.sub.ks.sup.mC.sub.dsT.sub.dsT.sub.dsT.sub.dsG.sub.dsA.s-
ub.d 41 2804
.sub.sG.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.ks.sup.mC.sub.ksT.sub.ksT.-
sub.e 1341103 N/A N/A 19913 19928 GTGCATCTTAAGATAC
G.sub.ksT.sub.ksG.sub.ks.sup.mC.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.dsT.sub-
.dsT 29 2806
.sub.dsA.sub.dsA.sub.dsG.sub.dsA.sub.ksT.sub.ksA.sub.ks.sup.mC.sub.e
1341115 N/A N/A 20190 20205 AGTTATTAGAAGTCAG
A.sub.ksG.sub.ksT.sub.ksT.sub.dsA.sub.dsT.sub.dsT.sub.dsA.sub.dsG.sub.ds
56 2746
A.sub.dsA.sub.dsG.sub.dsT.sub.ks.sup.mC.sub.ksA.sub.ksG.sub.e
1341118 N/A N/A 20114 20129 GCATCAAGACATTCTA
G.sub.ks.sup.mC.sub.ksA.sub.ksT.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsG.sub-
.ds 84 1565
A.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.dsT.sub.ks.sup.mC.sub.ksT.sub.ks-
A.sub.e 1341120 1084 1099 20899 20914 CTGCTGCTAGTGCCAA
.sup.mC.sub.ksT.sub.ksG.sub.ks.sup.mC.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.d-
sT.sub.ds 66 1743
A.sub.dsG.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.ks.sup.mC.sub.ksA.sub.ks-
A.sub.e 1341121 N/A N/A 12499 12514 AGAAATTCACCTTGAC
A.sub.ksG.sub.ksA.sub.ksA.sub.dsA.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsA.s-
ub.d 7 2284
.sub.s.sup.mC.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ksG.sub.ksA.sub.ks.s-
up.mC.sub.e 1341126 N/A N/A 20484 20499 CTTCATAGTGGACTTC
.sup.mC.sub.kT.sub.ksT.sub.ks.sup.mC.sub.dsA.sub.dsT.sub.dsA.sub.dsG.sub.-
dsT 57 711
.sub.dsG.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.ksT.sub.ksT.sub.ks.sup.mC-
.sub.e 1341131 N/A N/A 14196 14211 TATGTGATTGAGTTCT
T.sub.ksA.sub.ksT.sub.ksG.sub.dsT.sub.dsG.sub.dsA.sub.dsT.sub.dsT.sub.ds
43 2367
G.sub.dsA.sub.dsG.sub.dsT.sub.ksT.sub.ks.sup.mC.sub.ksT.sub.e
1341137 N/A N/A 12797 12812 TGTAAGAGTCAGTATC
T.sub.ksG.sub.ksT.sub.ksA.sub.dsA.sub.dsG.sub.dsA.sub.dsG.sub.dsT.sub.ds
46 2652
.sup.mC.sub.dsA.sub.dsG.sub.dsT.sub.ksA.sub.ksT.sub.ks.sup.mC.sub.e
1341138 N/A N/A 14172 14187 TTGAATAGCAAGCCAA
T.sub.ksT.sub.ksG.sub.ksA.sub.dsA.sub.dsT.sub.dsA.sub.dsG.sub.ds.sup.mC.s-
ub.d 33 1864
.sub.sA.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.ks.sup.mC.sub.ksA.sub.ksA.-
sub.e 1341143 1261 1276 21076 21091 AGGTAGCTTTTGTCCA
A.sub.ksG.sub.ksG.sub.ksT.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsT.s-
ub.d 58 109
.sub.sT.sub.dsT.sub.dsG.sub.dsT.sub.ks.sup.mC.sub.ks.sup.mC.sub.ksA.-
sub.e 1341145 1256 1271 21071 21086 GCTTTTGTCCACCTTT
G.sub.ks.sup.mC.sub.ksT.sub.ksT.sub.dsT.sub.dsT.sub.dsG.sub.dsT.sub.ds.su-
p.mC 81 1744
.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksT.sub.ksT.s-
ub.ksT.sub.e 1341150 1318 1333 21133 21148 TGAACAGTCTTAAACC
T.sub.ksG.sub.ksA.sub.ksA.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.dsT.sub.ds.su-
p.m 61 344
C.sub.dsT.sub.dsT.sub.dsA.sub.dsA.sub.ksA.sub.ks.sup.mC.sub.ks.sup.m-
C.sub.e 1341154 1314 1329 21129 21144 CAGTCTTAAACCTTCC
.sup.mC.sub.ksA.sub.ksG.sub.ksT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub-
.dsA 74 30
.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub.ksT.sub.ks.sup.mC.s-
ub.ks.sup.mC.sub.e 1341160 698 713 12116 12131 GAGACATGAGGTTTTG
G.sub.ksA.sub.ksG.sub.ksA.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.dsG.sub.dsA
61 725
.sub.dsG.sub.dsG.sub.dsT.sub.dsT.sub.ksT.sub.ksT.sub.ksG.sub.e
1341166 1324 1339 21139 21154 GCTACTTGAACAGTCT
G.sub.ks.sup.mC.sub.ksT.sub.ksA.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsG.sub-
.dsA 60 811
.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.ksT.sub.ks.sup.mC.sub.ksT-
.sub.e 1341184 1329 1344 21144 21159 GGAATGCTACTTGAAC
G.sub.ksG.sub.ksA.sub.ksA.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsA.s-
ub.d 68 1201
.sub.s.sup.mC.sub.dsT.sub.dsT.sub.dsG.sub.ksA.sub.ksA.sub.ks.sup.mC.-
sub.e 1341194 1337 1352 21152 21167 TACAGATTGGAATGCT
T.sub.ksA.sub.ks.sup.mC.sub.ksA.sub.dsG.sub.dsA.sub.dsT.sub.dsT.sub.dsG.s-
ub.d 66 1746
.sub.sG.sub.dsA.sub.dsA.sub.dsT.sub.ksG.sub.ks.sup.mC.sub.ksT.sub.e
1341266 1349 1364 21164 21179 CTGTGGCATGGCTACA
.sup.mC.sub.ksT.sub.ksG.sub.ksT.sub.dsG.sub.dsG.sub.ds.sup.mC.sub.dsA.sub-
.dsT 58 657
.sub.dsG.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.ksA.sub.ks.sup.mC.sub.ksA-
.sub.e 1341295 1354 1369 21169 21184 ATATTCTGTGGCATGG
A.sub.ksT.sub.ksA.sub.ksT.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.dsT.s-
ub.ds 58 968
G.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.ksT.sub.ksG.sub.ksG.sub.e
1341318 1358 1373 21173 21188 GTTGATATTCTGTGGC
G.sub.ksT.sub.ksT.sub.ksG.sub.dsA.sub.dsT.sub.dsA.sub.dsT.sub.dsT.sub.ds.-
sup.m 73 1280
C.sub.dsT.sub.dsG.sub.dsT.sub.ksG.sub.ksG.sub.ks.sup.mC.sub.e
1341392 1367 1382 21182 21197 TGTGTTCTTGTTGATA
T.sub.ksG.sub.ksT.sub.ksG.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsT.s-
ub.ds 65 1591
G.sub.dsT.sub.dsT.sub.dsG.sub.ksA.sub.ksT.sub.ksA.sub.e 1341400 796
811 15677 15692 CCATCTATCAGACTTC
.sup.mC.sub.ks.sup.mC.sub.ksA.sub.ksT.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.d-
sT.sub.ds 60 415
.sup.mC.sub.dsA.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.ksT.sub.ksT.sub.ks-
.sup.mC.sub.e 1341421 1420 1435 21235 21250 GGTTGAGATAAAGCTG
G.sub.ksG.sub.ksT.sub.ksT.sub.dsG.sub.dsA.sub.dsG.sub.dsA.sub.dsT.sub.ds
67 1826
A.sub.dsA.sub.dsA.sub.dsG.sub.ks.sup.mC.sub.ksT.sub.ksG.sub.e
1341426 1393 1408 21208 21223 TTGATCTCTTAGCTGT
T.sub.ksT.sub.ksG.sub.ksA.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.ds.sup.mC.sub-
.dsT 64 658
.sub.dsT.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.ksT.sub.ksG.sub.ksT.sub.e
1341431 1429 1444 21244 21259 ATATGTCCAGGTTGAG
A.sub.ksT.sub.ksA.sub.ksT.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.ds.sup.mC.sub-
.dsA 71 425
.sub.dsG.sub.dsG.sub.dsT.sub.dsT.sub.ksG.sub.ksA.sub.ksG.sub.e
1341432 1491 1506 21306 21321 ACCGTTTTGGGCTAAT
A.sub.ks.sup.mC.sub.ks.sup.mC.sub.ksG.sub.dsT.sub.dsT.sub.dsT.sub.dsT.sub-
.dsG 73 1438
.sub.dsG.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.ksA.sub.ksA.sub.ksT.sub.e
1341435 1466 1481 21281 21296 AGAGGCTAGGGAAATC
A.sub.ksGc.sub.sA.sub.kG.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.dsG
68 1048
.sub.dsG.sub.dsG.sub.dsA.sub.dsA.sub.ksA.sub.ksT.sub.ks.sup.mC.sub.e
1341441 1616 1631 21431 21446 GGTCACCTTTCATAAT
G.sub.ksG.sub.ksT.sub.ks.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.d-
sT.sub.ds 49 1985
T.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.ksA.sub.ksA.sub.ksT.sub.-
e 1341449 1771 1786 21586 21601 TAGCCAGTACAGTTCC
T.sub.ksA.sub.ksG.sub.ks.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.dsT.sub-
.ds 58 1987
A.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.dsT.sub.ksT.sub.ks.sup.mC.sub.ks-
.sup.mC.sub.e 1341451 1776 1791 21591 21606 TGTAATAGCCAGTACA
T.sub.ksG.sub.ksT.sub.ksA.sub.dsA.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.d
34 352
.sub.s.sup.mC.sub.dsA.sub.dsG.sub.dsT.sub.ksA.sub.ks.sup.mC.sub.ksA.-
sub.e 1341456 1707 1722 21522 21537 TCTGGGACCAAGGATA
T.sub.ks.sup.mC.sub.ksT.sub.ksG.sub.dsG.sub.dsG.sub.dsA.sub.ds.sup.mC.sub-
.ds.sup.m 57 1830
C.sub.dsA.sub.dsA.sub.dsG.sub.dsG.sub.ksA.sub.ksT.sub.ksA.sub.e
1341457 1716 1731 21531 21546 CTAAACATCTCTGGGA
.sup.mC.sub.ksT.sub.ksA.sub.ksA.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.dsT.sub-
.ds.sup.m 57 2259
C.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.ksG.sub.ksG.sub.ksA.sub.-
e 1341466 2196 2211 22011 22026 GATTAGTCTTGATGTA
G.sub.ksA.sub.ksT.sub.ksT.sub.dsA.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.dsT.s-
ub.ds 48 1521
T.sub.dsG.sub.dsA.sub.dsT.sub.ksG.sub.ksT.sub.ksA.sub.e 1341474 N/A
N/A 11578 11593 GTTATTCTCTTGACAA
G.sub.ksT.sub.ksT.sub.ksA.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.ds.su-
p.mC 35 2575
.sub.dsT.sub.dsT.sub.dsG.sub.dsA.sub.ks.sup.mC.sub.ksA.sub.ksA.sub.e
1341482 N/A N/A 16292 16307 TTAGTTAGAATAGTCT
T.sub.ksT.sub.ksA.sub.ksG.sub.dsT.sub.dsT.sub.dsA.sub.dsG.sub.dsA.sub.ds
67 1714
A.sub.dsT.sub.dsA.sub.dsG.sub.ksT.sub.ks.sup.mC.sub.ksT.sub.e
1341488 N/A N/A 19905 19920 TAAGATACCCAGGTTG
T.sub.ksA.sub.ksA.sub.ksG.sub.dsA.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.ds.su-
p.m 58 2790
C.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.dsG.sub.ksT.sub.ksT.sub.ksG.sub.-
e 1341492 1076 1091 20891 20906 AGTGCCAAACCAATGT
A.sub.ksG.sub.ksT.sub.ksG.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsAd.sub.sA.sub-
.ds 60 1120
A.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.ksT.sub.ksG.sub.ks-
T.sub.e 1341495 N/A N/A 17995 18010 TGAAGTTAGTATAGTT
T.sub.ksG.sub.ksA.sub.ksA.sub.dsG.sub.dsT.sub.dsT.sub.dsA.sub.dsG.sub.ds
70 1405 T.sub.dsA.sub.dsT.sub.dsA.sub.ksG.sub.ksT.sub.ksT.sub.e
1341498 N/A N/A 19999 20014 CAGTTTTCCTCATGAT
.sup.mC.sub.ksA.sub.ksG.sub.ksT.sub.dsT.sub.dsT.sub.dsT.sub.ds.sup.mC.sub-
.ds.sup.m 65 2331
C.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.ksG.sub.ksA.sub.ksT.sub.-
e 1341500 N/A N/A 20378 20393 CACAAGTAAGGTAAAG
.sup.mC.sub.ksA.sub.ks.sup.mC.sub.ksA.sub.dsA.sub.dsG.sub.dsT.sub.dsA.sub-
.ds 55 2448
A.sub.dsG.sub.dsG.sub.dsT.sub.dsA.sub.ksA.sub.ksA.sub.ksG.sub.e
1341503 N/A N/A 20388 20403 CTATAGTAATCACAAG
.sup.mC.sub.ksT.sub.ksA.sub.ksT.sub.dsA.sub.dsG.sub.dsT.sub.dsA.sub.dsA.s-
ub.d 53 1644
.sub.sT.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ksA.sub.ksA.sub.ksG.-
sub.e 1341510 1091 1106 20906 20921 CGTTTGACTGCTGCTA
.sup.mC.sub.ksG.sub.ksT.sub.ksT.sub.dsT.sub.dsG.sub.dsA.sub.ds.sup.mC.sub-
.dsT 75 264
.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.ks.sup.mC.sub.ksT.sub.ksA-
.sub.e 1341513 N/A N/A 13959 13974 GTCTACCTCTAAGTTA
G.sub.ksT.sub.ks.sup.mC.sub.ksT.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.d-
sT.sub.ds 41 2363
.sup.mC.sub.dsT.sub.dsA.sub.dsA.sub.dsG.sub.ksT.sub.ksT.sub.ksA.sub.-
e 1341516 N/A N/A 13949 13964 AAGTTAGCCCCCAGGA
A.sub.ksA.sub.ksG.sub.ksT.sub.dsT.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.ds.su-
p.m 23 2811
C.sub.ds.sup.mC.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ksG.sub.ksG.-
sub.ksA.sub.e
TABLE-US-00045 TABLE 45 Inhibition of HSD17B13 RNA by modified
oligonucleotides targeting SEQ ID NO.: 1, and 2 SEQ SEQ SEQ SEQ ID
NO: ID NO: ID NO: ID NO: % SEQ Compound 1 Start 1 Stop 2 Start 2
Stop Sequence Chemistry Notation in- ID Number Site Site Site Site
(5' to 3') (5' to 3') hibition NO 1245927 N/A N/A 3433 3448
AGTAGATGGTAAGTCA
A.sub.ksG.sub.ksT.sub.ksA.sub.dsG.sub.dsA.sub.dsT.sub.dsG.sub.dsG.sub.dsT
79 121 .sub.dsA.sub.dsA.sub.dsG.sub.dsT.sub.ks.sup.mC.sub.ksA.sub.k
1246023 N/A N/A 5046 5061 GAGTGAATCATTCAGT
G.sub.ksA.sub.ksG.sub.ksT.sub.dsG.sub.dsA.sub.dsA.sub.dsT.sub.ds.sup.mC.s-
ub.ds 80 1526
A.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ksG.sub.ksT.sub.k
1340980 610 625 N/A N/A GAACAATATGGGATGA
G.sub.ksA.sub.ksA.sub.ks.sup.mC.sub.dsA.sub.dsA.sub.dsT.sub.dsA.sub.dsT.s-
ub.ds 52 1735
G.sub.dsG.sub.dsG.sub.dsA.sub.ksT.sub.ksG.sub.ksA.sub.e 1340985
1492 1507 21307 21322 CACCGTTTTGGGCTAA
.sup.mC.sub.ksA.sub.ks.sup.mC.sub.ks.sup.mC.sub.dsG.sub.dsT.sub.dsT.sub.d-
sT.sub.dsT 71 1516
.sub.dsG.sub.dsG.sub.dsG.sub.ds.sup.mC.sub.ksT.sub.ksA.sub.ksA.sub.e
1340986 1501 1516 21316 21331 ATAGAGTTGCACCGTT
A.sub.ksA.sub.kG.sub.dsA.sub.dsG.sub.dsT.sub.dsT.sub.dsG.sub.ds.sup.m
71 192
.sub.dsG.sub.dsG.sub.dsG.sub.ds.sup.mC.sub.ksT.sub.ksA.sub.ksA.sub.e
1340989 812 827 15693 15708 CTTATTGGTAAGTATT
.sup.mC.sub.ksT.sub.ksT.sub.ksA.sub.dsT.sub.dsT.sub.dsG.sub.dsG.sub.dsT.s-
ub.ds 24 1350
A.sub.dsA.sub.dsG.sub.dsT.sub.ksA.sub.ksT.sub.ksT.sub.e 1340992
1621 1636 21436 21451 GAGTCGGTCACCTTTC
G.sub.ksA.sub.ksG.sub.ksT.sub.ds.sup.mC.sub.dsG.sub.dsG.sub.dsT.sub.ds.su-
p.mC.sub.d 74 350
.sub.sA.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub.ksT.sub.ksT.sub.ks.s-
up.mC.sub.e 1340996 1602 1617 21417 21432 ATGTATCTTATAAGAC
A.sub.ksT.sub.ksG.sub.KsT.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ds
24 1751
A.sub.dsT.sub.dsA.sub.dsA.sub.ksG.sub.ksA.sub.ks.sup.mC.sub.e
1340999 1617 1632 21432 21447 CGGTCACCTTTCATAA
.sup.mC.sub.ksG.sub.ksG.sub.ksT.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.d-
s.sup.mC.sub.ds 67 36
T.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ksT.sub.ksA.sub.ksA.sub.-
e 1341003 1625 1640 21440 21455 AATAGAGTCGGTCACC
A.sub.ksA.sub.ksT.sub.ksA.sub.dsG.sub.dsA.sub.dsG.sub.dsT.sub.ds.sup.mC.s-
ub.ds 58 662
G.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.ksA.sub.ks.sup.mC.sub.ks.sup.mC.-
sub.e 1341007 1629 1644 21444 21459 TTAAAATAGAGTCGGT
T.sub.ksT.sub.ksA.sub.ksA.sub.dsA.sub.dsA.sub.dsT.sub.dsA.sub.dsG.sub.dsA
71 973 .sub.dsG.sub.dsT.sub.ds.sup.mC.sub.ksG.sub.ksG.sub.ksT.sub.e
1341010 1708 1723 21523 21538 CTCTGGGACCAAGGAT
.sup.mC.sub.ksT.sub.ks.sup.mC.sub.ksT.sub.dsG.sub.dsG.sub.dsG.sub.dsA.sub-
.ds.sup.mC 62 1908
.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsG.sub.ksG.sub.ksA.sub.ksT.sub.e
1341015 1713 1728 21528 21543 AACATCTCTGGGACCA
A.sub.ksA.sub.ks.sup.mC.sub.ksA.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.ds.sup.-
mC.sub.dsT 61 273
.sub.dsG.sub.dsG.sub.dsG.sub.dsA.sub.ks.sup.mC.sub.ks.sup.mC.sub.ksA-
.sub.e 1341021 1773 1788 21588 21603 AATAGCCAGTACAGTT
A.sub.ksA.sub.ksT.sub.ksA.sub.dsG.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub-
.dsG.sub.d 61 118
.sub.sT.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.ksG.sub.ksT.sub.ksT.sub.e
1341022 1781 1796 21596 21611 TCTTATGTAATAGCCA
T.sub.ks.sup.mC.sub.ksT.sub.ksT.sub.dsA.sub.dsT.sub.dsG.sub.dsT.sub.dsA.s-
ub.ds 76 742
A.sub.dsT.sub.dsA.sub.dsG.sub.ks.sup.mC.sub.ks.sup.mC.sub.ksA.sub.e
1341023 1766 1781 21581 21596 AGTACAGTTCCTTTTC
A.sub.ksG.sub.ksT.sub.ksA.sub.sds.sup.m.sub.sC.sub.dssA.sub.dsG.sub.dsT.s-
ub.dsT.sub.ds 59 1597
.sup.mC.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ksT.sub.ksT.sub.ks.sup.mC.-
sub.e 1341024 1777 1792 21592 21607 ATGTAATAGCCAGTAC
A.sub.ksT.sub.ksG.sub.ksT.sub.dsA.sub.dsA.sub.dsT.sub.dsG.sub.ds.sup.m
63 430
C.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.ksT.sub.ksA.sub.ks.sup.mC.sub.e
1341034 2191 2206 22006 22021 GTCTTGATGTAGTGGG
G.sub.ksT.sub.ks.sup.mC.sub.ksT.sub.dsT.sub.dsG.sub.dsA.sub.dsT.sub.dsG.s-
ub.ds 70 1132
T.sub.dsA.sub.dsG.sub.dsT.sub.ksG.sub.ksG.sub.ksG.sub.e 1341040
1081 1096 20896 20911 CTGCTAGTGCCAAACC
.sup.mC.sub.ksT.sub.ksG.sub.ks.sup.mC.sub.dsT.sub.dsA.sub.dsG.sub.dsT.sub-
.dsG.sub.ds 67 1510
.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.ksA.sub.ks.sup.mC.sub.ks.s-
up.mC.sub.e 1341045 2254 2269 22069 22084 CAAGAGGATAGTCCAT
.sup.mC.sub.ksA.sub.ksA.sub.ksG.sub.dsA.sub.dsG.sub.dsG.sub.dsA.sub.dsT.s-
ub.ds 64 510
A.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.ks.sup.mC.sub.ksA.sub.ksT.sub.e
1341048 2245 2260 22060 22075 AGTCCATGCAAAAGCA
A.sub.ksG.sub.ksT.sub.ks.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.dsG.sub-
.ds.sup.mC 80 120
.sub.dsA.sub.dsA.sub.dsA.sub.dsA.sub.ksG.sub.ks.sup.mC.sub.ksA.sub.e
1341049 2355 2370 22170 22185 TTATAACTACAAGAGG
T.sub.ksT.sub.ksA.sub.ksT.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.dsA.s-
ub.ds.sup.m 43 1289
C.sub.dsA.sub.dsA.sub.dsG.sub.ksA.sub.ksG.sub.ksG.sub.e 1341051
1077 1092 20892 20907 TAGTGCCAAACCAATG
T.sub.ksA.sub.ksG.sub.ksT.sub.dsG.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub-
.dsA.sub.d 61 1198
.sub.sA.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ksA.sub.ksT.sub.ks
1341059 N/A N/A 9518 9533 CTACACTAATATTGAG
.sup.mC.sub.ksT.sub.ksA.sub.ks.sup.mC.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.d-
sA.sub.dsA 10 59
.sub.dsT.sub.dsA.sub.dsT.sub.dsT.sub.ksG.sub.ksA.sub.ksG.sub.e
1341065 N/A N/A 11853 11868 AGCAGAATTGTGAACG
A.sub.ksG.sub.ks.sup.mC.sub.ksA.sub.dsG.sub.dsA.sub.dsA.sub.dsT.sub.dsT.s-
ub.ds 56 844
G.sub.dsT.sub.dsG.sub.dsA.sub.ksA.sub.ks.sup.mC.sub.ksG.sub.e
1341066 N/A N/A 12423 12438 GGTGGTAACGGTGATC
G.sub.ksG.sub.ksT.sub.ksG.sub.dsG.sub.dsT.sub.dsA.sub.dsA.sub.ds.sup.mC.s-
ub.ds 47 2591
G.sub.dsG.sub.dsT.sub.dsG.sub.ksA.sub.ksT.sub.ks.sup.mC.sub.e
1341072 N/A N/A 15496 15511 CTGCATTAATGCCACC
.sup.mC.sub.ksT.sub.ksG.sub.ks.sup.mC.sub.dsA.sub.dsT.sub.dsT.sub.dsA.sub-
.dsA.sub.ds 40 1168
T.sub.dsG.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksA.sub.ks.sup.mC.sub.ks.s-
up.mC.sub.e 1341074 N/A N/A 14197 14212 TTATGTGATTGAGTTC
T.sub.ksT.sub.ksA.sub.ksT.sub.dsG.sub.dsT.sub.dsG.sub.dsA.sub.dsT.sub.dsT-
.sub.d 30 2431
.sub.sG.sub.dsA.sub.dsG.sub.ksT.sub.ksT.sub.ks.sup.mC.sub.e 1341078
N/A N/A 14916 14931 ATACATTAGCAAGCTA
A.sub.ksT.sub.ksA.sub.ks.sup.mC.sub.dsA.sub.dsT.sub.dsT.sub.dsA.sub.dsG.s-
ub.ds 48 309
.sup.mC.sub.dsA.sub.dsA.sub.dsG.sub.ks.sup.mC.sub.ksT.sub.ksA.sub.e
1341086 N/A N/A 16131 16146 GCTCCATAATAATAGC
G.sub.ks.sup.mC.sub.ksT.sub.ks.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.d-
sA.sub.dsA 8 2665
.sub.dsT.sub.dsA.sub.dsA.sub.dsT.sub.ksA.sub.ksG.sub.ks.sup.mC.sub.e
1341091 N/A N/A 17991 18006 GTTAGTATAGTTATCT
G.sub.ksT.sub.ksT.sub.ksA.sub.dsG.sub.dsT.sub.dsA.sub.dsT.sub.dsA.sub.dsG
71 1171
.sub.dsT.sub.dsT.sub.dsA.sub.ksT.sub.ks.sup.mC.sub.ksT.sub.e
1341094 N/A N/A 18097 18112 GAAATTGATACACCAA
G.sub.ksA.sub.ksA.sub.ksA.sub.dsT.sub.dsT.sub.dsG.sub.dsA.sub.dsT.sub.dsA
64 315
.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ks.sup.mC.sub.ksA.sub.ksA.s-
ub.e 1341104 N/A N/A 19910 19925 CATCTTAAGATACCCA
.sup.mC.sub.ksA.sub.ksT.sub.ks.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.dsA.sub-
.dsG.sub.ds 76 475
A.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.ks.sup.mC.sub.ks.sup.mC.sub.ksA.-
sub.e 1341106 N/A N/A 18695 18710 AAAGACTTTGAGACTC
A.sub.ksA.sub.ksA.sub.ksG.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsT.s-
ub.ds 67 1250
G.sub.dsA.sub.dsG.sub.dsA.sub.ks.sup.mC.sub.ksT.sub.ks.sup.mC.sub.e
1341109 1085 1100 20900 20915 ACTGCTGCTAGTGCCA
A.sub.ks.sup.mC.sub.ksT.sub.ksG.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.ds.sup.-
mC.sub.dsT 57 1821
.sub.dsA.sub.dsG.sub.dsT.sub.dsG.sub.ks.sup.mC.sub.ks.sup.mC.sub.ksA-
.sub.e 1341111 N/A N/A 20116 20131 CAGCATCAAGACATTC
.sup.mC.sub.ksA.sub.ksG.sub.ks.sup.mC.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.d-
sA.sub.ds 70 2191
A.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.ksT.sub.ksT.sub.ks
1341112 N/A N/A 20381 20396 AATCACAAGTAAGGTA
A.sub.ksA.sub.ksT.sub.ks.sup.mC.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.dsA.sub-
.dsG.sub.d 63 1333
.sub.sT.sub.dsA.sub.dsA.sub.dsG.sub.ksG.sub.ksT.sub.ksA.sub.e
1341117 N/A N/A 20192 20207 GCAGTTATTAGAAGTC
G.sub.ks.sup.mC.sub.ksA.sub.ksG.sub.dsT.sub.dsT.sub.dsA.sub.dsT.sub.dsT.s-
ub.ds 67 398
A.sub.dsG.sub.dsA.sub.dsA.sub.ksG.sub.ksT.sub.ks.sup.mC.sub.e
1341124 N/A N/A 12501 12516 GCAGAAATTCACCTTG
G.sub.ks.sup.mC.sub.ksA.sub.ksG.sub.dsA.sub.dsA.sub.dsA.sub.dsT.sub.dsT.s-
ub.ds 62 1002
.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksT.sub.ksT.sub.ksG.-
sub.e 1341128 N/A N/A 20486 20501 AACTTCATAGTGGACT
A.sub.ksA.sub.ks.sup.mC.sub.ksT.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.dsT.sub-
.dsA.sub.ds 70 2555
G.sub.dsT.sub.dsG.sub.dsG.sub.ksA.sub.ks.sup.mC.sub.ksT.sub.e
1341129 N/A N/A 20422 20437 ACAGTAAAATTATGCC
A.sub.ks.sup.mC.sub.ksA.sub.ksG.sub.dsT.sub.dsA.sub.dsA.sub.dsA.sub.dsA.s-
ub.ds 62 477
T.sub.dsT.sub.dsA.sub.dsT.sub.ksG.sub.ks.sup.mC.sub.ks.sup.mC.sub.e
1341135 N/A N/A 13952 13967 TCTAAGTTAGCCCCCA
T.sub.ks.sup.mC.sub.ksT.sub.ksA.sub.dsA.sub.dsG.sub.dsT.sub.dsT.sub.dsA.s-
ub.ds 0 928
G.sub.ds.sup.mC.sub.ds.sup.mC.sub.ds.sup.mC.sub.ks.sup.mC.sub.ks.sup-
.mC.sub.ksA.sub.e 1341139 N/A N/A 12799 12814 GCTGTAAGAGTCAGTA
G.sub.ks.sup.mC.sub.ksT.sub.ksG.sub.dsT.sub.dsA.sub.dsA.sub.dsG.sub.dsA.s-
ub.ds 52 693
G.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ksG.sub.ksT.sub.ksA.sub.e
1341140 1180 1195 20995 21010 GTTTTTAAGAGGCATG
G.sub.ksT.sub.ksT.sub.ksT.sub.dsT.sub.dsT.sub.dsA.sub.dsA.sub.dsG.sub.dsA-
.sub.d 78 1199
.sub.sG.sub.dsG.sub.ds.sup.mC.sub.ksA.sub.ksT.sub.ksG.sub.e 1341142
1257 1272 21072 21087 AGCTTTTGTCCACCTT
A.sub.ksG.sub.ks.sup.mC.sub.ksT.sub.dsT.sub.dsT.sub.dsT.sub.dsG.sub.dsT.s-
ub.ds.sup.m 69 1822
C.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksT.sub.ksT.sub.ks.sup.mC.sub.e
1341151 1315 1330 21130 21145 ACAGTCTTAAACCTTC
A.sub.ks.sup.mC.sub.ksA.sub.ksG.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub-
.dsA.sub.ds 73 110
A.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksT.sub.ksT.sub.ks.sup.mC.-
sub.e 1341153 1325 1340 21140 21155 TGCTACTTGAACAGTC
T.sub.ksC.sub.ks.sup.mC.sub.ksT.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.dsT.sub-
.dsG.sub.ds 68 889
A.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.ksG.sub.ksT.sub.ks.sup.mC.sub.e
1341156 1311 1326 21126 21141 TCTTAAACCTTCCCTG
T.sub.ks.sup.mC.sub.ksT.sub.ksT.sub.dsA.sub.dsA.sub.dsA.sub.ds.sup.mC.sub-
.ds.sup.mC 38 2160
.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ds.sup.mC.sub.ks.sup.mC.sub.ksT.s-
ub.ksG.sub.e 1341158 700 715 12118 12133 CAGAGACATGAGGTTT
.sup.mC.sub.ksA.sub.ksG.sub.ksA.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.dsA.sub-
.dsT.sub.d 45 2319
.sub.sG.sub.dsA.sub.dsG.sub.dsG.sub.ksT.sub.ksT.sub.ksT.sub.e
1341167 1321 1336 21136 21151 ACTTGAACAGTCTTAA
A.sub.ks.sup.mC.sub.ksT.sub.ksT.sub.dsG.sub.dsA.sub.dsA.sub.ds.sup.mC.sub-
.dsA.sub.d 60 578
.sub.sG.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.ksT.sub.ksA.sub.ksA.sub.e
1341173 1331 1346 21146 21161 TTGGAATGCTACTTGA
T.sub.ksT.sub.ksG.sub.ksG.sub.dsA.sub.dsA.sub.dsT.sub.dsG.sub.ds.sup.mC.s-
ub.ds 56 1279
T.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.ksT.sub.ksG.sub.ksA.sub.e
1341232 1340 1355 21155 21170 GGCTACAGATTGGAAT
G.sub.ksG.sub.ks.sup.mC.sub.ksT.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.dsG.sub-
.dsA.sub.d 28 1980
.sub.sT.sub.dsT.sub.dsG.sub.dsG.sub.ksA.sub.ksA.sub.ksT.sub.e
1341255 1351 1366 21166 21181 TTCTGTGGCATGGCTA
T.sub.ksT.sub.ks.sup.mC.sub.ksT.sub.dsG.sub.dsT.sub.dsG.sub.dsG.sub.ds.su-
p.mC.sub.ds 59 812
A.sub.dsT.sub.dsG.sub.dsG.sub.ks.sup.mC.sub.ksT.sub.ksA.sub.e
1341271 1355 1370 21170 21185 GATATTCTGTGGCATG
G.sub.ksA.sub.ksT.sub.ksA.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsG.s-
ub.ds 71 1046
T.sub.dsG.sub.dsG.sub.ds.sup.mC.sub.ksA.sub.ksT.sub.ksG.sub.e
1341321 1359 1374 21174 21189 TGTTGATATTCTGTGG
T.sub.ksG.sub.ksT.sub.ksT.sub.dsG.sub.dsA.sub.dsT.sub.dsA.sub.dsT.sub.dsT-
.sub.d 64 1358
.sub.s.sup.mC.sub.dsT.sub.dsG.sub.ksT.sub.ksG.sub.ksG.sub.e 1341323
798 813 15679 15694 TTCCATCTATCAGACT
T.sub.ksT.sub.ks.sup.mC.sub.ks.sup.mC.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.d-
sT.sub.dsA 43 571
.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.ksA.sub.ks.sup.mC.sub.ksT-
.sub.e 1341427 1395 1410 21210 21225 ACTTGATCTCTTAGCT
A.sub.ks.sup.mC.sub.ksT.sub.ksT.sub.dsG.sub.dsA.sub.dsT.sub.ds.sup.mC.sub-
.dsT.sub.ds 59 813
.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.ksG.sub.ks.sup.mC.sub.ksT.sub.e
1341428 1387 1402 21202 21217 TCTTAGCTGTGCACTC
T.sub.ks.sup.mC.sub.ksT.sub.ksT.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.dsT.sub-
.dsG.sub.ds 52 190
T.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.ks.sup.mC.sub.ksT.sub.ks.sup.mC.-
sub.e 1341436 1421 1436 21236 21251 AGGTTGAGATAAAGCT
A.sub.ksG.sub.ksG.sub.ksT.sub.dsT.sub.dsG.sub.dsA.sub.dsG.sub.dsA.sub.dsT
71 1904
.sub.dsA.sub.dsA.sub.dsA.sub.ksG.sub.ks.sup.mC.sub.ksT.sub.e
1341437 1431 1446 21246 21261 AAATATGTCCAGGTTG
A.sub.ksA.sub.ksA.sub.ksT.sub.dsA.sub.dsT.sub.dsG.sub.dsT.sub.ds.sup.mC.s-
ub.ds 74 581
.sup.mC.sub.dsA.sub.dsG.sub.dsG.sub.ksT.sub.ksT.sub.ksG.sub.e
1341446 1488 1503 21303 21318 GTTTTGGGCTAATGAA
G.sub.ksT.sub.ksT.sub.ksT.sub.dsT.sub.dsG.sub.dsG.sub.dsG.sub.ds.sup.mC.s-
ub.ds 47 1204
T.sub.dsA.sub.dsA.sub.dsT.sub.ksG.sub.ksA.sub.ksA.sub.e 1341447
1496 1511 21311 21326 GTTGCACCGTTTTGGG
G.sub.ksT.sub.kj.sub.ksG.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ds.sup.m-
C.sub.dsG 45 1827
.sub.dsT.sub.dsT.sub.dsT.sub.dsT.sub.ksG.sub.ksG.sub.ksG.sub.e
1341450 1726 1741 21541 21556 CTAAAATTGTCTAAAC
.sup.mC.sub.ksT.sub.ksA.sub.ksA.sub.dsA.sub.dsA.sub.dsT.sub.dsT.sub.dsG.s-
ub.ds 7 2590
T.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.ksA.sub.ksA.sub.ks.sup.mC.sub.e
1341454 1022 1037 20837 20852 CTTTGCAGCATTGATT
.sup.mC.sub.ksT.sub.ksTIc.sub.sT.sub.dsG.sub.ds.sup.mc.sub.dsA.sub.dsG.su-
b.ds.sup.mC 56 2463
.sub.dsA.sub.dsT.sub.dsT.sub.dsG.sub.ksA.sub.ksT.sub.ksT.sub.e
1341455 1717 1732 21532 21547 TCTAAACATCTCTGGG
T.sub.ks.sup.mC.sub.ksT.sub.ksA.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.dsA.sub-
.dsT.sub.ds 42 2287
.sup.mC.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.ksG.sub.ksG.sub.ksG.sub.e
1341460 N/A N/A 9337 9352 CCTCGATCCTATATAC
.sup.mC.sub.ks.sup.mC.sub.ksT.sub.ks.sup.mC.sub.dsG.sub.dsA.sub.dsT.sub.d-
s.sup.mC.sub.ds 11 2812
.sup.mC.sub.dsT.sub.dsA.sub.dsT.sub.dsA.sub.ksT.sub.ksA.sub.ks.sup.m-
C.sub.e 1341467 2184 2199 21999 22014 TGTAGTGGGAGTCGGA
T.sub.ksG.sub.ksT.sub.ksA.sub.dsG.sub.dsT.sub.dsG.sub.dsG.sub.dsG.sub.dsA
53 587 .sub.dsG.sub.dsT.sub.ds.sup.mC.sub.ksG.sub.ksG.sub.ksA.sub.e
1341469 N/A N/A 9971 9986 TTGAGTAGTGTAAGCT
T.sub.ksT.sub.ksG.sub.ksA.sub.dsG.sub.dsT.sub.dsA.sub.dsG.sub.dsT.sub.dsG
40 2346
.sub.dsT.sub.dsA.sub.dsA.sub.ksG.sub.ks.sup.mC.sub.ksT.sub.e
1341476 N/A N/A 11568 11583 TGACAATGGTTGATAG
T.sub.ksG.sub.ksA.sub.ks.sup.mC.sub.dsA.sub.dsA.sub.dsT.sub.dsG.sub.dsG.s-
ub.ds 38 1700
T.sub.dsT.sub.dsG.sub.dsA.sub.ksT.sub.ksA.sub.ksG.sub.e 1341477 N/A
N/A 9961 9976 TAAGCTGAGAGTTCTA
T.sub.ksA.sub.ksA.sub.ksG.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.dsA.sub.dsG.s-
ub.ds 48 2499
A.sub.dsG.sub.dsT.sub.dsT.sub.ks.sup.mC.sub.ksT.sub.ksA.sub.e
1341479 N/A N/A 17986 18001 TATAGTTATCTTCTCA
T.sub.ksA.sub.ksT.sub.ksA.sub.dsG.sub.dsT.sub.dsT.sub.dsA.sub.dsT.sub.ds.-
sup.m 59 2295
C.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ksT.sub.ks.sup.mC.sub.ksA.sub.e
1341481 N/A N/A 17996 18011 ATGAAGTTAGTATAGT
A.sub.ksT.sub.ksG.sub.ksA.sub.dsA.sub.dsG.sub.dsT.sub.dsT.sub.dsA.sub.dsG
61 1483 .sub.dsT.sub.dsA.sub.dsT.sub.ksA.sub.ksG.sub.ksT.sub.e
1341483 N/A N/A 16282 16297 TAGTCTTCAGCAAAGT
T.sub.ksA.sub.ksGr.sub.ksT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ds.sup.mC.su-
b.dsA.sub.ds 36 2632
G.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.ksA.sub.ksG.sub.ksT.sub.e
1341484 N/A N/A 16377 16392 ACCAAACTTCCAGCAG
A.sub.ks.sup.mC.sub.ks.sup.mC.sub.ksA.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.d-
sT.sub.dsT 36 1948
.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.ks.sup.mC.sub.ksA.s-
ub.ksG.sub.e 1341493 N/A N/A 19914 19929 AGTGCATCTTAAGATA
A.sub.ksG.sub.ksT.sub.ksG.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.ds.sup.mC.sub-
.dsT.sub.ds 12 2130
T.sub.dsA.sub.dsA.sub.dsG.sub.ksA.sub.ksT.sub.ksA.sub.e 1341505 N/A
N/A 19906 19921 TTAAGATACCCAGGTT
T.sub.ksT.sub.ksA.sub.ksA.sub.dsG.sub.dsA.sub.dsT.sub.dsA.sub.ds.sup.mC.s-
ub.ds 51 163
.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.ksG.sub.ksT.sub.ksT.sub.e
1341507 N/A N/A 20009 20024 AGAGAGTAATCAGTTT
A.sub.ksG.sub.ksA.sub.ksG.sub.dsA.sub.dsG.sub.dsT.sub.dsA.sub.dsA.sub.dsT
51 2651
.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.ksT.sub.ksT.sub.ksT.sub.e
1341509 N/A N/A 14165 14180 GCAAGCCAACAGAGAG
G.sub.ks.sup.mC.sub.ksA.sub.ksA.sub.dsG.sub.ds.sup.mC.sub.ds.sup.mC.sub.d-
sA.sub.ds 38 2556
A.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.dsA.sub.ksG.sub.ksA.sub.ksG.sub.-
e 1341511 N/A N/A 14175 14190 GCCTTGAATAGCAAGC
G.sub.ks.sup.mC.sub.ks.sup.mC.sub.ksT.sub.dsT.sub.dsG.sub.dsA.sub.dsA.sub-
.dsT.sub.ds 38 2063
A.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.ksA.sub.ksG.sub.ks.sup.mC.sub.e
TABLE-US-00046 TABLE 46 Inhibition of HSD17B13 RNA by modified
oligonucleotides targeting SEQ ID NO.: 1, and 2 SEQ ID SEQ ID SEQ
ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 Compound Start Stop Start Stop
Chemistry Notation % SEQ ID Number Site Site Site Site Sequence (5'
to 3') (5' to 3') inhibition NO 1245927 N/A N/A 3433 3448
AGTAGATGGTAAGTCA
A.sub.ksG.sub.ksT.sub.ksA.sub.dsG.sub.dsA.sub.dsT.sub.dsG.sub.dsG.sub.ds
79 121
T.sub.dsA.sub.dsA.sub.dsG.sub.dsT.sub.ks.sup.mC.sub.ksA.sub.k
1246023 N/A N/A 5046 5061 GAGTGAATCATTCAGT
G.sub.ksA.sub.ksG.sub.ksT.sub.dsG.sub.dsA.sub.dsA.sub.dsT.sub.ds.sup.mC.s-
ub.ds 87 1526
A.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ksG.sub.ksT.sub.k
1341648 1251 1266 21066 21081 TGTCCACCTTTAAATG
T.sub.ksG.sub.kST.sub.ks.sup.mC.sub.dsC.sub.ysA.sub.ds.sup.mC.sub.ds.sup.-
mC.sub.ds 17 1666
T.sub.dsT.sub.dsT.sub.dsA.sub.dsA.sub.dsA.sub.ksT.sub.ksG.sub.k
1341654 1317 1332 21132 21147 GAACAGTCTTAAACCT
G.sub.ksA.sub.ksA.sub.ks.sup.mC.sub.dsA.sub.ysG.sub.dsT.sub.ds.sup.mC.sub-
.ds 75 266
T.sub.dsT.sub.dsA.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.ks.sup.mC.sub.ks-
T.sub.k 1341658 1313 1328 21128 21143 AGTCUTAAACCTTCCC
A.sub.ksG.sub.ksT.sub.ks.sup.mC.sub.dsU.sub.ysT.sub.dsA.sub.dsA.sub.dsA.s-
ub.ds 52 2813
.sup.mC.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ks.sup.mC.su-
b.ks.sup.mC.sub.k 1341661 1321 1336 21136 21151 ACTTGAACAGTCTTAA
A.sub.ks.sup.mC.sub.ksT.sub.ksT.sub.dsG.sub.ysA.sub.dsA.sub.ds.sup.mC.sub-
.ds 29 578
A.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ksA.sub.ksA.sub.-
k 1341663 1308 1323 21123 21138 TAAACCTTCCCTGTGT
T.sub.ksA.sub.ksA.sub.ksA.sub.dsC.sub.ys.sup.mC.sub.dsT.sub.dsT.sub.ds.su-
p.mC.sub.ds 46 1745
.sup.mC.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.dsT.sub.ksG.sub.ksT.sub.k
1341668 1335 1350 21150 21165 CAGAUTGGAATGCTAC
.sup.mC.sub.ksA.sub.ksG.sub.ksA.sub.dsU.sub.ysT.sub.dsG.sub.dsG.sub.dsA.s-
ub.ds 70 2814
A.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.ksA.sub.ks.sup.mC.sub.k
1341672 1329 1344 21144 21159 GGAAUGCTACTTGAAC
G.sub.ksG.sub.ksA.sub.ksA.sub.dsU.sub.ysG.sub.ds.sup.mC.sub.dsT.sub.ds
62 2815
A.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsG.sub.dsA.sub.ksA.sub.ks.sup.m-
C.sub.k 1341677 1325 1340 21140 21155 TGCTACTTGAACAGTC
T.sub.ksG.sub.ks.sup.mC.sub.ksT.sub.dsA.sub.ys.sup.mC.sub.dsT.sub.dsT.sub-
.ds 65 889
G.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.ksT.sub.ks.sup.m-
C.sub.k 1341685 1342 1357 21157 21172 ATGGCTACAGATTGGA
A.sub.ksT.sub.ksG.sub.ksG.sub.dsC.sub.ysT.sub.dsA.sub.ds.sup.mC.sub.dsA.s-
ub.ds 44 111
G.sub.dsA.sub.dsT.sub.dsT.sub.dsG.sub.ksG.sub.ksA.sub.k 1341691
1357 1372 21172 21187 TTGAUATTCTGTGGCA
T.sub.ksT.sub.ksG.sub.ksA.sub.dsU.sub.ysA.sub.dsT.sub.dsT.sub.ds.sup.mC.s-
ub.ds 60 2816
T.sub.dsG.sub.dsT.sub.dsG.sub.dsG.sub.ks.sup.mC.sub.ksA.sub.k
1341692 1348 1363 21163 21178 TGTGGCATGGCTACAG
T.sub.ksG.sub.ksT.sub.ksG.sub.dsG.sub.ys.sup.mC.sub.dsA.sub.dsT.sub.dsG.s-
ub.ds 5 579
G.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.ksA.sub.ksG.sub.k
1341697 1353 1368 21168 21183 TATTCTGTGGCATGGC
T.sub.ksA.sub.ksT.sub.ksT.sub.dsC.sub.ysT.sub.dsG.sub.dsT.sub.dsG.sub.ds
55 890
G.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.dsG.sub.ksG.sub.ks.sup.mC.sub.k
1341698 1366 1381 21181 21196 GTGTUCTTGTTGATAT
G.sub.ksT.sub.ksG.sub.ksT.sub.dsU.sub.ys.sup.mC.sub.dsT.sub.dsT.sub.dsG.s-
ub.ds 52 2817
T.sub.dsT.sub.dsG.sub.dsA.sub.dsT.sub.ksA.sub.ksT.sub.k 1341702
1394 1409 21209 21224 CTTGATCTCTTAGCTG
.sup.mC.sub.ksT.sub.ksT.sub.ksG.sub.dsA.sub.ysT.sub.ds.sup.mC.sub.dsT.sub-
.ds 32 736
.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.ksT.sub.ks-
G.sub.k 1341703 1388 1403 21203 21218 CTCTUAGCTGTGCACT
.sup.mC.sub.ksT.sub.ks.sup.mC.sub.ksT.sub.dsU.sub.ysA.sub.dsG.sub.ds.sup.-
mC.sub.ds 67 2818
T.sub.dsG.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.ks.sup.mC.sub.ks-
T.sub.k 1341713 1421 1436 21236 21251 AGGTUGAGATAAAGCT
A.sub.ksG.sub.ksG.sub.ksT.sub.dsU.sub.ysG.sub.dsA.sub.dsG.sub.dsA.sub.ds
58 2819
T.sub.dsA.sub.dsA.sub.dsA.sub.dsG.sub.ks.sup.mC.sub.ksT.sub.k
1341716 696 711 12114 12129 GACAUGAGGTTTTGAT
G.sub.ksA.sub.ks.sup.mC.sub.ksA.sub.dsU.sub.ysG.sub.dsA.sub.dsG.sub.ds
34 2820
G.sub.dsT.sub.dsT.sub.dsT.sub.dsT.sub.dsG.sub.ksA.sub.ksT.sub.k
1341719 1416 1431 21231 21246 GAGAUAAAGCTGCCTG
G.sub.ksA.sub.ksG.sub.ksA.sub.dsU.sub.ysA.sub.dsA.sub.dsA.sub.dsG.sub.ds
39 2821
.sup.mC.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksT.sub.ksG.-
sub.k 1341726 1426 1441 21241 21256 TGTCCAGGTTGAGATA
T.sub.ksG.sub.ksT.sub.ks.sup.mC.sub.dsC.sub.ysA.sub.dsG.sub.dsG.sub.dsT.s-
ub.ds 41 191
T.sub.dsG.sub.dsA.sub.dsG.sub.dsA.sub.ksT.sub.ksA.sub.k 1341727
1464 1479 21279 21294 AGGCUAGGGAAATCTT
A.sub.ksG.sub.ksG.sub.ks.sup.mC.sub.dsU.sub.ysA.sub.dsG.sub.dsG.sub.ds
41 2822
G.sub.dsA.sub.dsA.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.ksT.sub.ksT.sub.-
k 1341729 1494 1509 21309 21324 TGCACCGTTTTGGGCT
T.sub.ksG.sub.ks.sup.mC.sub.ksA.sub.dsC.sub.ys.sup.mC.sub.dsG.sub.dsT.sub-
.ds 55 1671
T.sub.dsT.sub.dsT.sub.dsG.sub.dsG.sub.dsG.sub.ks.sup.mC.sub.ksT.sub.-
k 1341734 1490 1505 21305 21320 CCGTUTTGGGCTAATG
.sup.mC.sub.ks.sup.mC.sub.ksG.sub.ksT.sub.dsU.sub.ysT.sub.dsT.sub.dsG.sub-
.ds 51 2823
G.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.dsA.sub.ksT.sub.ksG.sub.-
k 1341739 1623 1638 21438 21453 TAGAGTCGGTCACCTT
T.sub.ksA.sub.ksG.sub.ksA.sub.dsG.sub.ysT.sub.ds.sup.mC.sub.dsG.sub.dsG.s-
ub.ds 55 506
T.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksT.sub.ksT.-
sub.k 1341743 1598 1613 21413 21428 ATCTUATAAGACTATA
A.sub.ksT.sub.ks.sup.mC.sub.ksT.sub.dsU.sub.ysA.sub.dsT.sub.dsA.sub.dsA.s-
ub.ds 35 2824
G.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.ksT.sub.ksA.sub.k
1341745 1498 1513 21313 21328 GAGTUGCACCGTTTTG
G.sub.ksA.sub.ksG.sub.ksT.sub.dsU.sub.ysG.sub.ds.sup.mC.sub.dsA.sub.ds
63 2825
.sup.mC.sub.ds.sup.mC.sub.dsG.sub.dsT.sub.dsT.sub.dsT.sub.ksT.sub.ks-
G.sub.k 1341753 1615 1630 21430 21445 GTCACCTTTCATAATG
G.sub.ksT.sub.ks.sup.mC.sub.ksA.sub.dsC.sub.ys.sup.mC.sub.dsT.sub.dsT.sub-
.ds 40 1907
T.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.dsA.sub.dsA.sub.ksT.sub.ksG.sub.-
k 1341755 1619 1634 21434 21449 GTCGGTCACCTTTCAT
G.sub.ksT.sub.ks.sup.mC.sub.ksG.sub.dsG.sub.ysT.sub.ds.sup.mC.sub.dsA.sub-
.ds 66 194
.sup.mC.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ksA.-
sub.ksT.sub.k 1341758 1627 1642 21442 21457 AAAAUAGAGTCGGTCA
A.sub.ksA.sub.ksA.sub.ksA.sub.dsU.sub.ysA.sub.dsG.sub.dsA.sub.dsG.sub.ds
62 2826
T.sub.ds.sup.mC.sub.dsG.sub.dsG.sub.dsT.sub.ks.sup.mC.sub.ksA.sub.k
1341759 1711 1726 21526 21541 CATCUCTGGGACCAAG
.sup.mC.sub.ksA.sub.ksT.sub.ks.sup.mC.sub.dsU.sub.ys.sup.mC.sub.dsT.sub.d-
sG.sub.ds 42 2827
G.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ksA.sub.ks-
G.sub.k 1341763 1715 1730 21530 21545 TAAACATCTCTGGGAC
T.sub.ksA.sub.ksA.sub.ksA.sub.dsC.sub.ysA.sub.dsT.sub.ds.sup.mC.sub.dsT.s-
ub.ds 49 351
.sup.mC.sub.dsT.sub.dsG.sub.dsG.sub.dsG.sub.ksA.sub.ks.sup.mT.sub.k
1341774 1705 1720 21520 21535 TGGGACCAAGGATATA
T.sub.ksG.sub.ksG.sub.ksG.sub.dsA.sub.ys.sup.mC.sub.ds.sup.mC.sub.dsA.sub-
.ds 51 1674
A.sub.dsG.sub.dsG.sub.dsA.sub.dsT.sub.dsA.sub.ksT.sub.ksA.sub.k
1341777 796 811 15677 15692 CCATCTATCAGACTTC
.sup.mC.sub.ks.sup.mC.sub.ksA.sub.ksT.sub.dsC.sub.ysT.sub.dsA.sub.dsT.sub-
.ds 56 415
.sup.mC.sub.dsA.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.ksT.sub.ks-
.sup.mC.sub.k 1341780 1770 1785 21585 21600 AGCCAGTACAGTTCCT
A.sub.ksG.sub.ks.sup.mC.sub.ks.sup.mC.sub.dsA.sub.ysG.sub.dsT.sub.dsA.sub-
.ds 65 1909
.sup.mC.sub.dsA.sub.dsG.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ks.sup.mC.-
sub.ksT.sub.k 1341785 1751 1766 21566 21581 CCTGUGTTAGCTTTAA
.sup.mC.sub.ks.sup.mC.sub.ksT.sub.ksG.sub.dsU.sub.ysG.sub.dsT.sub.dsT.sub-
.ds 28 2828
A.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsT.sub.ksA.sub.ksA.sub.-
k 1341786 1719 1734 21534 21549 TGTCUAAACATCTCTG
T.sub.ksG.sub.ksT.sub.ks.sup.mC.sub.dsU.sub.ysA.sub.dsA.sub.dsA.sub.ds
44 2829
.sup.mC.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.ds.sup.mC.sub.ksT.-
sub.ksG.sub.k 1341788 1783 1798 21598 21613 TTTCUTATGTAATAGC
T.sub.ksT.sub.ksT.sub.ks.sup.mC.sub.dsU.sub.ysT.sub.dsA.sub.dsT.sub.dsG.s-
ub.ds 50 2830
T.sub.dsA.sub.dsA.sub.dsT.sub.dsA.sub.ksG.sub.ks.sup.mC.sub.k
1341793 1775 1790 21590 21605 GTAAUAGCCAGTACAG
G.sub.ksT.sub.ksA.sub.ksA.sub.dsU.sub.ysA.sub.dsG.sub.ds.sup.mC.sub.ds
62 2831
.sup.mC.sub.dsA.sub.dsG.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.ksA.sub.ks-
G.sub.k 1341796 1779 1794 21594 21609 TTATGTAATAGCCAGT
T.sub.ksT.sub.ksA.sub.ksT.sub.dsG.sub.ysT.sub.dsA.sub.dsA.sub.dsT.sub.ds
56 586
A.sub.dsG.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ksG.sub.ksT.sub.k
1341800 2187 2202 22002 22017 TGATGTAGTGGGAGTC
T.sub.ksG.sub.ksA.sub.ksT.sub.dsG.sub.ysT.sub.dsA.sub.dsG.sub.dsT.sub.ds
43 820
G.sub.dsG.sub.dsG.sub.dsA.sub.dsG.sub.ksT.sub.ks.sup.mC.sub.k
1341805 2194 2209 22009 22024 TTAGUCTTGATGTAGT
T.sub.ksT.sub.ksA.sub.ksG.sub.dsU.sub.ys.sup.mC.sub.dsT.sub.dsT.sub.dsG.s-
ub.ds 50 2832
A.sub.dsT.sub.dsG.sub.dsT.sub.dsA.sub.ksG.sub.ksT.sub.k 1341809
2350 2365 22165 22180 ACTACAAGAGGTTATT
A.sub.ks.sup.mC.sub.ksT.sub.ksA.sub.dsC.sub.ysA.sub.dsA.sub.dsG.sub.dsA.s-
ub.ds 29 899
G.sub.dsG.sub.dsT.sub.dsT.sub.dsA.sub.ksT.sub.ksT.sub.k 1341810
2250 2265 22065 22080 AGGAUAGTCCATGCAA
A.sub.ksG.sub.ksG.sub.ksA.sub.dsU.sub.ysA.sub.dsG.sub.dsT.sub.ds 55
2833
.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.ksA.-
sub.ksA.sub.k 1341822 N/A N/A 9514 9529 ACTAATATTGAGGCAC
A.sub.ks.sup.mC.sub.ksT.sub.ksA.sub.dsA.sub.ysT.sub.dsA.sub.dsT.sub.dsT.s-
ub.ds 42 1772
G.sub.dsA.sub.dsG.sub.dsG.sub.ds.sup.mC.sub.ksA.sub.ks.sup.mC.sub.k
1341825 N/A N/A 9332 9347 ATCCUATATACATCCA
A.sub.ksT.sub.ks.sup.mC.sub.ks.sup.mC.sub.dsU.sub.ysA.sub.dsT.sub.dsA.sub-
.ds 64 2834
T.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.ks.sup.mC.-
sub.ksA.sub.k 1341828 N/A N/A 9601 9616 CATAUGTGAAGAGCTG
.sup.mC.sub.ksA.sub.ksT.sub.ksA.sub.dsU.sub.ysG.sub.dsT.sub.dsG.sub.dsA.s-
ub.ds 39 2835
A.sub.dsG.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.ksT.sub.ksG.sub.k
1341831 N/A N/A 11578 11593 GTTAUTCTCTTGACAA
G.sub.ksT.sub.ksT.sub.ksA.sub.dsU.sub.ysT.sub.ds.sup.mC.sub.dsT.sub.ds.su-
p.mC.sub.ds 29 2836
T.sub.dsT.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.ksA.sub.ksA.sub.k
1341833 N/A N/A 9966 9981 TAGTGTAAGCTGAGAG
T.sub.ksA.sub.ksG.sub.ksT.sub.dsG.sub.ysT.sub.dsA.sub.dsA.sub.dsG.sub.ds
31 1852
.sup.mC.sub.dsT.sub.dsG.sub.dsA.sub.dsG.sub.ksA.sub.ksG.sub.k
1341836 808 823 15689 15704 TTGGUAAGTATTCCAT
T.sub.ksT.sub.ksG.sub.ksG.sub.dsU.sub.ysA.sub.dsA.sub.dsG.sub.dsT.sub.ds
13 2837
A.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksA.sub.ksT.sub.k
1341839 N/A N/A 11546 11561 TCTTGACAATGGTTGC
T.sub.ks.sup.mC.sub.ksT.sub.ksT.sub.dsG.sub.ysA.sub.ds.sup.mC.sub.dsA.sub-
.dsA.sub.ds 67 2199
T.sub.dsG.sub.dsG.sub.dsT.sub.dsT.sub.ksG.sub.ks.sup.mC.sub.k
1341850 N/A N/A 14197 14212 TTATGTGATTGAGTTC
T.sub.ksT.sub.ksA.sub.ksT.sub.dsG.sub.ysT.sub.dsG.sub.dsA.sub.dsT.sub.dsT-
.sub.ds 35 2431
G.sub.dsA.sub.dsG.sub.dsT.sub.ksT.sub.ks.sup.mC.sub.k 1341856 N/A
N/A 12419 12434 GTAACGGTGATCAAAT
G.sub.ksT.sub.ksA.sub.ksA.sub.dsC.sub.ysG.sub.dsG.sub.dsT.sub.dsG.sub.ds
21 2345
A.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.ksA.sub.ksT.sub.k
1341863 N/A N/A 15496 15511 CTGCATTAATGCCACC
.sup.mC.sub.ksT.sub.ksG.sub.ks.sup.mC.sub.dsA.sub.ysT.sub.dsT.sub.dsA.sub-
.dsA.sub.ds 52 1168
T.sub.dsG.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ks.sup.mC.sub.ks.s-
up.mC.sub.k 1341864 1017 1032 20832 20847 CAGCATTGATTCGAAA
.sup.mC.sub.ksA.sub.ksG.sub.ks.sup.mC.sub.dsA.sub.ysT.sub.dsT.sub.dsG.sub-
.ds 37 263
A.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsG.sub.dsA.sub.ksA.sub.ksA.sub.-
k 1341867 N/A N/A 14916 14931 ATACATTAGCAAGCTA
A.sub.ksT.sub.ksA.sub.ks.sup.mC.sub.dsA.sub.ysT.sub.dsT.sub.dsA.sub.dsG.s-
ub.ds 36 309
.sup.mC.sub.dsA.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.ksT.sub.ksA.sub.k
1341871 N/A N/A 16289 16304 GTTAGAATAGTCTTCA
G.sub.ksT.sub.ksT.sub.ksA.sub.dsG.sub.ysA.sub.dsA.sub.dsT.sub.dsA.sub.ds
42 1481 G.sub.dsT.sub.dsT.sub.dsT.sub.dsT.sub.ksT.sub.ksA.sub.k
1341873 N/A N/A 16218 16233 TATAGACTGGGTAGGA
T.sub.ksA.sub.ksT.sub.ksA.sub.dsG.sub.ysA.sub.ds.sup.mC.sub.dsT.sub.dsG.s-
ub.ds 30 2808
G.sub.dsG.sub.dsT.sub.dsA.sub.dsG.sub.ksG.sub.ksA.sub.k 1341876 N/A
N/A 16127 16142 CATAATAATAGCTCTA
.sup.mC.sub.ksA.sub.ksT.sub.ksA.sub.dsA.sub.ysT.sub.dsA.sub.dsA.sub.dsT.s-
ub.ds 33 2511
A.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.ds.sup.mC.sub.ksT.sub.ksA.sub.k
1341878 N/A N/A 16382 16397 TCCCAACCAAACTTCC
T.sub.ks.sup.mC.sub.ks.sup.mC.sub.ks.sup.mC.sub.dsA.sub.ysA.sub.ds.sup.mC-
.sub.ds 43 2026
.sup.mC.sub.dsA.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ks-
.sup.mC.sub.ks.sup.mC.sub.k 1341885 N/A N/A 17994 18009
GAAGUTAGTATAGTTA
G.sub.ksA.sub.ksA.sub.ksG.sub.dsU.sub.ysT.sub.dsA.sub.dsG.sub.dsT.sub.ds
43 2838 A.sub.dsT.sub.dsA.sub.dsG.sub.dsT.sub.ksT.sub.ksA.sub.k
1341892 1083 1098 20898 20913 TGCTGCTAGTGCCAAA
T.sub.ksG.sub.ks.sup.mC.sub.ksT.sub.dsG.sub.ys.sup.mC.sub.dsT.sub.dsA.sub-
.ds 50 1665
G.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ksA.sub.ks-
A.sub.k 1341893 N/A N/A 17989 18004 TAGTATAGTTATCTTC
T.sub.ksA.sub.ksG.sub.ksT.sub.dsA.sub.ysT.sub.dsA.sub.dsG.sub.dsT.sub.ds
13 1093
T.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.ksT.sub.ks.sup.mC.sub.k
1341898 N/A N/A 19912 19927 TGCAUCTTAAGATACC
T.sub.ksG.sub.ks.sup.mC.sub.ksA.sub.dsU.sub.ys.sup.mC.sub.dsT.sub.dsT.sub-
.ds 51 2839
A.sub.dsA.sub.dsG.sub.dsA.sub.dsT.sub.dsA.sub.ks.sup.mC.sub.ks.sup.m-
C.sub.k 1341903 N/A N/A 18690 18705 CTTTGAGACTCTTGTT
.sup.mC.sub.ksT.sub.ksT.sub.ksT.sub.dsG.sub.ysA.sub.dsG.sub.dsA.sub.ds
15 2583
.sup.mC.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsG.sub.ksT.sub.ks-
T.sub.k 1341905 N/A N/A 18092 18107 TGATACACCAATGCAG
T.sub.ksG.sub.ksA.sub.ksT.sub.dsA.sub.ys.sup.mCdsA.sub.ds.sup.mC.sub.ds
38 2370
.sup.mC.sub.dsA.sub.dsA.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.ksA.sub.ks-
G.sub.k 1341910 N/A N/A 19904 19919 AAGAUACCCAGGTTGC
A.sub.ksA.sub.ksG.sub.ksA.sub.dsU.sub.ysA.sub.ds.sup.mC.sub.ds.sup.mC.sub-
.ds 37 2840
.sup.mC.sub.dsA.sub.dsG.sub.dsG.sub.dsT.sub.dsT.sub.ksG.sub.ks.sup.m-
C.sub.k 1341913 608 623 N/A N/A ACAAUATGGGATGAGG
A.sub.ks.sup.mC.sub.ksA.sub.ksA.sub.dsU.sub.ysA.sub.dsT.sub.dsG.sub.ds
70 2841
G.sub.dsG.sub.dsA.sub.dsT.sub.dsG.sub.dsA.sub.ksG.sub.ksG.sub.k
1341916 N/A N/A 19908 19923 TCTTAAGATACCCAGG
T.sub.ks.sup.mC.sub.ksT.sub.ksT.sub.dsA.sub.ysA.sub.dsG.sub.dsA.sub.dsT.s-
ub.ds 51 319
A.sub.ds.sup.mC.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ksG.sub.ksG.-
sub.k 1341918 N/A N/A 19916 19931 GGAGUGCATCTTAAGA
G.sub.ksG.sub.ksA.sub.ksG.sub.dsU.sub.ysG.sub.ds.sup.mC.sub.dsA.sub.ds
32 2842
T.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.dsA.sub.ksG.sub.ksA.sub.-
k 1341920 N/A N/A 20112 20127 ATCAAGACATTCTAGC
A.sub.ksT.sub.ks.sup.mC.sub.ksA.sub.ksA.sub.ysG.sub.dsA.sub.ds.sup.mC.sub-
.ds 37 1488
A.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.ksG.sub.ks.sup.m-
C.sub.k 1341927 1079 1094 20894 20909 GCTAGTGCCAAACCAA
G.sub.ks.sup.mC.sub.ksT.sub.ksA.sub.dsG.sub.ysT.sub.dsG.sub.ds.sup.mC.sub-
.ds 65 1354
.sup.mC.sub.dsA.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksA.-
sub.ksA.sub.k 1341929 N/A N/A 20385 20400 TAGTAATCACAAGTAA
T.sub.ksA.sub.ksG.sub.ksT.sub.dsA.sub.ysA.sub.dsT.sub.ds.sup.mC.sub.dsA.s-
ub.ds 38 1489
.sup.mC.sub.dsA.sub.dsA.sub.dsG.sub.dsT.sub.ksA.sub.ksA.sub.k
1341931 N/A N/A 20197 20212 ACATUGCAGTTATTAG
A.sub.ks.sup.mC.sub.ksA.sub.ksT.sub.dsU.sub.ysG.sub.ds.sup.mC.sub.dsA.sub-
.ds 26 2843
G.sub.dsT.sub.dsT.sub.dsA.sub.dsT.sub.dsT.sub.ksA.sub.ksG.sub.k
1341936 N/A N/A 20187 20202 TATTAGAAGTCAGCCC
T.sub.ksA.sub.ksT.sub.ksT.sub.dsA.sub.ysG.sub.dsA.sub.dsA.sub.dsG.sub.ds
29 164
T.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.ks.sup.mC.sub.ks.s-
up.mC.sub.k 1341940 N/A N/A 20482 20497 TCATAGTGGACTTCAT
T.sub.ks.sup.mC.sub.ksA.sub.ksT.sub.dsA.sub.ysG.sub.dsT.sub.dsG.sub.dsG.s-
ub.ds 44 633
A.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ksA.sub.ksT.sub.k
1341946 1075 1090 20890 20905 GTGCCAAACCAATGTT
G.sub.ksT.sub.ksG.sub.ks.sup.mC.sub.dsC.sub.ysA.sub.dsA.sub.dsA.sub.ds
30 1042
.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsT.sub.dsG.sub.ksT.sub.ks-
T.sub.k 1341951 N/A N/A 12801 12816 AGGCUGTAAGAGTCAG
A.sub.ksG.sub.ksG.sub.ks.sup.mC.sub.dsU.sub.ysG.sub.dsT.sub.dsA.sub.ds
52 2844
A.sub.dsG.sub.dsA.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.ksA.sub.ksG.sub.-
k 1341955 N/A N/A 12496 12511 AATTCACCTTGACTAA
A.sub.ksA.sub.ksT.sub.ksT.sub.dsC.sub.ysA.sub.ds.sup.mC.sub.ds.sup.mC.sub-
.ds 0 2144
T.sub.dsT.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.ksA.sub.ksA.sub.-
k
TABLE-US-00047 TABLE 47 Inhibition of HSD17B13 RNA by modified
oligonucleotides targeting SEQ ID NO.: 1, and 2 SEQ ID SEQ ID SEQ
ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ Compound Start Stop Start
Stop Chemistry Notation % ID Number Site Site Site Site Sequence
(5' to 3') (5' to 3') inhibition NO 1245927 N/A N/A 3433 3448
AGTAGATGGTAAGTCA
A.sub.ksG.sub.ksT.sub.ksA.sub.dsG.sub.dsA.sub.dsT.sub.dsG.sub.dsG.sub.ds
86 121
T.sub.dsA.sub.dsA.sub.dsG.sub.dsT.sub.ks.sup.mC.sub.ksA.sub.k
1246023 N/A N/A 5046 5061 GAGTGAATCATTCAGT
G.sub.ksA.sub.ksG.sub.ksT.sub.dsG.sub.dsA.sub.dsA.sub.dsT.sub.ds.sup.mC.s-
ub.ds 87 1526
A.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ksG.sub.ksT.sub.k
1341649 1314 1329 21129 21144 CAGTCTTAAACCTTCC
.sup.mC.sub.ksA.sub.ksG.sub.ksT.sub.dsC.sub.ysT.sub.dsT.sub.dsA.sub.dsA.s-
ub.ds 59 30
A.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ks.sup.mC.sub.ks.s-
up.mC.sub.k 1341652 1318 1333 21133 21148 TGAACAGTCTTAAACC
T.sub.ksG.sub.ksA.sub.ksA.sub.dsC.sub.ysA.sub.dsG.sub.dsT.sub.ds.sup.mC.s-
ub.ds 57 344
T.sub.dsT.sub.dsA.sub.dsA.sub.dsA.sub.ks.sup.mCk.sup.mC.sub.k
1341655 1256 1271 21071 21086 GCTTUTGTCCACCTTT
G.sub.ks.sup.mC.sub.ksT.sub.ksT.sub.dsU.sub.ysT.sub.dsG.sub.dsT.sub.ds.su-
p.mC.sub.ds 75 2845
.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub.ksT.sub.ksT.-
sub.k 1341666 1309 1324 21124 21139 TTAAACCTTCCCTGTG
T.sub.ksT.sub.ksA.sub.ksA.sub.dsA.sub.ys.sup.mC.sub.ds.sup.mC.sub.dsT.sub-
.ds 23 2807
T.sub.ds.sup.mC.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.ksT.-
sub.ksG.sub.k 1341669 1326 1341 21141 21156 ATGCUACTTGAACAGT
A.sub.ksT.sub.ksG.sub.ks.sup.mG.sub.dsU.sub.ysA.sub.ds.sup.mC.sub.dsT.sub-
.ds 46 2846
T.sub.dsG.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.ksG.sub.ksT.sub.-
k 1341671 1330 1345 21145 21160 TGGAATGCTACTTGAA
T.sub.ksG.sub.ksG.sub.ksA.sub.dsA.sub.ysT.sub.dsG.sub.ds.sup.mC.sub.dsT.s-
ub.ds 79 2203
A.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsG.sub.ksA.sub.ksA.sub.k
1341673 1336 1351 21151 21166 ACAGATTGGAATGCTA
A.sub.ks.sup.mC.sub.ksA.sub.ksG.sub.dsA.sub.ysT.sub.dsT.sub.dsG.sub.dsG.s-
ub.ds 70 1668
A.sub.dsA.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.ksT.sub.ksA.sub.k
1341674 1322 1337 21137 21152 TACTUGAACAGTCTTA
T.sub.ksA.sub.ks.sup.mC.sub.ksT.sub.dsU.sub.ysG.sub.dsA.sub.dsA.sub.ds
38 2847
.sup.mC.sub.dsA.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.ksT.sub.ks-
A.sub.k 1341686 1344 1359 21159 21174 GCATGGCTACAGATTG
G.sub.ks.sup.mC.sub.ksA.sub.ksT.sub.dsG.sub.ysG.sub.ds.sup.mC.sub.dsT.sub-
.ds 76 267
A.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.dsA.sub.dsT.sub.ksT.sub.ksG.sub.-
k 1341689 1354 1369 21169 21184 ATATUCTGTGGCATGG
A.sub.ksT.sub.ksA.sub.ksT.sub.dsU.sub.ys.sup.mC.sub.dsT.sub.dsG.sub.dsT.s-
ub.ds 63 2848
G.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.ksG.sub.ksG.sub.k
1341693 1358 1373 21173 21188 GTTGATATTCTGTGGC
G.sub.ksT.sub.ksT.sub.ksG.sub.dsA.sub.ysT.sub.dsA.sub.dsT.sub.dsT.sub.ds
68 1280
.sup.mC.sub.dsT.sub.dsG.sub.dsT.sub.dsG.sub.ksG.sub.ks.sup.mC.sub.k
1341694 1349 1364 21164 21179 CTGTGGCATGGCTACA
.sup.mC.sub.ksT.sub.ksG.sub.ksT.sub.dsG.sub.ysG.sub.ds.sup.mC.sub.dsA.sub-
.ds 35 657
T.sub.dsG.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.ks.sup.mC.sub.ks-
A.sub.k 1341701 1389 1404 21204 21219 TCTCUTAGCTGTGCAC
T.sub.ks.sup.mC.sub.ksT.sub.ks.sup.mC.sub.dsU.sub.ysT.sub.dsA.sub.dsG.sub-
.ds 49 2849
.sup.mC.sub.dsT.sub.dsG.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.ksA.sub.ks-
.sup.mC.sub.k 1341706 1367 1382 21182 21197 TGTGUTCTTGTTGATA
T.sub.ksG.sub.ksT.sub.ksG.sub.dsU.sub.ysT.sub.ds.sup.mC.sub.dsT.sub.dsT.s-
ub.ds 41 2850
G.sub.dsT.sub.dsT.sub.dsG.sub.dsA.sub.ksT.sub.ksA.sub.k 1341707 698
713 12116 12131 GAGACATGAGGTTTTG
G.sub.ksA.sub.ksG.sub.ksA.sub.dsC.sub.ysA.sub.dsT.sub.dsG.sub.dsA.sub.ds
61 725 G.sub.dsG.sub.dsT.sub.dsT.sub.dsT.sub.ksT.sub.ksG.sub.k
1341708 1395 1410 21210 21225 ACTTGATCTCTTAGCT
A.sub.ks.sup.mC.sub.ksT.sub.ksT.sub.dsG.sub.ysA.sub.dsT.sub.ds.sup.mC.sub-
.ds 39 813
T.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.dsG.sub.ks.sup.mC.sub.ks-
T.sub.k 1341709 1418 1433 21233 21248 TTGAGATAAAGCTGCC
T.sub.ksT.sub.ksG.sub.ksA.sub.dsG.sub.ysA.sub.dsT.sub.dsA.sub.dsA.sub.ds
51 1670
A.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.ks.sup.mC.sub.ks.sup.mC.-
sub.k 1341717 1422 1437 21237 21252 CAGGUTGAGATAAAGC
.sup.mC.sub.ksA.sub.ksG.sub.ksG.sub.dsU.sub.ysT.sub.dsG.sub.dsA.sub.ds
55 2851
G.sub.dsA.sub.dsT.sub.dsA.sub.dsA.sub.dsA.sub.ksG.sub.ks.sup.mC.sub.-
k 1341722 1466 1481 21281 21296 AGAGGCTAGGGAAATC
A.sub.ksG.sub.ksA.sub.ksG.sub.dsG.sub.ys.sup.mC.sub.dsT.sub.dsA.sub.ds
48 1048
G.sub.dsG.sub.dsG.sub.dsA.sub.dsA.sub.dsA.sub.ksT.sub.ks.sup.mC.sub.-
k 1341723 1429 1444 21244 21259 ATATGTCCAGGTTGAG
A.sub.ksT.sub.ksA.sub.ksT.sub.dsG.sub.ysT.sub.ds.sup.mC.sub.ds.sup.mC.sub-
.ds 48 425
A.sub.dsG.sub.dsG.sub.dsT.sub.dsT.sub.dsG.sub.ksA.sub.ksG.sub.k
1341733 1491 1506 21306 21321 ACCGUTTTGGGCTAAT
A.sub.ks.sup.mC.sub.ks.sup.mC.sub.ksG.sub.dsU.sub.ysT.sub.dsT.sub.dsT.sub-
.ds 65 2852
G.sub.dsG.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.ksA.sub.ksT.sub.-
k 1341737 1495 1510 21310 21325 TTGCACCGTTTTGGGC
T.sub.ksT.sub.ksG.sub.ks.sup.mC.sub.dsA.sub.ys.sup.mC.sub.ds.sup.mC.sub.d-
sG.sub.ds 50 1749
T.sub.dsT.sub.dsT.sub.dsT.sub.dsG.sub.dsG.sub.ksG.sub.ks.sup.mC.sub.-
k 1341740 1499 1514 21314 21329 AGAGUTGCACCGTTTT
A.sub.ksG.sub.ksA.sub.ksG.sub.dsU.sub.ysT.sub.dsG.sub.ds.sup.mC.sub.ds
68 2853
A.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsG.sub.dsT.sub.dsT.sub.ksT.sub.ks-
T.sub.k 1341741 1624 1639 21439 21454 ATAGAGTCGGTCACCT
A.sub.ksT.sub.ksA.sub.ksG.sub.dsA.sub.ysG.sub.dsT.sub.ds.sup.mC.sub.dsG.s-
ub.ds 50 584
G.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ks.sup.mC.sub.ksT.-
sub.k 1341742 1600 1615 21415 21430 GTATCTTATAAGACTA
G.sub.ksT.sub.ksA.sub.ksT.sub.dsC.sub.ysT.sub.dsT.sub.dsA.sub.dsT.sub.ds
79 1595
A.sub.dsA.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.ksT.sub.ksA.sub.k
1341751 1616 1631 21431 21446 GGTCACCTTTCATAAT
G.sub.ksG.sub.ksT.sub.ks.sup.mC.sub.dsA.sub.ys.sup.mC.sub.ds.sup.mC.sub.d-
sT.sub.ds 48 1985
T.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.dsA.sub.ksA.sub.ksT.sub.-
k 1341756 798 813 15679 15694 TTCCATCTATCAGACT
T.sub.ksT.sub.ks.sup.mC.sub.ks.sup.mC.sub.dsA.sub.ysT.sub.ds.sup.mC.sub.d-
sT.sub.ds 38 571
A.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.dsA.sub.ks.sup.mC.sub.ks-
T.sub.k 1341757 1620 1635 21435 21450 AGTCGGTCACCTTTCA
A.sub.ksG.sub.ksT.sub.ks.sup.mC.sub.dsG.sub.ysG.sub.dsT.sub.ds.sup.mC.sub-
.ds 61 272
A.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsT.sub.ks.sup.mC.-
sub.ksA.sub.k 1341760 1712 1727 21527 21542 ACATCTCTGGGACCAA
A.sub.ks.sup.mC.sub.ksA.sub.ksT.sub.dsC.sub.ysT.sub.ds.sup.mC.sub.dsT.sub-
.ds 68 195
G.sub.dsG.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksA.sub.ks-
A.sub.k 1341765 1628 1643 21443 21458 TAAAATAGAGTCGGTC
T.sub.ksA.sub.ksA.sub.ksA.sub.dsA.sub.ysT.sub.dsA.sub.dsG.sub.dsA.sub.ds
52 895
G.sub.dsT.sub.ds.sup.mC.sub.dsG.sub.dsG.sub.ksT.sub.ks.sup.mC.sub.k
1341770 1721 1736 21536 21551 ATTGUCTAAACATCTC
A.sub.ksT.sub.ksT.sub.ksG.sub.dsU.sub.ys.sup.mC.sub.dsT.sub.dsA.sub.dsA.s-
ub.ds 73 2854
A.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.ksT.sub.ks.sup.mC.-
sub.k 1341771 1716 1731 21531 21546 CTAAACATCTCTGGGA
.sup.mC.sub.ksT.sub.ksA.sub.ksA.sub.dsA.sub.ys.sup.mC.sub.dsA.sub.dsT.sub-
.ds 32 2259
.sup.mC.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.dsG.sub.ksG.sub.ks-
A.sub.k 1341776 1707 1722 21522 21537 TCTGGGACCAAGGATA
T.sub.ks.sup.mC.sub.ksT.sub.ksG.sub.dsG.sub.ysG.sub.dsA.sub.ds.sup.mC.sub-
.ds 31 1830
.sup.mC.sub.dsA.sub.dsA.sub.dsG.sub.dsG.sub.dsA.sub.ksT.sub.ksA.sub.-
k 1341779 1752 1767 21567 21582 TCCTGTGTTAGCTTTA
T.sub.ks.sup.mC.sub.ks.sup.mC.sub.ksT.sub.dsG.sub.ysT.sub.dsG.sub.dsT.sub-
.ds 72 1442
T.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ksT.sub.ksA.sub.-
k 1341784 1771 1786 21586 21601 TAGCCAGTACAGTTCC
T.sub.ksA.sub.ksG.sub.ks.sup.mC.sub.dsC.sub.ysA.sub.dsG.sub.dsT.sub.dsA.s-
ub.ds 70 1987
.sup.mC.sub.dsA.sub.dsG.sub.dsT.sub.dsT.sub.ks.sup.mC.sub.ks.sup.mC.-
sub.k 1341791 1784 1799 21599 21614 GTTTCTTATGTAATAG
G.sub.ksT.sub.ksT.sub.ksT.sub.dsC.sub.ysT.sub.dsT.sub.dsA.sub.dsT.sub.ds
25 897 G.sub.dsT.sub.dsA.sub.dsA.sub.dsT.sub.ksA.sub.ksG.sub.k
1341795 1776 1791 21591 21606 TGTAATAGCCAGTACA
T.sub.ksG.sub.ksT.sub.ksA.sub.dsA.sub.ysT.sub.dsA.sub.dsG.sub.ds.sup.mC.s-
ub.ds 40 352
.sup.mC.sub.dsA.sub.dsG.sub.dsT.sub.dsA.sub.ks.sup.mC.sub.ksA.sub.k
1341797 1780 1795 21595 21610 CTTAUGTAATAGCCAG
.sup.mC.sub.ksT.sub.ksT.sub.ksA.sub.dsU.sub.ysG.sub.dsT.sub.dsA.sub.dsA.s-
ub.ds 75 2855
T.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksA.sub.ksG.sub.k
1341799 2196 2211 22011 22026 GATTAGTCTTGATGTA
G.sub.ksA.sub.ksT.sub.ksT.sub.dsA.sub.ysG.sub.dsT.sub.dsmG.sub.dsT.sub.ds
45 1521 T.sub.dsG.sub.dsA.sub.dsT.sub.dsG.sub.ksT.sub.ksA.sub.k
1341804 2189 2204 22004 22019 CTTGATGTAGTGGGAG
.sup.mG.sub.ksT.sub.ksT.sub.ksG.sub.dsA.sub.ysT.sub.dsG.sub.dsT.sub.dsA.s-
ub.ds 67 976
G.sub.dsT.sub.dsG.sub.dsG.sub.dsG.sub.ksA.sub.ksG.sub.k 1341808
2353 2368 22168 22183 ATAACTACAAGAGGTT
A.sub.ksT.sub.ksA.sub.ksA.sub.dsC.sub.ysT.sub.dsA.sub.ds.sup.mC.sub.dsA.s-
ub.ds 61 1133
A.sub.dsG.sub.dsA.sub.dsG.sub.dsG.sub.ksT.sub.ksT.sub.k 1341813
2252 2267 22067 22082 AGAGGATAGTCCATGC
A.sub.ksG.sub.ksA.sub.ksG.sub.dsG.sub.ysA.sub.dsT.sub.dsA.sub.dsG.sub.ds
53 354
T.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.ksG.sub.ks.sup.mC.-
sub.k 1341818 610 625 N/A N/A GAACAATATGGGATGA
G.sub.ksA.sub.ksA.sub.ks.sup.mC.sub.dsA.sub.ysA.sub.dsT.sub.dsA.sub.dsT.s-
ub.ds 50 1735
G.sub.dsG.sub.dsG.sub.dsA.sub.dsT.sub.ksG.sub.ksA.sub.k 1341823 N/A
N/A 9516 9531 ACACUAATATTGAGGC
A.sub.ks.sup.mC.sub.ksA.sub.ks.sup.mC.sub.dsU.sub.ysA.sub.dsA.sub.dsT.sub-
.ds 43 2856
A.sub.dsT.sub.dsT.sub.dsG.sub.dsA.sub.dsG.sub.ksG.sub.ks.sup.mC.sub.-
k 1341824 810 825 15691 15706 TATTGGTAAGTATTCC
T.sub.ksA.sub.ksT.sub.ksT.sub.dsG.sub.ysG.sub.dsT.sub.dsA.sub.dsA.sub.ds
41 1272
G.sub.dsT.sub.dsA.sub.dsT.sub.dsT.sub.ks.sup.mC.sub.ks.sup.mC.sub.k
1341826 N/A N/A 9334 9349 CGATCCTATATACATC
.sup.mC.sub.ksG.sub.ksA.sub.ksT.sub.dsC.sub.ys.sup.mC.sub.dsT.sub.dsA.sub-
.ds 28 2788
T.sub.dsA.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.ksT.sub.ks.sup.m-
C.sub.k 1341835 N/A N/A 9968 9983 AGTAGTGTAAGCTGAG
A.sub.ksG.sub.ksT.sub.ksA.sub.dsG.sub.ysT.sub.dsG.sub.dsT.sub.dsA.sub.ds
68 2155
A.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.ksA.sub.ksG.sub.k
1341837 N/A N/A 9603 9618 CACAUATGTGAAGAGC
.sup.mCkSA.sub.ks.sup.mC.sub.ksA.sub.dsU.sub.ysA.sub.dsT.sub.dsG.sub.ds
65 2857
T.sub.dsG.sub.dsA.sub.dsA.sub.dsG.sub.dsA.sub.ksG.sub.ks.sup.mC.sub.-
k 1341843 N/A N/A 11568 11583 TGACAATGGTTGATAG
T.sub.ksG.sub.ksA.sub.ks.sup.mC.sub.dsA.sub.ysA.sub.dsT.sub.dsG.sub.dsG.s-
ub.ds 42 1700
T.sub.dsT.sub.dsG.sub.dsA.sub.dsT.sub.ksA.sub.ksG.sub.k 1341844 N/A
N/A 11853 11868 AGCAGAATTGTGAACG
A.sub.ksG.sub.ks.sup.mC.sub.ksA.sub.dsG.sub.ysA.sub.dsA.sub.dsT.sub.dsT.s-
ub.ds 51 844
G.sub.dsT.sub.dsG.sub.dsA.sub.dsA.sub.ks.sup.mC.sub.ksG.sub.k
1341848 N/A N/A 12421 12436 TGGTAACGGTGATCAA
T.sub.ksG.sub.ksG.sub.ksT.sub.dsA.sub.ysA.sub.ds.sup.mC.sub.dsG.sub.dsG.s-
ub.ds 41 67
T.sub.dsG.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.ksA.sub.ksA.sub.k
1341854 N/A N/A 14199 14214 TATTATGTGATTGAGT
T.sub.ksA.sub.ksT.sub.ksT.sub.dsA.sub.ysT.sub.dsG.sub.dsT.sub.dsG.sub.ds
28 73 A.sub.dsT.sub.dsT.sub.dsG.sub.dsA.sub.ksG.sub.ksT.sub.k
1341858 N/A N/A 14918 14933 TAATACATTAGCAAGC
T.sub.ksA.sub.ksA.sub.ksT.sub.dsA.sub.ys.sup.mC.sub.dsA.sub.dsT.sub.dsT.s-
ub.ds 26 2266
A.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.ksG.sub.ks.sup.mC.sub.k
1341865 1019 1034 20834 20849 TGCAGCATTGATTCGA
T.sub.ksG.sub.ks.sup.mC.sub.ksA.sub.dsG.sub.ys.sup.mC.sub.dsA.sub.ds
65 419
T.sub.dsT.sub.dsG.sub.dsA.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ksG.sub.-
ksA.sub.k 1341866 N/A N/A 15498 15513 TGCTGCATTAATGCCA
T.sub.ksG.sub.ks.sup.mC.sub.ksT.sub.dsG.sub.ys.sup.mC.sub.dsA.sub.dsT.sub-
.ds 32 2485
T.sub.dsA.sub.dsA.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.ks.sup.mC.sub.ks-
A.sub.k 1341869 N/A N/A 16129 16144 TCCAUAATAATAGCTC
T.sub.ks.sup.mC.sub.ks.sup.mC.sub.ksA.sub.dsU.sub.ysA.sub.dsA.sub.dsT.sub-
.ds 58 2858
A.sub.dsA.sub.dsT.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.ksT.sub.ks.sup.m-
C.sub.k 1341872 N/A N/A 16292 16307 TTAGUTAGAATAGTCT
T.sub.ksT.sub.ksA.sub.ksG.sub.dsU.sub.ysT.sub.dsA.sub.dsG.sub.dsA.sub.ds
35 2859 A.sub.dsT.sub.dsA.sub.dsGdST.sub.ks.sup.mC.sub.ksT.sub.k
1341875 N/A N/A 16223 16238 CTTTUTATAGACTGGG
.sup.mC.sub.ksT.sub.ksT.sub.ksT.sub.dsU.sub.ysT.sub.dsA.sub.dsT.sub.dsA.s-
ub.ds 34 2860
G.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.ksG.sub.ksG.sub.k
1341879 N/A N/A 17990 18005 TTAGUATAGTTATCTT
T.sub.ksT.sub.ksA.sub.ksG.sub.dsU.sub.ysA.sub.dsT.sub.dsA.sub.dsG.sub.ds
22 2861
T.sub.dsT.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.ksT.sub.ksT.sub.k
1341881 N/A N/A 17995 18010 TGAAGTTAGTATAGTT
T.sub.ksG.sub.ksA.sub.ksA.sub.dsG.sub.ysT.sub.dsT.sub.dsA.sub.dsG.sub.ds
62 1405 T.sub.dsA.sub.dsT.sub.dsA.sub.dsG.sub.ksT.sub.ksT.sub.k
1341884 N/A N/A 16384 16399 AATCCCAACCAAACTT
A.sub.ksA.sub.ksT.sub.ksm.sub.dsC.sub.ysm.sub.dsA.sub.dsA.sub.ds 7
2755
.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.ksT.-
sub.ksT.sub.k 1341888 N/A N/A 18095 18110 AATTGATACACCAATG
A.sub.ksA.sub.ksT.sub.ksT.sub.dsG.sub.ysA.sub.dsT.sub.dsA.sub.ds.sup.mC.s-
ub.ds 40 2525
A.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.ksT.sub.ksG.sub.k
1341897 1084 1099 20899 20914 CTGCUGCTAGTGCCAA
.sup.mC.sub.ksT.sub.ksG.sub.ks.sup.mC.sub.dsU.sub.ysG.sub.ds.sup.mC.sub.d-
sT.sub.ds 66 2862
A.sub.dsG.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksA.sub.ks-
A.sub.k 1341902 N/A N/A 19913 19928 GTGCATCTTAAGATAC
G.sub.ksT.sub.ksG.sub.ks.sup.mC.sub.dsA.sub.ysT.sub.ds.sup.mC.sub.dsT.sub-
.ds 40 2806
T.sub.dsA.sub.dsA.sub.dsG.sub.dsA.sub.dsT.sub.ksA.sub.ks.sup.mC.sub.-
k 1341906 N/A N/A 18693 18708 AGACUTTGAGACTCTT
A.sub.ksG.sub.ksA.sub.ks.sup.mC.sub.dsU.sub.ysT.sub.dsT.sub.dsG.sub.dsA.s-
ub.ds 48 2863
G.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.ds.sup.mC.sub.ksT.sub.ksT.sub.k
1341909 N/A N/A 19909 19924 ATCTUAAGATACCCAG
A.sub.ksT.sub.ks.sup.mC.sub.ksT.sub.dsU.sub.ysA.sub.dsA.sub.dsG.sub.dsA.s-
ub.ds 55 2864
T.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksA.sub.ksG.-
sub.k 1341911 1080 1095 20895 20910 TGCTAGTGCCAAACCA
T.sub.ksG.sub.ks.sup.mC.sub.ksT.sub.dsA.sub.ysG.sub.dsT.sub.dsG.sub.ds
80 1432
.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.ks.s-
up.mC.sub.ksA.sub.k 1341912 N/A N/A 19905 19920 TAAGATACCCAGGTTG
T.sub.ksA.sub.ksA.sub.ksG.sub.dsA.sub.ysT.sub.dsA.sub.ds.sup.mC.sub.ds
11 2790
.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.dsG.sub.dsT.sub.ksT.sub.ks-
G.sub.k 1341922 N/A N/A 20114 20129 GCATCAAGACATTCTA
G.sub.ks.sup.mC.sub.ksA.sub.ksT.sub.dsC.sub.ysA.sub.dsA.sub.dsG.sub.ds
51 1565 A
.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ksT.sub.k-
sA.sub.k 1341926 N/A N/A 19999 20014 CAGTUTTCCTCATGAT
.sup.mC.sub.ksA.sub.ksG.sub.ksT.sub.dsU.sub.ysT.sub.dsT.sub.ds.sup.mC.sub-
.ds 0 2865
.sup.mC.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.dsG.sub.ksA.sub.ks-
T.sub.k 1341932 1076 1091 20891 20906 AGTGCCAAACCAATGT
A.sub.ksG.sub.ksT.sub.ksG.sub.dsC.sub.ysC.sub.dsA.sub.dsA.sub.ds 24
1120
A.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsT.sub.ksG.sub.ks-
T.sub.k 1341933 N/A N/A 20388 20403 CTATAGTAATCACAAG
.sup.mC.sub.ksT.sub.ksA.sub.ksT.sub.dsA.sub.ysG.sub.dsT.sub.dsA.sub.dsA.s-
ub.ds 37 1644
T.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.ksA.sub.ksG.sub.k
1341935 N/A N/A 20190 20205 AGTTATTAGAAGTCAG
A.sub.ksG.sub.ksT.sub.ksT.sub.dsA.sub.ysT.sub.dsT.sub.dsA.sub.dsG.sub.ds
25 2746
A.sub.dsA.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.ksA.sub.ksG.sub.k
1341938 N/A N/A 20378 20393 CACAAGTAAGGTAAAG
.sup.mC.sub.ksA.sub.ks.sup.mC.sub.ksA.sub.dsA.sub.ysG.sub.dsT.sub.dsA.sub-
.ds 43 2448
A.sub.dsG.sub.dsG.sub.dsT.sub.dsA.sub.dsA.sub.ksA.sub.ksG.sub.k
1341944 N/A N/A 20484 20499 CTTCATAGTGGACTTC
.sup.mC.sub.ksT.sub.ksT.sub.ks.sup.mC.sub.dsA.sub.ysT.sub.dsA.sub.dsG.sub-
.ds 35 711
T.sub.dsG.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.ksT.sub.ks.sup.m-
C.sub.k 1341952 N/A N/A 12804 12819 CTCAGGCTGTAAGAGT
.sup.mC.sub.ksT.sub.ks.sup.mC.sub.ksA.sub.dsG.sub.ysG.sub.ds.sup.mC.sub.d-
sT.sub.ds 46 2240
G.sub.dsT.sub.dsA.sub.dsA.sub.dsG.sub.dsA.sub.ksG.sub.ksT.sub.k
1341956 N/A N/A 12499 12514 AGAAATTCACCTTGAC
A.sub.ksG.sub.ksA.sub.ksA.sub.dsA.sub.ysT.sub.dsT.sub.ds.sup.mC.sub.dsA.s-
ub.ds 9 2284
.sup.mC.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsG.sub.ksA.sub.ks.sup.mC.-
sub.k
TABLE-US-00048 TABLE 48 Inhibition of HSD17B13 RNA by modified
oligonucleotides targeting SEQ ID NO.: 1, and 2 SEQ ID SEQ ID SEQ
ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 Compound Start Stop Start Stop
Chemistry Notation % SEQ Number Site Site Site Site Sequence (5' to
3') (5' to 3') inhibition ID NO 1245927 N/A N/A 3433 3448
AGTAGATGGTAAGTCA
A.sub.ksG.sub.ksT.sub.ksA.sub.dsG.sub.dsA.sub.dsT.sub.dsG.sub.dsG.sub.ds
82 121
T.sub.dsA.sub.dsA.sub.dsG.sub.dsT.sub.ks.sup.mC.sub.ksA.sub.k
1246023 N/A N/A 5046 5061 GAGTGAATCATTCAGT
G.sub.ksA.sub.ksG.sub.ksT.sub.dsG.sub.dsA.sub.dsA.sub.dsT.sub.ds.sup.mC.s-
ub.ds 86 1526
A.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ksG.sub.ksT.sub.k
1341651 1315 1330 21130 21145 ACAGUCTTAAACCTTC
A.sub.ks.sup.mC.sub.ksA.sub.ksG.sub.dsU.sub.ys.sup.mC.sub.dsT.sub.dsT.sub-
.ds 81 2866
A.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub.ksT.sub.ks-
.sup.mC.sub.k 1341656 1257 1272 21072 21087 AGCTUTTGTCCACCTT
A.sub.ksG.sub.ks.sup.mC.sub.ksT.sub.dsU.sub.ysT.sub.dsT.sub.dsG.sub.dsT.s-
ub.ds 72 2867
.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksT.su-
b.ksT.sub.k 1341657 613 628 N/A N/A CTGGAACAATATGGGA
.sup.mC.sub.ksT.sub.ksG.sub.ksG.sub.dsA.sub.ysA.sub.ds.sup.mC.sub.dsA.sub-
.ds 45 1969
A.sub.dsT.sub.dsA.sub.dsT.sub.dsG.sub.dsG.sub.dsG.sub.ksA.sub.k
1341659 1327 1342 21142 21157 AATGCTACTTGAACAG
A.sub.ksA.sub.ksT.sub.ksG.sub.dsC.sub.ysT.sub.dsA.sub.ds.sup.mC.sub.dsT.s-
ub.ds 34 1045
T.sub.dsG.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.ksA.sub.ksG.sub.k
1341662 1319 1334 21134 21149 TTGAACAGTCTTAAAC
T.sub.ksT.sub.ksG.sub.ksA.sub.dsA.sub.ys.sup.mC.sub.dsA.sub.dsG.sub.dsT.s-
ub.ds 11 422
.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.dsA.sub.ksA.sub.ks.sup.mC.sub.k
1341665 1310 1325 21125 21140 CTTAAACCTTCCCTGT
.sup.mC.sub.ksT.sub.ksT.sub.ksA.sub.dsA.sub.ysA.sub.ds.sup.mC.sub.ds.sup.-
mC.sub.ds 24 1823
T.sub.dsT.sub.ds.sup.mC.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub.ksG.-
sub.ksT.sub.k 1341675 1323 1338 21138 21153 CTACUTGAACAGTCTT
.sup.mC.sub.ksT.sub.ksA.sub.ks.sup.mC.sub.dsU.sub.ysT.sub.dsG.sub.dsA.sub-
.ds 79 2868
A.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.ksT.sub.ks-
T.sub.k 1341679 1355 1370 21170 21185 GATAUTCTGTGGCATG
GsA.sub.ksT.sub.ksA.sub.dsU.sub.ysT.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.ds
60 2869
T.sub.dsG.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.ksT.sub.ksG.sub.k
1341681 1337 1352 21152 21167 TACAGATTGGAATGCT
T.sub.ksA.sub.ks.sup.mC.sub.ksA.sub.dsG.sub.ysA.sub.dsT.sub.dsT.sub.dsG.s-
ub.ds 60 1746
G.sub.dsA.sub.dsA.sub.dsT.sub.dsG.sub.ks.sup.mC.sub.ksT.sub.k
1341682 700 715 12118 12133 CAGAGACATGAGGTTT
.sup.mC.sub.ksA.sub.ksG.sub.ksA.sub.dsG.sub.ysA.sub.ds.sup.mC.sub.dsA.sub-
.ds 61 2319
T.sub.dsG.sub.dsA.sub.dsG.sub.dsG.sub.dsT.sub.ksT.sub.ksT.sub.k
1341684 1331 1346 21146 21161 TTGGAATGCTACTTGA
T.sub.ksT.sub.ksG.sub.ksG.sub.dsA.sub.ysA.sub.dsT.sub.dsG.sub.ds.sup.mC.s-
ub.ds 65 1279
T.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ksG.sub.ksA.sub.k
1341687 1346 1361 21161 21176 TGGCATGGCTACAGAT
T.sub.ksG.sub.ksG.sub.ks.sup.mC.sub.dsA.sub.ysT.sub.dsG.sub.dsG.sub.ds
57 423
.sup.mC.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.ksA.sub.ks-
T.sub.k 1341688 1359 1374 21174 21189 TGTTGATATTCTGTGG
T.sub.ksG.sub.ksT.sub.ksT.sub.dsG.sub.ysA.sub.dsT.sub.dsA.sub.dsT.sub.ds
48 1358 T.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.dsTkSG.sub.ksG.sub.k
1341695 1351 1366 21166 21181 TTCTGTGGCATGGCTA
T.sub.ksT.sub.ks.sup.mC.sub.ksT.sub.dsG.sub.ysT.sub.dsG.sub.dsG.sub.ds.su-
p.mC.sub.ds 65 812
A.sub.dsT.sub.dsG.sub.dsG.sub.dsmG.sub.ksT.sub.ksA.sub.k 1341700
1384 1399 21199 21214 TAGCUGTGCACTCATT
T.sub.ksA.sub.ksG.sub.ks.sup.mC.sub.dsU.sub.ysG.sub.dsT.sub.dsG.sub.ds
60 2870
.sup.mC.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ksT.-
sub.ksT.sub.k 1341704 1391 1406 21206 21221 GATCUCTTAGCTGTGC
G.sub.ksA.sub.ksT.sub.ks.sup.mC.sub.dsU.sub.ys.sup.mC.sub.dsT.sub.dsT.sub-
.ds 65 2871
A.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.dsT.sub.ksG.sub.ks.sup.m-
C.sub.k 1341710 1419 1434 21234 21249 GTTGAGATAAAGCTGC
G.sub.ksT.sub.ksT.sub.ksG.sub.dsA.sub.ysG.sub.dsA.sub.dsT.sub.dsA.sub.ds
51 1748
A.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.ksG.sub.ks.sup.mC.sub.k
1341712 1423 1438 21238 21253 CCAGGTTGAGATAAAG
.sup.mC.sub.ks.sup.mC.sub.ksA.sub.ksG.sub.dsG.sub.ysT.sub.dsT.sub.dsG.sub-
.ds 49 33
A.sub.dsG.sub.dsA.sub.dsT.sub.dsA.sub.dsA.sub.ksA.sub.ksG.sub.k
1341715 1398 1413 21213 21228 GAAACTTGATCTCTTA
G.sub.ksA.sub.ksA.sub.ksA.sub.dsC.sub.ysT.sub.dsT.sub.dsG.sub.dsA.sub.ds
59 2717
T.sub.ds.sup.mC.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.ksT.sub.ksA.sub.k
1341720 1496 1511 21311 21326 GTTGCACCGTTTTGGG
G.sub.ksT.sub.ksT.sub.ksG.sub.dsC.sub.ysA.sub.ds.sup.mC.sub.ds.sup.mC.sub-
.ds 38 1827
G.sub.dsT.sub.dsT.sub.dsT.sub.dsT.sub.dsG.sub.ksG.sub.ksG.sub.k
1341724 1431 1446 21246 21261 AAATATGTCCAGGTTG
A.sub.ksA.sub.ksA.sub.ksT.sub.dsA.sub.ysT.sub.dsG.sub.dsT.sub.ds.sup.mC.s-
ub.ds 63 581
.sup.mC.sub.dsA.sub.dsG.sub.dsG.sub.dsT.sub.ksT.sub.ksG.sub.k
1341730 1488 1503 21303 21318 GTTTUGGGCTAATGAA
G.sub.ksT.sub.ksT.sub.ksT.sub.dsU.sub.ysG.sub.dsG.sub.dsG.sub.ds.sup.mC.s-
ub.ds 30 2872
T.sub.dsA.sub.dsA.sub.dsT.sub.dsG.sub.ksA.sub.ksA.sub.k 1341732 801
816 15682 15697 GTATUCCATCTATCAG
G.sub.ksT.sub.ksA.sub.ksT.sub.dsU.sub.ys.sup.mC.sub.ds.sup.mC.sub.dsA.sub-
.ds 41 2873
T.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.ksA.sub.ks-
G.sub.k 1341735 1492 1507 21307 21322 CACCGTTTTGGGCTAA
.sup.mC.sub.ksA.sub.ks.sup.mCks.sup.mC.sub.dsG.sub.ysT.sub.dsT.sub.dsT.su-
b.ds 82 1516
T.sub.dsG.sub.dsG.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.ksA.sub.ksA.sub.-
k 1341746 1501 1516 21316 21331 ATAGAGTTGCACCGTT
A.sub.ksT.sub.ksA.sub.ksG.sub.dsA.sub.ysG.sub.dsT.sub.dsT.sub.dsG.sub.ds
59 192
.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsG.sub.ksT.sub.ksT.-
sub.k 1341747 1602 1617 21417 21432 ATGTATCTTATAAGAC
A.sub.ksT.sub.ksG.sub.ksT.sub.dsA.sub.ysT.sub.ds.sup.mC.sub.dsT.sub.dsT.s-
ub.ds 3 1751
A.sub.dsT.sub.dsA.sub.dsA.sub.dsG.sub.ksA.sub.ks.sup.mC.sub.k
1341749 1621 1636 21436 21451 GAGTCGGTCACCTTTC
G.sub.ksA.sub.ksG.sub.ksT.sub.dsC.sub.ysG.sub.dsG.sub.dsT.sub.ds.sup.mC.s-
ub.ds 55 350
A.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ksT.sub.ks.sup.mC.-
sub.k 1341750 1625 1640 21440 21455 AATAGAGTCGGTCACC
A.sub.ksA.sub.ksT.sub.ksA.sub.dsG.sub.ysA.sub.dsG.sub.dsT.sub.ds.sup.mC.s-
ub.ds 57 662
G.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ks.sup.mC.sub.ks.sup.mC.-
sub.k 1341752 1617 1632 21432 21447 CGGTCACCTTTCATAA
.sup.mC.sub.ksG.sub.ksG.sub.ksT.sub.dsC.sub.ysA.sub.ds.sup.mC.sub.ds.sup.-
mC.sub.ds 42 36
T.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.ksA.sub.ksA.sub.-
k 1341762 1713 1728 21528 21543 AACAUCTCTGGGACCA
A.sub.ksA.sub.ks.sup.mC.sub.ksA.sub.dsU.sub.ys.sup.mC.sub.dsT.sub.ds.sup.-
mC.sub.ds 64 2874
T.sub.dsG.sub.dsG.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.ks.sup.mC.sub.ks-
A.sub.k 1341766 1629 1644 21444 21459 TTAAAATAGAGTCGGT
T.sub.ksT.sub.ksA.sub.ksA.sub.dsA.sub.ysA.sub.dsT.sub.dsA.sub.dsG.sub.ds
70 973
A.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.dsG.sub.ksG.sub.ksT.sub.k
1341769 1726 1741 21541 21556 CTAAAATTGTCTAAAC
.sup.mC.sub.ksT.sub.ksA.sub.ksA.sub.dsA.sub.ysA.sub.dsT.sub.dsT.sub.dsG.s-
ub.ds 13 2590
T.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.dsA.sub.ksA.sub.ks.sup.mC.sub.k
1341772 1717 1732 21532 21547 TCTAAACATCTCTGGG
T.sub.ks.sup.mC.sub.ksT.sub.ksA.sub.dsA.sub.ysA.sub.ds.sup.mC.sub.dsA.sub-
.ds 36 2287
T.sub.ds.sup.mC.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.ksG.sub.ks-
G.sub.k 1341775 1708 1723 21523 21538 CTCTGGGACCAAGGAT
.sup.mC.sub.ksT.sub.ks.sup.mC.sub.ksT.sub.dsG.sub.ysG.sub.dsG.sub.dsA.sub-
.ds 43 1908
.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsG.sub.dsG.sub.ksA.sub.ks-
T.sub.k 1341778 1773 1788 21588 21603 AATAGCCAGTACAGTT
A.sub.ksA.sub.ksT.sub.ksA.sub.dsG.sub.ys.sup.mC.sub.ds.sup.mC.sub.dsA.sub-
.ds 66 118
G.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.ksT.sub.ksT.sub.-
k 1341782 1766 1781 21581 21596 AGTACAGTTCCTTTTC
A.sub.ksG.sub.ksT.sub.ksA.sub.dsC.sub.ysA.sub.dsG.sub.dsT.sub.dsT.sub.ds
56 1597
.sup.mC.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsT.sub.ksT.sub.ks.sup.mC.-
sub.k 1341790 791 806 15672 15687 TATCAGACTTCTTACG
T.sub.ksA.sub.ksT.sub.ks.sup.mC.sub.dsA.sub.ysG.sub.dsA.sub.ds.sup.mC.sub-
.ds 27 103
T.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.ks.sup.mC.sub.ks-
G.sub.k 1341794 1777 1792 21592 21607 ATGTAATAGCCAGTAC
A.sub.ksT.sub.ksG.sub.ksT.sub.dsA.sub.ysA.sub.dsT.sub.dsA.sub.dsG.sub.ds
42 430
.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.dsT.sub.ksA.sub.ks.sup.mC.-
sub.k 1341798 1781 1796 21596 21611 TCTTATGTAATAGCCA
T.sub.ks.sup.mC.sub.ksT.sub.ksT.sub.dsA.sub.ysT.sub.dsG.sub.dsT.sub.dsA.s-
ub.ds 64 742
A.sub.dsT.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.ks.sup.mC.sub.ksA.sub.k
1341802 2191 2206 22006 22021 GTCTUGATGTAGTGGG
G.sub.ksT.sub.ks.sup.mC.sub.ksT.sub.dsU.sub.ysG.sub.dsA.sub.dsT.sub.dsG.s-
ub.ds 63 2875
T.sub.dsA.sub.dsG.sub.dsT.sub.dsG.sub.ksG.sub.ksG.sub.k 1341803
2184 2199 21999 22014 TGTAGTGGGAGTCGGA
T.sub.ksG.sub.ksT.sub.ksA.sub.dsG.sub.ysT.sub.dsG.sub.dsG.sub.dsG.sub.ds
50 587
A.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.dsG.sub.ksG.sub.ksA.sub.k
1341811 2355 2370 22170 22185 TTATAACTACAAGAGG
T.sub.ksT.sub.ksA.sub.ksT.sub.dsA.sub.ysA.sub.ds.sup.mC.sub.dsT.sub.dsA.s-
ub.ds 58 1289
.sup.mC.sub.dsA.sub.dsA.sub.dsG.sub.dsA.sub.ksG.sub.ksG.sub.k
1341812 812 827 15693 15708 CTTAUTGGTAAGTATT
.sup.mC.sub.ksT.sub.ksT.sub.ksA.sub.dsU.sub.ysT.sub.dsG.sub.dsG.sub.dsT.s-
ub.ds 0 2876
A.sub.dsA.sub.dsG.sub.dsT.sub.dsA.sub.ksT.sub.ksT.sub.k 1341814
2254 2269 22069 22084 CAAGAGGATAGTCCAT
.sup.mC.sub.ksA.sub.ksA.sub.ksG.sub.dsA.sub.ysG.sub.dsG.sub.dsA.sub.dsT.s-
ub.ds 60 510
A.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksA.sub.ksT.sub.k
1341815 2245 2260 22060 22075 AGTCCATGCAAAAGCA
A.sub.ksG.sub.ksT.sub.ks.sup.mC.sub.dsC.sub.ysA.sub.dsT.sub.dsG.sub.ds
73 120
.sup.mC.sub.dsA.sub.dsA.sub.dsA.sub.dsA.sub.dsG.sub.ks.sup.mC.sub.ks-
A.sub.k 1341819 N/A N/A 9337 9352 CCTCGATCCTATATAC
.sup.mC.sub.ks.sup.mC.sub.ksT.sub.ks.sup.mC.sub.dsG.sub.ysA.sub.dsT.sub.d-
s.sup.mC.sub.ds 9 2812
mC.sub.dsT.sub.dsA.sub.dsT.sub.dsA.sub.dsT.sub.ksA.sub.ks.sup.mC.sub-
.k 1341821 N/A N/A 9518 9533 CTACACTAATATTGAG
.sup.mC.sub.ksT.sub.ksA.sub.ks.sup.mC.sub.dsA.sub.ys.sup.mC.sub.dsT.sub.d-
sA.sub.ds 29 59
A.sub.dsT.sub.dsA.sub.dsT.sub.dsT.sub.dsG.sub.ksA.sub.ksG.sub.k
1341829 N/A N/A 9961 9976 TAAGCTGAGAGTTCTA
T.sub.ksA.sub.ksA.sub.ksG.sub.dsC.sub.ysT.sub.dsG.sub.dsA.sub.dsG.sub.ds
27 2499
A.sub.dsG.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ksT.sub.ksA.sub.k
1341834 N/A N/A 9971 9986 TTGAGTAGTGTAAGCT
T.sub.ksT.sub.ksG.sub.ksA.sub.dsG.sub.ysT.sub.dsA.sub.dsG.sub.dsT.sub.ds
35 2346
G.sub.dsT.sub.dsA.sub.dsA.sub.dsG.sub.ks.sup.mC.sub.ksT.sub.k
1341838 1022 1037 20837 20852 CTTTGCAGCATTGATT
.sup.mC.sub.ksT.sub.ksT.sub.ksT.sub.dsG.sub.ys.sup.mC.sub.dsA.sub.dsG.sub-
.ds 19 2463
.sup.mC.sub.dsA.sub.dsT.sub.dsT.sub.dsG.sub.dsA.sub.ksT.sub.ksT.sub.-
k 1341841 N/A N/A 11571 11586 TCTTGACAATGGTTGA
T.sub.ks.sup.mC.sub.ksT.sub.ksT.sub.dsG.sub.ysA.sub.ds.sup.mC.sub.dsA.sub-
.ds 56 2440
A.sub.dsT.sub.dsG.sub.dsG.sub.dsT.sub.dsT.sub.ksG.sub.ksA.sub.k
1341846 N/A N/A 11855 11870 TAAGCAGAATTGTGAA
T.sub.ksA.sub.ksA.sub.ksG.sub.dsC.sub.ysA.sub.dsG.sub.dsA.sub.dsA.sub.ds
26 2361 T.sub.dsT.sub.dsG.sub.dsT.sub.dsG.sub.ksA.sub.ksA.sub.k
1341849 N/A N/A 14194 14209 TGTGATTGAGTTCTCC
T.sub.ksG.sub.ksT.sub.ksG.sub.dsA.sub.ysT.sub.dsT.sub.dsG.sub.dsA.sub.ds
34 2020
G.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.ks.sup.mC.sub.ks.sup.mC.-
sub.k 1341852 N/A N/A 12423 12438 GGTGGTAACGGTGATC
G.sub.ksG.sub.ksT.sub.ksG.sub.dsG.sub.ysT.sub.dsA.sub.dsA.sub.ds.sup.mC.s-
ub.ds 35 2591
G.sub.dsG.sub.dsT.sub.dsG.sub.dsA.sub.ksT.sub.ks.sup.mC.sub.k
1341857 N/A N/A 14204 14219 CAGAUTATTATGTGAT
.sup.mC.sub.ksA.sub.ksG.sub.ksA.sub.dsU.sub.ysT.sub.dsA.sub.dsT.sub.dsT.s-
ub.ds 32 2877
A.sub.dsT.sub.dsG.sub.dsT.sub.dsG.sub.ksA.sub.ksT.sub.k 1341859 N/A
N/A 15491 15506 TTAAUGCCACCCTACC
T.sub.ksT.sub.ksA.sub.ksA.sub.dsU.sub.ysG.sub.ds.sup.mC.sub.ds.sup.mC.sub-
.ds 8 2878
A.sub.ds.sup.mC.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.ks.s-
up.mC.sub.ks.sup.mC.sub.k 1341868 N/A N/A 16282 16297
TAGTCTTCAGCAAAGT
T.sub.ksA.sub.ksG.sub.ksT.sub.dsC.sub.ysT.sub.dsT.sub.ds.sup.mC.sub.dsA.s-
ub.ds 41 2632
G.sub.ds.sup.mC.sub.dsA.sub.dsAdSA.sub.ksG.sub.ksT.sub.k 1341874
N/A N/A 16131 16146 GCTCCATAATAATAGC
G.sub.ks.sup.mC.sub.ksT.sub.ks.sup.mC.sub.dsC.sub.ysA.sub.dsT.sub.dsA.sub-
.ds 16 2665
A.sub.dsT.sub.dsA.sub.dsA.sub.dsT.sub.dsA.sub.ksG.sub.ks.sup.mC.sub.-
k 1341880 N/A N/A 17991 18006 GTTAGTATAGTTATCT
G.sub.ksT.sub.ksT.sub.ksA.sub.dsG.sub.ysT.sub.dsA.sub.dsT.sub.dsA.sub.ds
52 1171
G.sub.dsT.sub.dsT.sub.dsA.sub.dsT.sub.ks.sup.mC.sub.ksT.sub.k
1341883 N/A N/A 17996 18011 ATGAAGTTAGTATAGT
A.sub.ksT.sub.ksG.sub.ksA.sub.dsA.sub.ysG.sub.dsT.sub.dsT.sub.dsA.sub.ds
38 1483 G.sub.dsT.sub.dsA.sub.dsT.sub.dsA.sub.ksG.sub.ksT.sub.k
1341886 N/A N/A 16377 16392 ACCAAACTTCCAGCAG
A.sub.ks.sup.mC.sub.ks.sup.mC.sub.ksA.sub.dsA.sub.ysA.sub.ds.sup.mC.sub.d-
sT.sub.ds 54 1948
T.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.ksA.-
sub.ksG.sub.k 1341891 N/A N/A 18097 18112 GAAAUTGATACACCAA
G.sub.ksA.sub.ksA.sub.ksA.sub.dsU.sub.ysT.sub.dsG.sub.dsA.sub.dsT.sub.ds
58 2879
A.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksA.sub.ksA.-
sub.k 1341894 N/A N/A 17986 18001 TATAGTTATCTTCTCA
T.sub.ksA.sub.ksT.sub.ksA.sub.dsG.sub.ysT.sub.dsT.sub.dsA.sub.dsT.sub.ds
33 2295
.sup.mC.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.ks.sup.mC.sub.ksA.-
sub.k 1341899 N/A N/A 18695 18710 AAAGACTTTGAGACTC
A.sub.ksA.sub.ksA.sub.ksG.sub.dsA.sub.ys.sup.mC.sub.dsT.sub.dsT.sub.dsT.s-
ub.ds 76 1250
G.sub.dsA.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.ksT.sub.ks.sup.mC.sub.k
1341901 N/A N/A 19914 19929 AGTGCATCTTAAGATA
A.sub.ksG.sub.ksT.sub.ksG.sub.dsC.sub.ysA.sub.dsT.sub.ds.sup.mC.sub.dsT.s-
ub.ds 17 2130
T.sub.dsA.sub.dsA.sub.dsG.sub.dsA.sub.ksT.sub.ksA.sub.k 1341904
1081 1096 20896 20911 CTGCUAGTGCCAAACC
.sup.mC.sub.ksT.sub.ksG.sub.ks.sup.mC.sub.dsU.sub.ysA.sub.dsG.sub.dsT.sub-
.ds 67 2880
G.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsA.sub.ks.sup.mC.-
sub.ks.sup.mC.sub.k 1341915 N/A N/A 19906 19921 TTAAGATACCCAGGTT
T.sub.ksT.sub.ksA.sub.ksA.sub.dsG.sub.ysA.sub.dsT.sub.dsA.sub.ds.sup.mC.s-
ub.ds 30 163
.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.dsG.sub.ksT.sub.ksT.sub.k
1341917 N/A N/A 19910 19925 CATCUTAAGATACCCA
.sup.mC.sub.ksA.sub.ksT.sub.ks.sup.mC.sub.dsU.sub.ysT.sub.dsA.sub.dsA.sub-
.ds 56 2881
G.sub.dsA.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.ks.sup.mC.-
sub.ksA.sub.k 1341921 N/A N/A 20116 20131 CAGCATCAAGACATTC
.sup.mC.sub.ksA.sub.ksG.sub.ks.sup.mC.sub.dsA.sub.ysT.sub.ds.sup.mC.sub.d-
sA.sub.ds 52 2191
A.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.ksT.sub.ks.sup.m-
C.sub.k 1341925 N/A N/A 20009 20024 AGAGAGTAATCAGTTT
A.sub.ksG.sub.ksA.sub.ksG.sub.dsA.sub.ysG.sub.dsT.sub.dsA.sub.dsA.sub.ds
25 2651
T.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.dsT.sub.ksT.sub.ksT.sub.k
1341934 N/A N/A 20192 20207 GCAGUTATTAGAAGTC
G.sub.ks.sup.mC.sub.ksA.sub.ksG.sub.dsU.sub.ysT.sub.dsA.sub.dsT.sub.dsT.s-
ub.ds 59 2882
A.sub.dsG.sub.dsA.sub.dsA.sub.dsG.sub.ksT.sub.ks.sup.mC.sub.k
1341937 1077 1092 20892 20907 TAGTGCCAAACCAATG
T.sub.ksA.sub.ksG.sub.ksT.sub.dsG.sub.ys.sup.mC.sub.ds.sup.mC.sub.dsA.sub-
.ds 55 1198
A.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.ksT.sub.ks-
G.sub.k 1341939 1085 1100 20900 20915 ACTGCTGCTAGTGCCA
A.sub.ks.sup.mC.sub.ksT.sub.ksG.sub.dsC.sub.ysT.sub.dsG.sub.ds.sup.mC.sub-
.ds 64 1821
T.sub.dsA.sub.dsG.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.ks.sup.mC.sub.ks-
A.sub.k 1341943 N/A N/A 20486 20501 AACTUCATAGTGGACT
A.sub.ksA.sub.ks.sup.mC.sub.ksT.sub.dsU.sub.ys.sup.mC.sub.dsA.sub.dsT.sub-
.ds 38 2883
A.sub.dsG.sub.dsT.sub.dsG.sub.dsG.sub.dsA.sub.ks.sup.mC.sub.ksT.sub.-
k 1341945 N/A N/A 20422 20437 ACAGUAAAATTATGCC
A.sub.ks.sup.mC.sub.ksA.sub.ksG.sub.dsU.sub.ysA.sub.dsA.sub.dsA.sub.ds
24 2884
A.sub.dsT.sub.dsT.sub.dsA.sub.dsT.sub.dsG.sub.ks.sup.mC.sub.ks.sup.m-
C.sub.k 1341947 N/A N/A 20381 20396 AATCACAAGTAAGGTA
A.sub.ksA.sub.ksT.sub.ks.sup.mC.sub.dsA.sub.ysmC.sub.dsA.sub.dsA.sub.ds
31 1333
G.sub.dsT.sub.dsA.sub.dsA.sub.dsG.sub.dsG.sub.ksT.sub.ksA.sub.k
1341954 N/A N/A 12501 12516 GCAGAAATTCACCTTG
G.sub.ks.sup.mC.sub.ksA.sub.ksG.sub.dsA.sub.ysA.sub.dsA.sub.dsT.sub.dsT.s-
ub.ds 54 1002
.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub.ksT.sub.ksG.-
sub.k
TABLE-US-00049 TABLE 49 Inhibition of HSD17B13 RNA by modified
oligonucleotides targeting SEQ ID NO.: 1, and 2 SEQ ID SEQ ID SEQ
ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ Compound Start Stop Start
Stop Sequence Chemistry Notation % ID Number Site Site Site Site
(5' to 3') (5' to 3') inhibition NO 1245927 N/A N/A 3433 3448
AGTAGATGGTAAGTCA
A.sub.ksG.sub.ksT.sub.ksA.sub.dsG.sub.dsA.sub.dsT.sub.dsG.sub.dsG.sub.ds
86 121
T.sub.dsA.sub.dsA.sub.dsG.sub.dsT.sub.ks.sup.mC.sub.ksA.sub.k
1246023 N/A N/A 5046 5061 GAGTGAATCATTCAGT
G.sub.ksA.sub.ksG.sub.ksT.sub.dsG.sub.dsA.sub.dsA.sub.dsT.sub.ds.sup.mC.s-
ub.ds 82 1526
A.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ksG.sub.ksT.sub.k
1341508 N/A N/A 14189 14204 TTGAGTTCTCCACTGC
T.sub.ksT.sub.ksG.sub.ksA.sub.dsG.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsT.s-
ub.ds 26 2885
.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ksT.sub.ksG.sub.ks.s-
up.mC.sub.e 1341518 1251 1266 21066 21081 TGTCCACCTTTAAATG
T.sub.ksG.sub.ksT.sub.ks.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.d-
s.sup.mC.sub.dsT.sub.ds 28 1666
T.sub.dsT.sub.dsA.sub.dsA.sub.ksA.sub.ksT.sub.kgG.sub.e 1341519
1310 1325 21125 21140 CTTAAACCTTCCCTGT
.sup.mC.sub.ksT.sub.ksT.sub.ksA.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.ds.sup.-
mC.sub.ds 34 1823
T.sub.dsT.sub.ds.sup.mC.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksT.sub.ksG.-
sub.ksT.sub.e 1341520 1328 1343 21143 21158 GAATGCTACTTGAACA
G.sub.ksA.sub.ksA.sub.ksT.sub.dsG.sub.ds.sup.mC.sub.dST.sub.dsA.sub.ds
56 1123
.sup.mC.sub.dsT.sub.dsT.sub.dsG.sub.dsA.sub.ksA.sub.ks.sup.mC.sub.ks-
A.sub.e 1341521 1330 1345 21145 21160 TGGAATGCTACTTGAA
T.sub.ksG.sub.ksG.sub.ksA.sub.dsA.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.dsT.s-
ub.ds 57 2203
A.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ksG.sub.ksA.sub.ksA.sub.e
1341522 1320 1335 21135 21150 CTTGAACAGTCTTAAA
.sup.mC.sub.ksT.sub.ksT.sub.ksG.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.dsA.sub-
.ds 43 500
G.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ksA.sub.ksA.sub.ksA.sub.-
e 1341523 1309 1324 21124 21139 TTAAACCTTCCCTGTG
T.sub.ksT.sub.ksA.sub.ksA.sub.dSA.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub-
.ds 18 2807
T.sub.ds.sup.mC.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub.ksG.sub.ksT.-
sub.ksG.sub.e 1341524 1319 1334 21134 21149 TTGAACAGTCTTAAAC
T.sub.ksT.sub.ksG.sub.ksA.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.dsT.s-
ub.ds 35 422
.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.ksA.sub.ksA.sub.ks.sup.mC.sub.e
1341525 1264 1279 21079 21094 GGGAGGTAGCTTTTGT
G.sub.ksG.sub.ksG.sub.ksA.sub.dsG.sub.dsG.sub.dsT.sub.dsA.sub.dSG.sub.ds
40 343
.sup.mC.sub.dsT.sub.dsT.sub.dsT.sub.ksT.sub.ksG.sub.ksT.sub.e
1341526 1308 1323 21123 21138 TAAACCTTCCCTGTGT
T.sub.ksA.sub.ksA.sub.ksA.sub.ds.sup.mC.sub.ds.sup.mC.sub.dST.sub.dsT.sub-
.ds 23 1745
.sup.mC.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.ksT.sub.ksG.-
sub.ksT.sub.e 1341527 1175 1190 20990 21005 TAAGAGGCATGAAAGG
T.sub.ksA.sub.ksA.sub.ksG.sub.dsA.sub.dsG.sub.dsG.sub.ds.sup.mC.sub.dsA.s-
ub.ds 36 2751
T.sub.dsG.sub.dsA.sub.dsA.sub.ksA.sub.ksG.sub.ksG.sub.e 1341530 693
708 12111 12126 ATGAGGTTTTGATACC
A.sub.ksT.sub.kSG.sub.ksA.sub.dsG.sub.dsG.sub.dsT.sub.dsT.sub.dsT.sub.ds
20 569
T.sub.dsG.sub.dsA.sub.dsT.sub.ksA.sub.ks.sup.mC.sub.ks.sup.mC.sub.e
1341531 1336 1351 21151 21166 ACAGATTGGAATGCTA
A.sub.ks.sup.mC.sub.ksA.sub.ksG.sub.dsA.sub.dsT.sub.dST.sub.dsG.sub.dsG.s-
ub.ds 68 1668
A.sub.dsA.sub.dsT.sub.dsG.sub.ks.sup.mC.sub.ksT.sub.ksA.sub.e
1341557 1347 1362 21162 21177 GTGGCATGGCTACAGA
G.sub.ksT.sub.ksG.sub.ksG.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.dsG.sub.dsG.s-
ub.ds 38 501
.sup.mC.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.ksA.sub.ksG.sub.ksA.sub.e
1341561 1346 1361 21161 21176 TGGCATGGCTACAGAT
T.sub.ksG.sub.ksG.sub.ks.sup.mC.sub.dsA.sub.dsT.sub.dsG.sub.dsG.sub.ds
68 423
.sup.mC.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.ksG.sub.ksA.sub.ks-
T.sub.e 1341573 1348 1363 21163 21178 TGTGGCATGGCTACAG
T.sub.ksG.sub.ksT.sub.ksG.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.dsG.s-
ub.ds 25 579
G.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.ks.sup.mC.sub.ksA.sub.ksG.sub.e
1341576 801 816 15682 15697 GTATTCCATCTATCAG
G.sub.ksT.sub.ksA.sub.ksT.sub.dsT.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub-
.ds 51 727
T.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.dsT.sub.ks.sup.mC.sub.ksA.sub.ks-
G.sub.e 1341608 N/A N/A 19914 19929 AGTGCATCTTAAGATA
A.sub.ksG.sub.ksT.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.ds.sup.mC.sub-
.ds 27 2130
T.sub.dsT.sub.dsA.sub.dsA.sub.ksG.sub.esA.sub.ksT.sub.esA.sub.k
1341610 N/A N/A 19915 19930 GAGTGCATCTTAAGAT
G.sub.ksA.sub.ksG.sub.dsT.sub.dSG.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.ds
27 2256
.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.ksA.sub.esG.sub.ksA.sub.esT.sub.-
k 1341611 N/A N/A 18690 18705 CTTTGAGACTCTTGTT
.sup.mC.sub.ksT.sub.ksT.sub.dsT.sub.dsG.sub.dsA.sub.dSG.sub.dsA.sub.ds
42 2583
.sup.mC.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.ksT.sub.esG.sub.ksT.sub.es-
T.sub.k 1341612 N/A N/A 19904 19919 AAGATACCCAGGTTGC
A.sub.ksA.sub.ksG.sub.dsA.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub-
.ds 59 2712
.sup.mC.sub.dsA.sub.dsG.sub.dsG.sub.ksT.sub.esT.sub.ksG.sub.es.sup.m-
C.sub.k 1341613 N/A N/A 18092 18107 TGATACACCAATGCAG
T.sub.ksG.sub.ksA.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub-
.ds 62 2370
.sup.mC.sub.dsA.sub.dsA.sub.dsT.sub.ksG.sub.es.sup.mC.sub.ksA.sub.es-
G.sub.k 1341618 N/A N/A 19906 19921 TTAAGATACCCAGGTT
T.sub.ksT.sub.ksA.sub.dsA.sub.dsG.sub.dsA.sub.dsTc.sub.sA.sub.ds.sup.mC.s-
ub.ds 48 163
.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ksG.sub.esG.sub.ksT.sub.esT.sub.k
1341619 N/A N/A 20388 20403 CTATAGTAATCACAAG
.sup.mC.sub.ksT.sub.ksA.sub.dsT.sub.dsA.sub.dsG.sub.dsT.sub.dsA.sub.dsA.s-
ub.ds 36 1644
T.sub.ds.sup.mC.sub.dsA.sub.ks.sup.mC.sub.esA.sub.ksA.sub.esG.sub.k
1341620 N/A N/A 20187 20202 TATTAGAAGTCAGCCC
T.sub.ksA.sub.ksT.sub.dsT.sub.dsA.sub.dsG.sub.dsA.sub.dsA.sub.dsG.sub.ds
36 164
T.sub.ds.sup.mC.sub.dsA.sub.ksG.sub.es.sup.mC.sub.ks.sup.mC.sub.es.s-
up.mC.sub.k 1341621 N/A N/A 20109 20124 AAGACATTCTAGCCTG
A.sub.ksA.sub.ksG.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.dST.sub.dST.sub.ds
25 2744
.sup.mC.sub.dsT.sub.dsA.sub.dsG.sub.ks.sup.mC.sub.es.sup.mC.sub.ksT.-
sub.esG.sub.k 1341622 N/A N/A 20197 20212 ACATTGCAGTTATTAG
A.sub.ks.sup.mC.sub.ksA.sub.dsT.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.dsA.sub-
.ds 46 2309
G.sub.dsT.sub.dsT.sub.dsA.sub.ksT.sub.esT.sub.ksA.sub.esG.sub.k
1341623 N/A N/A 20119 20134 TTACAGCATCAAGACA
T.sub.ksT.sub.ksA.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.dsA.sub-
.ds 22 2409
T.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.ksG.sub.esA.sub.ks.sup.mC.sub.es-
A.sub.k 1341624 N/A N/A 19916 19931 GGAGTGCATCTTAAGA
G.sub.ksG.sub.ksA.sub.dsG.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.dsT.s-
ub.ds 34 2810
.sup.mC.sub.dsT.sub.dsT.sub.ksA.sub.esA.sub.ksG.sub.esA.sub.k
1341625 N/A N/A 20009 2<X>24 AGAGAGTAATCAGTTT
A.sub.ksG.sub.ksA.sub.dsG.sub.dsA.sub.dsG.sub.dsT.sub.dsA.sub.dsA.sub.ds
52 2651
T.sub.ds.sup.mC.sub.dsA.sub.ksG.sub.esT.sub.ksT.sub.esT.sub.k
1341626 N/A N/A 19905 19920 TAAGATACCCAGGTTG
T.sub.ksA.sub.ksA.sub.dsG.sub.dsA.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.ds
30 2790
.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.ksG.sub.esT.sub.ksT.sub.es-
G.sub.k 1341627 N/A N/A 19999 20014 CAGTTTTCCTCATGAT
.sup.mC.sub.ksA.sub.ksG.sub.dsT.sub.dsT.sub.dsT.sub.dsT.sub.ds.sup.mC.sub-
.ds 59 2331
.sup.mC.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ksT.sub.esG.sub.ksA.sub.es-
T.sub.k 1341628 N/A N/A 20378 20393 CACAAGTAAGGTAAAG
.sup.mC.sub.ksA.sub.ks.sup.mC.sub.dsA.sub.dSA.sub.dsG.sub.dsT.sub.dsA.sub-
.ds 38 2448
A.sub.dsG.sub.dsG.sub.dsT.sub.ksA.sub.esA.sub.ksA.sub.esG.sub.k
1341629 N/A N/A 12804 12819 CTCAGGCTGTAAGAGT
.sup.mC.sub.ksT.sub.kS.sup.mC.sub.dsA.sub.dSG.sub.dsG.sub.ds.sup.mC.sub.d-
sT.sub.ds 10 2240
G.sub.dsT.sub.dsA.sub.dsA.sub.ksGc.sub.sA.sub.ksG.sub.esT.sub.k
1341630 N/A N/A 14165 14180 GCAAGCCAACAGAGAG
G.sub.ks.sup.mC.sub.ksA.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.ds.sup.mC.sub.d-
sA.sub.ds 12 2556
A.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.ksA.sub.esG.sub.ksA.sub.esG.sub.-
k 1341631 N/A N/A 14175 14190 GCCTTGAATAGCAAGC
G.sub.ks.sup.mC.sub.ks.sup.mC.sub.dsT.sub.dsT.sub.dsG.sub.dsA.sub.dsA.sub-
.ds 16 2063
T.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.ksA.sub.esA.sub.ksG.sub.es.sup.m-
C.sub.k 1341632 N/A N/A 13959 13974 GTCTACCTCTAAGTTA
G.sub.ksT.sub.ks.sup.mC.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.d-
sT.sub.ds 15 2363
.sup.mC.sub.dsT.sub.dsA.sub.dsA.sub.ksG.sub.esT.sub.ksT.sub.esA.sub.-
k 1341633 N/A N/A 13949 13964 AAGTTAGCCCCCAGGA
A.sub.ksA.sub.ksG.sub.dsT.sub.dsT.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.ds
12 2811
.sup.mC.sub.ds.sup.mC.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksA.sub.esG.su-
b.ksG.sub.esA.sub.k 1341634 N/A N/A 12496 12511 AATTCACCTTGACTAA
A.sub.ksA.sub.ksT.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ds.sup.-
mC.sub.ds 9 2144
T.sub.dsT.sub.dsG.sub.dsA.sub.ks.sup.mC.sub.esT.sub.ksA.sub.esA.sub.-
k 1341635 N/A N/A 20479 20494 TAGTGGACTTCATTAG
T.sub.ksA.sub.ksG.sub.dsT.sub.dsG.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.dST.s-
ub.ds 41 2351
T.sub.ds.sup.mC.sub.dsA.sub.ksT.sub.esT.sub.ksA.sub.esG.sub.k
1341636 N/A N/A 20489 20504 CATAACTTCATAGTGG
.sup.mC.sub.ksA.sub.ksT.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.dsT.sub-
.ds 15 866
.sup.mC.sub.dsA.sub.dsT.sub.dsA.sub.ksG.sub.esT.sub.ksG.sub.esG.sub.-
k 1341637 N/A N/A 12794 12809 AAGAGTCAGTATCCTC
A.sub.ksA.sub.ksG.sub.dsA.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.dsG.s-
ub.ds 14 2572
T.sub.dsA.sub.dsT.sub.ks.sup.mC.sub.es.sup.mC.sub.ksT.sub.es.sup.mC.-
sub.k 1341638 1394 1409 21209 21224 CTTGATCTCTTAGCTG
.sup.mC.sub.ksT.sub.kST.sub.ksG.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.dsT.sub-
.ds 36 736
.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.dsG.sub.ks.sup.mC.sub.ksT.sub.ks-
G.sub.e 1341639 1416 1431 21231 21246 GAGATAAAGCTGCCTG
G.sub.ksA.sub.ksG.sub.ksA.sub.dST.sub.dsA.sub.dsA.sub.dsA.sub.dsG.sub.ds
55 1592
.sup.mC.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.ks.sup.mC.sub.ksT.sub.ksG.-
sub.e 1341640 1426 1441 21241 21256 TGTCCAGGTTGAGATA
T.sub.ksG.sub.ksT.sub.ks.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.dsG.sub-
.ds 45 191
T.sub.dsT.sub.dsG.sub.dsA.sub.dsG.sub.ksA.sub.ksT.sub.ksA.sub.e
1341641 1415 1430 21230 21245 AGATAAAGCTGCCTGC
A.sub.ksG.sub.ksA.sub.ksT.sub.dsA.sub.dsA.sub.dsA.sub.dsG.sub.ds.sup.mC.s-
ub.ds 44 1515
T.sub.dsG.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksT.sub.ksG.sub.ks.sup.mC.-
sub.e 1341642 1425 1440 21240 21255 GTCCAGGTTGAGATAA
G.sub.ksT.sub.kS.sup.mC.sub.ks.sup.mC.sub.dsA.sub.dsG.sub.dsG.sub.dsT.sub-
.ds 52 113
T.sub.dsG.sub.dsA.sub.dsG.sub.dsA.sub.ksT.sub.ksA.sub.ksA.sub.e
1341643 791 806 15672 15687 TATCAGACTTCTTACG
T.sub.ksA.sub.ksT.sub.ks.sup.mC.sub.dsA.sub.dsG.sub.dsA.sub.ds.sup.mC.sub-
.ds 28 103
T.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ksA.sub.ks.sup.mC.sub.ks-
G.sub.e 1341644 1398 1413 21213 21228 GAAACTTGATCTCTTA
G.sub.ksA.sub.ksA.sub.ksA.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsG.sub.dsA.s-
ub.ds 79 2717
T.sub.ds.sup.mC.sub.dsT.sub.ds.sup.mC.sub.ksT.sub.ksT.sub.ksA.sub.e
1341645 1388 1403 21203 21218 CTCTTAGCTGTGCACT
.sup.mC.sub.ksT.sub.ks.sup.mC.sub.ksT.sub.dsT.sub.dsA.sub.dsG.sub.ds.sup.-
mC.sub.ds 66 268
T.sub.dsG.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.ksA.sub.ks.sup.mC.sub.ks-
T.sub.e 1341646 1384 1399 21199 21214 TAGCTGTGCACTCATT
T.sub.ksA.sub.ksG.sub.ks.sup.mC.sub.dsT.sub.dsG.sub.dsT.sub.dsG.sub.ds
66 1981
.sup.mC.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.ds.sup.mC.sub.ksA.sub.ksT.-
sub.ksT.sub.e 1341647 N/A N/A 14189 14204 TTGAGTTCTCCACTGC
T.sub.ksT.sub.ksG.sub.dsA.sub.dsG.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsT.s-
ub.ds 20 2885
.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ks.sup.mC.sub.esT.sub.ksG.sub.es.s-
up.mC.sub.k 1341949 N/A N/A 12799 12814 GCTGUAAGAGTCAGTA
G.sub.ks.sup.mC.sub.ksT.sub.ksG.sub.dsU.sub.ysA.sub.dsA.sub.dsG.sub.dsA.s-
ub.ds 28 2886
G.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.ksT.sub.ksA.sub.k
1341950 1088 1103 20903 20918 TTGACTGCTGCTAGTG
T.sub.ksT.sub.ksG.sub.ksA.sub.dsC.sub.ysT.sub.dsG.sub.ds.sup.mC.sub.dsT.s-
ub.ds 40 28
G.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.dSG.sub.ksT.sub.ksG.sub.k
1341958 N/A N/A 12797 12812 TGTAAGAGTCAGTATC
T.sub.ksG.sub.ksT.sub.ksA.sub.dsA.sub.ysG.sub.dsA.sub.dsG.sub.dsT.sub.ds
29 2652
.sup.mC.sub.dsA.sub.dsG.sub.dsT.sub.dsA.sub.ksT.sub.ks.sup.mC.sub.k
1341959 1091 1106 20906 20921 CGTTUGACTGCTGCTA
.sup.mC.sub.ksG.sub.ksT.sub.ksT.sub.dsU.sub.ysG.sub.dsA.sub.ds.sup.mC.sub-
.ds 54 2887
T.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.ksT.sub.ks-
A.sub.k 1341960 N/A N/A 14172 14187 TTGAATAGCAAGCCAA
T.sub.ksT.sub.ksG.sub.ksA.sub.dsA.sub.ysT.sub.dsA.sub.dsG.sub.ds.sup.mC.s-
ub.ds 30 1864
A.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksA.sub.ksA.sub.k
1341961 N/A N/A 14175 14190 GCCTUGAATAGCAAGC
G.sub.ks.sup.mC.sub.ks.sup.mC.sub.ksT.sub.dsU.sub.ysG.sub.dsA.sub.dsA.sub-
.ds 12 2888
T.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.ksG.sub.ks.sup.m-
C.sub.k 1341962 N/A N/A 13949 13964 AAGTUAGCCCCCAGGA
A.sub.ksA.sub.ksG.sub.ksT.sub.dsU.sub.ySA.sub.dSG.sub.ds.sup.mC.sub.ds
0 2889
.sup.mC.sub.ds.sup.mC.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsG.su-
b.ksG.sub.ksA.sub.k 1341963 N/A N/A 13952 13967 TCTAAGTTAGCCCCCA
T.sub.ks.sup.mC.sub.ksT.sub.ksA.sub.dsA.sub.ysG.sub.dsT.sub.dgT.sub.dsA.s-
ub.ds 7 928
G.sub.ds.sup.mC.sub.ds.sup.mC.sub.ds.sup.mC.sub.ds.sup.mC.sub.ks.sup-
.mC.sub.ksA.sub.k 1341964 N/A N/A 13956 13971 TACCUCTAAGTTAGCC
T.sub.ksA.sub.ksT.sub.ks.sup.mC.sub.dsU.sub.ys.sup.mC.sub.dsT.sub.dsA.sub-
.ds 13 2890
A.sub.dsG.sub.dsT.sub.dsT.sub.dsA.sub.dsG.sub.ks.sup.mC.sub.ks.sup.m-
C.sub.k 1341965 N/A N/A 13954 13969 CCTCUAAGTTAGCCCC
.sup.mC.sub.ks.sup.mC.sub.ksT.sub.ks.sup.mC.sub.dsU.sub.ysA.sub.dsA.sub.d-
sG.sub.ds 8 2891
T.sub.dsT.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.ds.sup.mC.sub.ks.sup.mC.-
sub.ks.sup.mC.sub.k 1341966 N/A N/A 13959 13974 GTCTACCTCTAAGTTA
G.sub.ksT.sub.ks.sup.mC.sub.ksT.sub.dsA.sub.ys.sup.mC.sub.ds.sup.mC.sub.d-
sT.sub.ds 15 2363
.sup.mC.sub.dsT.sub.dsA.sub.dsA.sub.dsG.sub.dsT.sub.ksT.sub.ksA.sub.-
k 1341967 N/A N/A 12794 12809 AAGAGTCAGTATCCTC
A.sub.ksA.sub.ksG.sub.ksA.sub.dsGv.sub.sT.sub.ds.sup.mC.sub.dsA.sub.dsG.s-
ub.ds 55 2572
T.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksT.sub.ks.sup.mC.-
sub.k 1341968 1202 1217 21017 21032 GTATGTTTATGTAAGC
G.sub.kST.sub.ksA.sub.ksT.sub.dsG.sub.ysT.sub.dST.sub.dsT.sub.dsA.sub.ds
66 1511
T.sub.dsG.sub.dsT.sub.dsA.sub.dsA.sub.ksG.sub.ks.sup.mC.sub.k
1341969 1200 1215 21015 21030 ATGTUTATGTAAGCAC
A.sub.ksT.sub.ksG.sub.ksT.sub.dsU.sub.ysT.sub.dsA.sub.dsT.sub.dsG.sub.ds
45 2892
T.sub.dsA.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.ksA.sub.ks.sup.mC.sub.k
1341970 N/A N/A 14168 14183 ATAGCAAGCCAACAGA
A.sub.ksT.sub.ksA.sub.ksG.sub.dsC.sub.ysA.sub.dsA.sub.dsG.sub.ds.sup.mC.s-
ub.ds 1 2633
.sup.mC.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.ksG.sub.ksA.sub.k
1341971 606 621 10492 10507 AATAUGGGATGAGGTA
A.sub.ksA.sub.ksT.sub.ksA.sub.dsU.sub.ysG.sub.dsG.sub.dsG.sub.dsA.sub.ds
38 2893 T.sub.dsG.sub.dsA.sub.dsG.sub.dsG.sub.ksT.sub.ksA.sub.k
1341972 1175 1190 20990 21005 TAAGAGGCATGAAAGG
T.sub.ksA.sub.ksA.sub.ksG.sub.dsA.sub.ysG.sub.dsG.sub.ds.sup.mC.sub.dsA.s-
ub.ds 50 2751
T.sub.dsG.sub.dsA.sub.dsA.sub.dsA.sub.ksG.sub.ksG.sub.k 1341973
1180 1195 20995 21010 GTTTUTAAGAGGCATG
G.sub.ksT.sub.kST.sub.ksT.sub.dsU.sub.ysT.sub.dsA.sub.dsA.sub.dsG.sub.ds
38 2894
A.sub.dsG.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.ksT.sub.ksG.sub.k
1341974 N/A N/A 14165 14180 GCAAGCCAACAGAGAG
G.sub.ks.sup.mC.sub.ksA.sub.ksA.sub.dsG.sub.ys.sup.mC.sub.ds.sup.mC.sub.d-
sA.sub.ds 26 2556
A.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.dsA.sub.dsG.sub.ksA.sub.ksG.sub.-
k 1341975 N/A N/A 14170 14185 GAATAGCAAGCCAACA
G.sub.ksA.sub.ksA.sub.ksT.sub.dsA.sub.ysG.sub.ds.sup.mC.sub.dsA.sub.dsA.s-
ub.ds 23 1708
G.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.ks.sup.mC.sub.ksA.-
sub.k 1341976 N/A N/A 14192 14207 TGATUGAGTTCTCCAC
T.sub.ksG.sub.ksA.sub.ksT.sub.dsU.sub.ysG.sub.dsA.sub.dsG.sub.dsT.sub.ds
4 2895
T.sub.ds.sup.mC.sub.dsT.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksA.sub.ks.s-
up.mC.sub.k 1341977 N/A N/A 14189 14204 TTGAGTTCTCCACTGC
T.sub.ksT.sub.ksG.sub.ksA.sub.dsG.sub.ysT.sub.dsT.sub.ds.sup.mC.sub.dsT.s-
ub.ds 18 2885
.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.ksG.sub.ks.s-
up.mC.sub.k 1341978 1261 1276 21076 21091 AGGTAGCTTTTGTCCA
A.sub.ksG.sub.ksG.sub.ksT.sub.dsA.sub.ysG.sub.ds.sup.mC.sub.dsT.sub.dsT.s-
ub.ds 59 109
T.sub.dsT.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.ks.sup.mC.sub.ksA.sub.k
1341979 1259 1274 21074 21089 GTAGCTTTTGTCCACC
G.sub.ksT.sub.ksA.sub.ksG.sub.dsC.sub.ysT.sub.dsT.sub.dsT.sub.dsT.sub.ds
64 1978
G.sub.dsT.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.kS.sup.mC.sub.ks.s-
up.mC.sub.k 1341980 1258 1273 21073 21088 TAGCUTTTGTCCACCT
T.sub.ksA.sub.ksG.sub.ks.sup.mC.sub.dsU.sub.ysT.sub.dsT.sub.dsT.sub.dsG.s-
ub.ds 67 2896
T.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ks.sup.mC.su-
b.ksT.sub.k
Example 4: Design of and Antisense Inhibition by Human HSD17B13
Modified Oligonucleotides in HepRG Cells
[0524] Modified oligonucleotides complementary to an HSD17B13
nucleic acid were synthesized and tested for their effect on
HSD17B13 RNA levels in vitro. specifies the chemistry of each
modified oligonucleotide; wherein subscript `d` represents a
2'-.beta.-D-deoxyribosyl sugar moiety, subscript `e` represents a
2'-MOE sugar moiety, subscript `y` represents a 2'-O-methyl sugar
moiety, subscript `k` represents a cEt modified sugar moiety,
subscript `s` represents a phosphorothioate internucleoside
linkage, and superscript `m` before the cytosine residue represents
a 5-methyl cytosine. "Start site" indicates the 5'-most nucleoside
of the target sequence to which the modified oligonucleotide is
complementary. "Stop site" indicates the 3'-most nucleoside of the
target sequence to which the modified oligonucleotide is
complementary. As shown in the Tables below, the modified
oligonucleotide are complementary to either the human HSD17B13
mRNA, designated herein as SEQ ID NO: 1 (GENBANK Accession No.
NM_178135.4) or to the human HSD17B13 genomic sequence, designated
herein as SEQ ID NO: 2 (the complement of GENBANK Accession No.
NC_000004.12 truncated from nucleotides 87301001 to 87326000) or to
both. `N/A` indicates that the modified oligonucleotide is not
complementary to that particular target sequence with 100%
complementarity.
[0525] The modified oligonucleotides were tested in a series of
experiments using the same culture conditions. The results for each
experiment are presented in separate tables shown below. Cultured
HepaRG cells at a density of 30,000 cells per well were transfected
using electroporation with 1,000 nM of modified oligonucleotide.
After a treatment period of approximately 24 hours, RNA was
isolated from the cells and HSD17B13 RNA levels were measured by
quantitative real-time RTPCR. Human primer probe set RTS43553 was
used to measure RNA levels. HSD17B13 RNA levels were adjusted
according to total RNA content, as measured by RIBOGREEN.RTM..
Results are presented as percent inhibition of HSD17B13 relative to
untreated control cells. As used herein, a value of `0` indicates
that treatment with the modified oligonucleotide did not inhibit
HSD17B13 mRNA levels.
TABLE-US-00050 TABLE 50 Inhibition of HSD17B13 RNA by modified
oligonucleotides targeting SEQ ID NO.: 1, and 2 SEQ ID SEQ ID SEQ
ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ Compound Start Stop Start
Stop Sequence Chemistry Notation % ID Number Site Site Site Site
(5' to 3') (5' to 3') inhibition NO 1245927 N/A N/A 3433 3448
AGTAGATGGTAAGTCA
A.sub.ksG.sub.ksT.sub.ksA.sub.dsG.sub.dsA.sub.dsT.sub.ds 81 121
G.sub.dsG.sub.dsT.sub.dsA.sub.dsA.sub.dsG.sub.dsT.sub.ks
.sup.mC.sub.ksA.sub.k 1246023 N/A N/A 5046 5061 GAGTGAATCATTCAGT
G.sub.ksA.sub.ksG.sub.ksT.sub.dsG.sub.dsA.sub.dsA.sub.ds 83 1526
T.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ds
A.sub.ksG.sub.ksT.sub.k 1340072 N/A N/A 19913 19928
GTGCATCTTAAGATAC
G.sub.ksT.sub.ksG.sub.ks.sup.mC.sub.dsA.sub.dsT.sub.ds 47 2806
.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.dsA.sub.dsG.sub.ds
A.sub.dsT.sub.ksA.sub.ks.sup.mC.sub.k 1340095 N/A N/A 19395 19410
ATAAGAGATGAGTAGG
A.sub.ksT.sub.ksA.sub.ksA.sub.dsG.sub.dsA.sub.dsG.sub.ds 56 2897
A.sub.dsT.sub.dsG.sub.dsA.sub.dsG.sub.dsT.sub.dsA.sub.ks
G.sub.ksG.sub.k 1340097 N/A N/A 14604 14619 TGCGAGAAATCTAAGA
T.sub.ksG.sub.ks.sup.mC.sub.ksG.sub.dsA.sub.dsG.sub.dsA.sub.ds 50
2898 A.sub.dsA.sub.dsT.sub.dsinC.sub.dsT.sub.dsA.sub.ds
A.sub.ksG.sub.ksA.sub.k 1340102 N/A N/A 10521 10536
TATAACATGGCTGGCA
T.sub.ksA.sub.ksT.sub.ksA.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.ds 33
2899 T.sub.dsG.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.dsG.sub.ks
.sup.mC.sub.ksA.sub.k 1340109 1432 1447 21247 21262
AAAATATGTCCAGGTT
A.sub.ksA.sub.ksA.sub.ksA.sub.dsT.sub.dsA.sub.dsT.sub.ds 74 2900
G.sub.dsT.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.ds
G.sub.ksT.sub.ksT.sub.k 1340134 N/A N/A 9967 9982 GTAGTGTAAGCTGAGA
G.sub.ksT.sub.ksA.sub.ksG.sub.dsT.sub.dsG.sub.dsT.sub.ds 81 2901
A.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.ds
A.sub.ksG.sub.ksA.sub.k 1340137 N/A N/A 18139 18154
ATGTTATCTCAAGTCA
A.sub.ksT.sub.ksG.sub.ksT.sub.dsT.sub.dsA.sub.dsT.sub.ds 79 2902
.sup.mC.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsG.sub.ds
T.sub.ks.sup.mC.sub.ksA.sub.k 1340138 1632 1647 21447 21462
GATTTAAAATAGAGTC
G.sub.ksA.sub.ksT.sub.ksT.sub.dsT.sub.dsA.sub.dsA.sub.ds 46 2903
A.sub.dsA.sub.dsT.sub.dsA.sub.dsG.sub.dsA.sub.dsG.sub.ks
T.sub.ks.sup.mC.sub.k 1340155 N/A N/A 9442 9457 CTCCCACAAAACTAAC
.sup.mC.sub.ksT.sub.ks.sup.mC.sub.ks.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ds
13 2904
.sup.mC.sub.dsA.sub.dsA.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.ds
T.sub.dsA.sub.ksA.sub.ks.sup.mC.sub.k 1340172 N/A N/A 11623 11638
TTCTGTAGGACTCTGC
T.sub.ksT.sub.ks.sup.mC.sub.ksT.sub.dsG.sub.dsT.sub.dsA.sub.ds 72
2905 G.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.ds.sup.mC.sub.ds
T.sub.ksG.sub.ks.sup.mC.sub.k 1340180 N/A N/A 20417 20432
AAAATTATGCCTTGTG
A.sub.ksA.sub.ksA.sub.ksA.sub.dsT.sub.dsT.sub.dsA.sub.ds 50 2906
T.sub.dsG.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ds
TG.sub.ksT.sub.ksG.sub.k 1340182 N/A N/A 14915 14930
TACATTAGCAAGCTAA
T.sub.ksA.sub.ks.sup.mC.sub.ksA.sub.dsT.sub.dsT.sub.dsA.sub.ds 29
2907 G.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.ds
T.sub.ksA.sub.ksA.sub.k 1340213 N/A N/A 20593 20608
GCTGAGAGTTATCTGG
G.sub.ks.sup.mC.sub.ksT.sub.ksG.sub.dsA.sub.dsG.sub.dsA.sub.ds 65
2908 G.sub.dsT.sub.dsT.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.ks
G.sub.ksG.sub.k 1340249 N/A N/A 18037 18052 TCATAGTTTATATGGA
T.sub.ks.sup.mC.sub.ksA.sub.ksT.sub.dsA.sub.dsG.sub.dsT.sub.ds 44
2909 T.sub.dsT.sub.dsA.sub.dsT.sub.dsA.sub.dsT.sub.dsG.sub.ks
G.sub.ksA.sub.k 1340263 N/A N/A 13609 13624 TTGAAGACAATACAGG
T.sub.ksT.sub.ksG.sub.ksA.sub.dsA.sub.dsG.sub.dsA.sub.ds 63 2910
.sup.mC.sub.dsA.sub.dsA.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.ds
A.sub.ksG.sub.ksG.sub.k 1340282 N/A N/A 19535 19550
ATAGGCTAAAATGGTC
A.sub.ksT.sub.ksA.sub.ksG.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.ds 61
2911 A.sub.dsA.sub.dsA.sub.dsA.sub.dsT.sub.dsG.sub.dsG.sub.ks
T.sub.ks.sup.mC.sub.k 1340287 N/A N/A 18696 18711 AAAAGACTTTGAGACT
A.sub.ksA.sub.ksA.sub.ksA.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.ds 32
2912 T.sub.dsT.sub.dsT.sub.dsG.sub.dsA.sub.dsG.sub.dsA.sub.ks
.sup.mC.sub.ksT.sub.k 1340288 N/A N/A 11115 11130 ACAGAGGAGTTTGCAG
A.sub.ks.sup.mC.sub.ksA.sub.ksG.sub.dsA.sub.dsG.sub.dsG.sub.ds 37
2913 A.sub.dsG.sub.dsT.sub.dsT.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.ks
A.sub.ksG.sub.k 1340289 1309 1324 21124 21139 TTAAACCTTCCCTGTG
T.sub.ksT.sub.ksA.sub.ksA.sub.dsA.sub.ds.sup.mC.sub.ds 22 2807
.sup.mC.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ds.sup.mC.sub.ds.sup.mC.su-
b.ds T.sub.dsG.sub.ksT.sub.ksG.sub.k 1340295 1178 1193 20993 21008
TTTTAAGAGGCATGAA
T.sub.ksT.sub.ksT.sub.ksT.sub.dsA.sub.dsA.sub.dsG.sub.ds 53 2914
A.sub.dsG.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.dsG.sub.ks
A.sub.ksA.sub.k 1340301 N/A N/A 20113 20128 CATCAAGACATTCTAG
.sup.mC.sub.ksA.sub.ksT.sub.ks.sup.mC.sub.dsA.sub.dsA.sub.ds 49
2915 G.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.dsT.sub.ds
.sup.mC.sub.dsT.sub.ksA.sub.ksG.sub.k 1340306 N/A N/A 19732 19747
AACTGAAGGTCTGAGC
A.sub.ksA.sub.ks.sup.mC.sub.ksT.sub.dsG.sub.dsA.sub.dsA.sub.ds 55
2916 G.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.dsA.sub.ks
G.sub.ks.sup.mC.sub.k 1340315 N/A N/A 14284 14299 TGAATGTAAAGGCTGG
T.sub.ksG.sub.ksA.sub.ksA.sub.dsT.sub.dsG.sub.dsT.sub.ds 38 2917
A.sub.dsA.sub.dsA.sub.dsG.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.ks
G.sub.ksG.sub.k 1340333 1764 1779 21579 21594 TACAGTTCCTTTTCCT
T.sub.ksA.sub.ks.sup.mC.sub.ksA.sub.dsG.sub.dsT.sub.dsT.sub.ds 68
2918 .sup.mC.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsT.sub.dsT.sub.ds
.sup.mC.sub.ks.sup.mC.sub.ksT.sub.k 1340340 N/A N/A 6913 6928
TCGGGAAGTTTAGACA
T.sub.ks.sup.mC.sub.ksG.sub.ksG.sub.dsG.sub.dsA.sub.dsA.sub.ds 43
2919 G.sub.dsT.sub.dsT.sub.dsT.sub.dsA.sub.dsG.sub.dsA.sub.ks
.sup.mC.sub.ksA.sub.k 1340341 N/A N/A 6330 6345 GACTTTCATAGGGAGA
G.sub.ksA.sub.ks.sup.mC.sub.ksT.sub.dsT.sub.dsT.sub.ds 72 2920
.sup.mC.sub.dsA.sub.dsT.sub.dsA.sub.dsG.sub.dsG.sub.dsG.sub.ds
A.sub.ksG.sub.ksA.sub.k 1340346 N/A N/A 11510 11525
ATTATGAGGATCTGGA
A.sub.ksT.sub.ksrrksA.sub.dsT.sub.dsG.sub.dsA.sub.ds 49 2921
G.sub.dsG.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.ks
G.sub.ksA.sub.k 1340359 N/A N/A 13949 13964 AAGTTAGCCCCCAGGA
A.sub.ksA.sub.ksG.sub.ksT.sub.dsT.sub.dsA.sub.dsG.sub.ds 36 2811
.sup.mC.sub.ds.sup.mC.sub.ds.sup.mC.sub.ds.sup.mC.sub.ds.sup.mC.sub.-
ds A.sub.dsG.sub.ksG.sub.ksA.sub.k 1340362 N/A N/A 6734 6749
GATTACCCCTGGCTTT
G.sub.ksA.sub.ksT.sub.ksT.sub.dsA.sub.ds.sup.mC.sub.ds 31 2922
.sup.mC.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.dsG.sub.ds
.sup.mC.sub.dsT.sub.ksT.sub.ksT.sub.k 1340391 N/A N/A 12204 12219
TATCATACCACATACC
T.sub.ksA.sub.ksT.sub.ks.sup.mC.sub.dsA.sub.dsT.sub.dsA.sub.ds 24
2923
.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.ds
A.sub.ks.sup.mC.sub.ks.sup.mC.sub.k 1340393 N/A N/A 5744 5759
CACTGATTTAGTTGGT
.sup.mC.sub.ksA.sub.ks.sup.mC.sub.ksT.sub.dsG.sub.dsA.sub.ds 66
2924 T.sub.dsT.sub.dsT.sub.dsA.sub.dsG.sub.dsT.sub.dsT.sub.ds
G.sub.ksG.sub.ksT.sub.k 1340399 N/A N/A 15419 15434
CCAGTAGGTGTGTTTC
.sup.mC.sub.ks.sup.m.sub.nC.sub.ksA.sub.ksG.sub.dsT.sub.dsA.sub.ds
55 2925 G.sub.dsG.sub.dsT.sub.dsG.sub.dsT.sub.dsG.sub.dsT.sub.ds
T.sub.ksT.sub.ks.sup.mC.sub.k 1340403 N/A N/A 5673 5688
GGTCAGTAGAGAGCAT
G.sub.ksG.sub.ksT.sub.ks.sup.mC.sub.dsA.sub.dsG.sub.dsT.sub.ds 79
2926 A.sub.dsG.sub.dsA.sub.dsG.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.ks
A.sub.ksT.sub.k 1340409 683 698 12101 12116 GATACCAGTTTTTCCC
G.sub.ksA.sub.ksT.sub.ksA.sub.ds.sup.mC.sub.ds.sup.mC.sub.ds 75
2927 A.sub.dsG.sub.dsT.sub.dsT.sub.dsT.sub.dsT.sub.dsT.sub.ds
.sup.mC.sub.ks.sup.mC.sub.ks.sup.mC.sub.k 1340411 N/A N/A 9206 9221
AGATGTACACTGACAA
A.sub.ksG.sub.ksA.sub.ksT.sub.dsG.sub.dsT.sub.dsA.sub.ds 66 2928
.sup.mC.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.dsA.sub.ds
.sup.mC.sub.ksA.sub.ksA.sub.k 1340420 N/A N/A 20193 20208
TGCAGTTATTAGAAGT
T.sub.ksG.sub.ks.sup.mC.sub.ksA.sub.dsG.sub.dsT.sub.dsT.sub.ds 46
2929 A.sub.dsT.sub.dsT.sub.dsA.sub.dsG.sub.dsAc.sub.isA.sub.ks
G.sub.ksT.sub.k 1340444 N/A N/A 8963 8978 CTCCGTTATAAGTTTC
.sup.mC.sub.ksT.sub.ks.sup.mC.sub.ks.sup.mC.sub.dsG.sub.dsT.sub.ds
59 2930 T.sub.dsA.sub.dsT.sub.dsA.sub.dsA.sub.dsG.sub.dsT.sub.ds
T.sub.ksT.sub.ks.sup.mC.sub.k 1340456 N/A N/A 16218 16233
TATAGACTGGGTAGGA
T.sub.ksA.sub.ksT.sub.ksA.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.ds 61
2808 T.sub.dsG.sub.dsG.sub.dsG.sub.dsT.sub.dsA.sub.dsG.sub.ks
G.sub.ksA.sub.k 1340460 N/A N/A 9775 9790 ACTAGAACTCCCAACC
A.sub.ks.sup.mC.sub.ksT.sub.ksA.sub.dsG.sub.dsA.sub.dsA.sub.ds 20
2931
.sup.mC.sub.dsT.sub.ds.sup.mC.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.su-
b.ds A.sub.ks.sup.mC.sub.ks.sup.mC.sub.k 1340467 N/A N/A 8129 8144
TTAGAGTGCTTAGTTC
T.sub.ksT.sub.ksA.sub.ksG.sub.dsA.sub.dsG.sub.dsT.sub.ds 58 2932
G.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.dsG.sub.dsT.sub.ks
T.sub.ks.sup.mC.sub.k 1340473 N/A N/A 3608 3623 TTTAGCAGCTTGGAAG
T.sub.ksT.sub.ksT.sub.ksA.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.ds 43
2933 G.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsG.sub.dsG.sub.dsA.sub.ks
A.sub.ksG.sub.k 1340474 N/A N/A 16425 16440 TGATATGTCAATACTC
T.sub.ksG.sub.ksA.sub.ksT.sub.dsA.sub.dsT.sub.dsG.sub.ds 57 2934
T.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsT.sub.dsA.sub.ds
.sup.mC.sub.ksT.sub.ds.sup.mC.sub.k 1340490 N/A N/A 10124 10139
GGATATGTCATCTAAA
G.sub.ksG.sub.ksA.sub.ksT.sub.dsA.sub.dsT.sub.dsG.sub.ds 68 2935
T.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.ds
A.sub.ksA.sub.ksA.sub.k 1340494 N/A N/A 5896 5911 GTCCTTTGTATTTCGC
G.sub.ksT.sub.ks.sup.mC.sub.ks.sup.mC.sub.dsT.sub.dsT.sub.ds 45
2936 T.sub.dsG.sub.dsT.sub.dsA.sub.dsT.sub.dsT.sub.dsT.sub.ds
.sup.mC.sub.ksG.sub.ks.sup.mC.sub.k 1340520 N/A N/A 3701 3716
ATTTTCAGATCCCGTT
A.sub.ksT.sub.ksT.sub.ksT.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ds 67
2937
G.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.ds.sup.mC.sub.ds.sup.mC.sub.ds
G.sub.ksT.sub.ksT.sub.k 1340530 N/A N/A 3490 3505 TACAGACTAAGGGACC
T.sub.ksA.sub.ks.sup.mC.sub.ksA.sub.dsG.sub.dsA.sub.ds 68 2938
.sup.mC.sub.dsT.sub.dsA.sub.dsA.sub.dsG.sub.dsG.sub.dsG.sub.ds
A.sub.ks.sup.mC.sub.ks.sup.mC.sub.k 1340531 N/A N/A 9337 9352
CCTCGATCCTATATAC
.sup.mC.sub.ks.sup.mC.sub.ksT.sub.ks.sup.mC.sub.dsG.sub.dsA.sub.ds
31 2812
T.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.dsT.sub.ds
A.sub.dsT.sub.ksA.sub.ks.sup.mC.sub.k 1340532 N/A N/A 12801 12816
AGGCTGTAAGAGTCAG
A.sub.ksG.sub.ksG.sub.ks.sup.mC.sub.dsT.sub.dsG.sub.dsT.sub.ds 74
2809 A.sub.dsA.sub.dsG.sub.dsA.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.ks
A.sub.ksG.sub.k 1340565 N/A N/A 5844 5859 CCCCAAACATGGATGT
.sup.mC.sub.ks.sup.mC.sub.ks.sup.mC.sub.ks.sup.mC.sub.dsA.sub.dsA.sub.ds
62 2939
A.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.dsG.sub.dsG.sub.dsA.sub.ds
T.sub.ksG.sub.ksT.sub.k 1340586 811 826 15692 15707
TTATTGGTAAGTATTC
T.sub.ksT.sub.ksA.sub.ksT.sub.dsT.sub.dsG.sub.dsG.sub.ds 17 2940
T.sub.dsA.sub.dsA.sub.dsG.sub.dsT.sub.dsA.sub.dsT.sub.ks
T.sub.ks.sup.mC.sub.k 1340599 N/A N/A 6599 6614 GGCTACTTTCAAACCT
G.sub.ksG.sub.ks.sup.mC.sub.ksT.sub.dsA.sub.ds.sup.mC.sub.ds 54
2941 T.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsA.sub.ds
.sup.mC.sub.ks.sup.mC.sub.ksT.sub.k 1340600 N/A N/A 8538 8553
GTTTTGCAAGTTTATC
G.sub.ksT.sub.ksT.sub.ksT.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.ds 73
2942 A.sub.dsA.sub.dsG.sub.dsT.sub.dsT.sub.dsT.sub.dsA.sub.ks
T.sub.ks.sup.mC.sub.k 1340612 N/A N/A 6450 6465 AGTAGTAATTCTAAAC
A.sub.ksG.sub.ksT.sub.ksA.sub.dsG.sub.dsT.sub.dsA.sub.ds 23 2943
A.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.dsA.sub.ks
A.sub.ks.sup.mC.sub.k 1340625 N/A N/A 7527 7542 TCCGAAAAAAGTGGAG
T.sub.ks.sup.mC.sub.ks.sup.mC.sub.ksG.sub.dsA.sub.dsA.sub.ds 12
2944 A.sub.dsA.sub.dsA.sub.dsA.sub.dsG.sub.dsT.sub.dsG.sub.ds
G.sub.ksA.sub.ksG.sub.k 1340627 N/A N/A 10292 10307
GAGAGAACTTATACAA
G.sub.ksA.sub.ksG.sub.ksA.sub.dsG.sub.dsA.sub.dsA.sub.ds 37 2945
.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.dsT.sub.dsA.sub.ds
.sup.mC.sub.ksA.sub.ksA.sub.k 1340629 77 92 3171 3186
CAGAAGGATTTCTAGG
.sup.mC.sub.ksA.sub.ksG.sub.ksA.sub.dsA.sub.dsG.sub.dsG.sub.ds 43
2946 A.sub.dsT.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.ks
G.sub.ksG.sub.k 1340633 N/A N/A 4662 4677 CCCGCCCTTAAGTCAT
.sup.mC.sub.ks.sup.mC.sub.ks.sup.mC.sub.ksG.sub.ds.sup.mC.sub.ds 45
2947 .sup.mC.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.dsA.sub.ds
G.sub.dsT.sub.ds.sup.mC.sub.ksA.sub.ksT.sub.k 1340643 N/A N/A 5277
5292 GCTAGACAATTGCAAA
G.sub.ks.sup.mC.sub.ksT.sub.ksA.sub.dsG.sub.dsA.sub.ds 77 2948
.sup.mC.sub.dsA.sub.dsA.sub.dsT.sub.dsT.sub.dsG.sub.ds
.sup.mC.sub.dsA.sub.ksA.sub.ksA.sub.k 1340686 N/A N/A 5189 5204
TTCCCAACGCAACAGT
T.sub.ksT.sub.ks.sup.mC.sub.ks.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ds
60 2949
A.sub.ds.sup.mC.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.ds
.sup.mC.sub.dsA.sub.ksG.sub.ksT.sub.k 1340694 N/A N/A 5648 5663
GAGCATTCATCAGATG
G.sub.ksA.sub.ksG.sub.ks.sup.mC.sub.dsA.sub.dsT.sub.dsT.sub.ds 64
2950 .sup.mC.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.ds
A.sub.ksT.sub.ksG.sub.k 1340698 N/A N/A 6087 6102 AGTTTTCACCTCAGGT
A.sub.ksG.sub.ksT.sub.ksT.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ds 82
2951
A.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ds
G.sub.ksG.sub.ksT.sub.k 1340709 N/A N/A 9116 9131 AGACAGACCAAGTAGC
A.sub.ksG.sub.ksA.sub.ks.sup.mC.sub.dsA.sub.dsG.sub.dsA.sub.ds 21
2952 .sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsG.sub.dsT.sub.ds
A.sub.ksG.sub.ks.sup.mC.sub.k 1340719 N/A N/A 9944 9959
ACCACACTAATGAATC
A.sub.ks.sup.mC.sub.ks.sup.mC.sub.ksA.sub.ds.sup.mC.sub.dsA.sub.ds
54 2953
.sup.mC.sub.dsT.sub.dsA.sub.dsA.sub.dsT.sub.dsG.sub.dsA.sub.ds
A.sub.ksT.sub.ks.sup.mC.sub.k 1340726 N/A N/A 6262 6277
TGAGATGGGCAAGGCC
T.sub.ksG.sub.ksA.sub.ksG.sub.dsA.sub.dsT.sub.dsG.sub.ds 53 2954
G.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsG.sub.dsG.sub.ks
.sup.mC.sub.ks.sup.mC.sub.k 1340728 N/A N/A 8645 8660
GGCAAGACAGACTGTT
G.sub.ksG.sub.ks.sup.mC.sub.ksA.sub.dsA.sub.dsG.sub.dsA.sub.ds 75
2955 .sup.mC.sub.dsA.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.ds
G.sub.ksT.sub.ksT.sub.k 1340729 N/A N/A 14191 14206
GATTGAGTTCTCCACT
G.sub.ksA.sub.ksT.sub.ksT.sub.dsG.sub.dsA.sub.dsG.sub.ds 45 2956
T.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.ds.sup.mC.sub.ds.sup.mC.sub.ds
A.sub.ks.sup.mC.sub.ksT.sub.k 1340739 N/A N/A 16288 16303
TTAGAATAGTCTTCAG
T.sub.ksT.sub.ksA.sub.ksG.sub.dsA.sub.dsA.sub.dsT.sub.ds 52 2957
A.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ds
.sup.mC.sub.ksA.sub.ksG.sub.k 1340752 N/A N/A 9590 9605
AGCTGGTAAAGGTAAG
A.sub.ksG.sub.ks.sup.mC.sub.ksT.sub.dsG.sub.dsG.sub.dsT.sub.ds 55
2958 A.sub.dsA.sub.dsA.sub.dsG.sub.dsG.sub.dsT.sub.dsA.sub.ks
A.sub.ksG.sub.k 1340755 N/A N/A 3995 4010 ATGTAGTGTTTACAAG
A.sub.ksT.sub.ksG.sub.ksT.sub.dsA.sub.dsG.sub.dsT.sub.ds 58 2959
G.sub.dsT.sub.dsT.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.ks
A.sub.ksG.sub.k 1340769 N/A N/A 12666 12681 GTTAACCTGCAGCAGA
G.sub.ksT.sub.ksT.sub.ksA.sub.dsA.sub.ds.sup.mC.sub.ds 51 2960
.sup.mC.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.ds
.sup.mC.sub.dsA.sub.ksG.sub.ksA.sub.k 1340791 N/A N/A 17953 17968
TAGAAACTGCTCCTCA
T.sub.ksA.sub.ksG.sub.ksA.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.ds 32
2961
T.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.ds.sup.mC.sub.ds.sup.mC.sub.ds
T.sub.ks.sup.mC.sub.ksA.sub.k 1340795 N/A N/A 7789 7804
GTGACATAACTACTTC
G.sub.ksT.sub.ksG.sub.ksA.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.ds 68
2962 A.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.ds
T.sub.ksT.sub.ks.sup.mC.sub.k 1340801 N/A N/A 4246 4261
TAAGTGTAAGAGACAT
T.sub.ksA.sub.ksA.sub.ksG.sub.dsT.sub.dsG.sub.dsT.sub.ds 63 2963
A.sub.dsA.sub.dsG.sub.dsA.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.ks
A.sub.ksT.sub.k 1340810 N/A N/A 12480 12495 GGAGCTAGATACTCAA
G.sub.ksG.sub.ksA.sub.ksG.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.ds 42
2964 G.sub.dsA.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.ds
.sup.mC.sub.ksA.sub.ksA.sub.k 1340819 N/A N/A 18530 18545
TCCTACAGTGCTTAGT
T.sub.ks.sup.mC.sub.ks.sup.mC.sub.ksT.sub.dsA.sub.ds.sup.mC.sub.ds
44 2965
A.sub.dsG.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ds
A.sub.ksG.sub.ksT.sub.k 1340907 N/A N/A 5121 5136 AAGGAGCCAGTTATGA
A.sub.ksA.sub.ksG.sub.rksG.sub.dsA.sub.dsG.sub.ds 57 2966
.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.dsT.sub.dsT.sub.ds
A.sub.dsT.sub.ksG.sub.ksA.sub.k 1340917 N/A N/A 9666 9681
ATGCAGCTATAGGTAG
A.sub.ksT.sub.ksG.sub.ks.sup.mC.sub.dsA.sub.dsG.sub.ds 41 2967
.sup.mC.sub.dsT.sub.dsA.sub.dsT.sub.dsA.sub.dsG.sub.dsG.sub.ds
T.sub.ksA.sub.ksG.sub.k
TABLE-US-00051 TABLE 51 Inhibition of HSD17B13 RNA by modified
oligonucleotides targeting SEQ ID NO.: 1, and 2 SEQ ID SEQ ID SEQ
ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ Compound Start Stop Start
Stop Sequence Chemistry Notation % ID Number Site Site Site Site
(5' to 3') (5' to 3') inhibition NO 1245927 N/A N/A 3433 3448
AGTAGATGGTAAGTCA
A.sub.ksG.sub.ksT.sub.ksA.sub.dsG.sub.dsA.sub.dsT.sub.ds 77 121
G.sub.dsG.sub.dsT.sub.dsA.sub.dsA.sub.dsG.sub.dsT.sub.ks
.sup.mC.sub.ksA.sub.k 1246023 N/A N/A 5046 5061 GAGTGAATCATTCAGT
G.sub.ksA.sub.ksG.sub.ksT.sub.dsG.sub.dsA.sub.dsA.sub.ds 81 1526
T.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ds
A.sub.ksG.sub.ksT.sub.k 1341164 610 625 N/A N/A GAACAATATGGGATGA
G.sub.ksA.sub.ksA.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsT.sub.ds 49
1735 A.sub.dsT.sub.dsG.sub.dsG.sub.dsG.sub.ksA.sub.esT.sub.ks
G.sub.esA.sub.k 1341172 812 827 15693 15708 CTTATTGGTAAGTATT
.sup.mC.sub.ksT.sub.ksT.sub.dsA.sub.dsT.sub.dsT.sub.dsG.sub.ds 9
1350 G.sub.dsT.sub.dsA.sub.dsA.sub.dsG.sub.ksT.sub.esA.sub.ks
T.sub.esT.sub.k 1341178 698 713 12116 12131 GAGACATGAGGTTTTG
G.sub.ksA.sub.ksG.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.ds 49
725 G.sub.dsA.sub.dsG.sub.dsG.sub.dsT.sub.ksT.sub.esT.sub.ks
T.sub.esG.sub.k 1341186 1079 1094 20894 20909 GCTAGTGCCAAACCAA
G.sub.ks.sup.mC.sub.ksT.sub.dsA.sub.dsG.sub.dsT.sub.dsG.sub.ds 62
1354
.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsA.sub.ks.sup.mC.sub.es
.sup.mC.sub.ksA.sub.esA.sub.k 1341188 1017 1032 20832 20847
CAGCATTGATTCGAAA
.sup.mC.sub.ksA.sub.ksG.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.ds 58 263
T.sub.dsG.sub.dsA.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ksG.sub.es
A.sub.ksA.sub.esA.sub.k 1341192 1200 1215 21015 21030
ATGTTTATGTAAGCAC
A.sub.ksT.sub.ksG.sub.dsT.sub.dsT.sub.dsT.sub.dsA.sub.ds 61 2622
T.sub.dsG.sub.dsT.sub.dsA.sub.dsA.sub.ksG.sub.es.sup.mC.sub.ks
A.sub.es.sup.mC.sub.k 1341196 1088 1103 20903 20918
TTGACTGCTGCTAGTG
T.sub.ksT.sub.ksG.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.ds 29
28 .sup.mC.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.ksA.sub.es
G.sub.ksT.sub.esG.sub.k 1341199 1083 1098 20898 20913
TGCTGCTAGTGCCAAA
T.sub.ksG.sub.ks.sup.mC.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.ds 40
1665 T.sub.dsA.sub.dsG.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.ks
.sup.mC.sub.esA.sub.ksA.sub.esA.sub.k 1341203 1311 1326 21126 21141
TCTTAAACCTTCCCTG
T.sub.ks.sup.mC.sub.ksT.sub.dsT.sub.dsA.sub.dsA.sub.dsA.sub.ds 24
2160
.sup.mC.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ks.sup.mC.su-
b.es .sup.mC.sub.ksT.sub.esG.sub.k 1341208 1315 1330 21130 21145
ACAGTCTTAAACCTTC
A.sub.ks.sup.mC.sub.ksA.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.ds 46 110
T.sub.dsT.sub.dsA.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.ks
.sup.mC.sub.esT.sub.ksT.sub.es.sup.mC.sub.k 1341209 1257 1272 21072
21087 AGCTTTTGTCCACCTT
A.sub.ksG.sub.ks.sup.mC.sub.dsT.sub.dsT.sub.dsT.sub.dsT.sub.ds 62
1822
G.sub.dsT.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ks.sup.mC.sub.es
.sup.mC.sub.ksT.sub.esT.sub.k 1341215 1323 1338 21138 21153
CTACTTGAACAGTCTT
.sup.mC.sub.ksT.sub.ksA.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ds 47 734
G.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.ksT.sub.es
.sup.mC.sub.ksT.sub.esT.sub.k 1341221 1327 1342 21142 21157
AATGCTACTTGAACAG
A.sub.ksA.sub.ksT.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.ds 39
1045 .sup.mC.sub.dsT.sub.dsT.sub.dsG.sub.dsA.sub.ksA.sub.es
.sup.mC.sub.ksA.sub.esG.sub.k 1341224 1337 1352 21152 21167
TACAGATTGGAATGCT
T.sub.ksA.sub.ks.sup.mC.sub.dsA.sub.dsG.sub.dsA.sub.dsT.sub.ds 35
1746 T.sub.dsG.sub.dsG.sub.dsA.sub.dsA.sub.ksT.sub.esG.sub.ks
.sup.mC.sub.esT.sub.k 1341229 1331 1346 21146 21161
TTGGAATGCTACTTGA
T.sub.ksT.sub.ksG.sub.dsG.sub.dsA.sub.dsA.sub.dsT.sub.ds 54 1279
G.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.ksT.sub.es
T.sub.ksG.sub.esA.sub.k 1341230 1351 1366 21166 21181
TTCTGTGGCATGGCTA
T.sub.ksT.sub.ks.sup.mC.sub.dsT.sub.dsG.sub.dsT.sub.dsG.sub.ds 50
812 G.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.dsG.sub.ksG.sub.es
.sup.mC.sub.ksT.sub.esA.sub.k 1341235 1355 1370 21170 21185
GATATTCTGTGGCATG
G.sub.ksA.sub.ksT.sub.dsA.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ds 52
1046 T.sub.dsG.sub.dsT.sub.dsG.sub.dsG.sub.ks.sup.mC.sub.esA.sub.ks
T.sub.esG.sub.k 1341245 1391 1406 21206 21221 GATCTCTTAGCTGTGC
G.sub.ksA.sub.ksT.sub.ds.sup.mC.sub.dsT.sub.ds.sup.mC.sub.ds 45 502
T.sub.dsT.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.ksG.sub.es
T.sub.ksG.sub.es.sup.mC.sub.k 1341249 1359 1374 21174 21189
TGTTGATATTCTGTGG
T.sub.ksG.sub.ksT.sub.dsT.sub.dsG.sub.dsA.sub.dsT.sub.ds 54 1358
A.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.ksG.sub.esT.sub.ks
G.sub.esG.sub.k 1341252 1431 1446 21246 21261 AAATATGTCCAGGTTG
A.sub.ksA.sub.ksA.sub.dsT.sub.dsA.sub.dsT.sub.dsG.sub.ds 61 581
T.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.ksG.sub.es
T.sub.ksT.sub.esG.sub.k 1341253 1419 1434 21234 21249
GTTGAGATAAAGCTGC
G.sub.ksT.sub.ksT.sub.dsG.sub.dsA.sub.dsG.sub.dsA.sub.ds 40 1748
T.sub.dsA.sub.dsA.sub.dsA.sub.dsG.sub.ks.sup.mC.sub.esT.sub.ks
G.sub.es.sup.mC.sub.k 1341256 1423 1438 21238 21253
CCAGGTTGAGATAAAG
.sup.mC.sub.ks.sup.mC.sub.ksA.sub.dsG.sub.dsG.sub.dsT.sub.ds 55 33
T.sub.dsG.sub.dsA.sub.dsG.sub.dsA.sub.dsT.sub.ksA.sub.es
A.sub.ksA.sub.esG.sub.k 1341264 1492 1507 21307 21322
CACCGTTTTGGGCTAA
.sup.mC.sub.ksA.sub.ks.sup.mC.sub.ds.sup.mC.sub.dsG.sub.dsT.sub.ds
42 1516
T.sub.dsT.sub.dsT.sub.dsG.sub.dsG.sub.dsG.sub.ks.sup.mC.sub.es
T.sub.ksA.sub.esA.sub.k 1341270 1602 1617 21417 21432
ATGTATCTTATAAGAC
A.sub.ksT.sub.ksG.sub.dsT.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.ds 18
1751 T.sub.dsT.sub.dsA.sub.dsT.sub.dsA.sub.ksA.sub.esG.sub.ks
A.sub.es.sup.mC.sub.k 1341272 1501 1516 21316 21331
ATAGAGTTGCACCGTT
A.sub.ksT.sub.ksA.sub.dsG.sub.dsA.sub.dsG.sub.dsT.sub.ds 45 192
T.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ks.sup.mC.sub.es
G.sub.ksT.sub.esT.sub.k 1341276 1617 1632 21432 21447
CGGTCACCTTTCATAA
.sup.mC.sub.ksG.sub.ksG.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ds 70 36
.sup.mC.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ks
A.sub.esT.sub.ksA.sub.esA.sub.k 1341278 1621 1636 21436 21451
GAGTCGGTCACCTTTC
G.sub.ksA.sub.ksG.sub.dsT.sub.ds.sup.mC.sub.dsG.sub.dsG.sub.ds 62
350
T.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksT.sub.es
T.sub.ksT.sub.es.sup.mC.sub.k 1341282 1625 1640 21440 21455
AATAGAGTCGGTCACC
A.sub.ksA.sub.ksT.sub.dsA.sub.dsG.sub.dsA.sub.dsG.sub.ds 13 662
T.sub.ds.sup.mC.sub.dsG.sub.dsG.sub.dsT.sub.ks.sup.mC.sub.es
A.sub.ks.sup.mC.sub.es.sup.mC.sub.k 1341289 1629 1644 21444 21459
TTAAAATAGAGTCGGT
T.sub.ksT.sub.ksA.sub.dsA.sub.dsA.sub.dsA.sub.dsT.sub.ds 51 973
A.sub.dsG.sub.dsA.sub.dsG.sub.dsT.sub.ks.sup.mC.sub.esG.sub.ks
G.sub.esT.sub.k 1341293 1713 1728 21528 21543 AACATCTCTGGGACCA
A.sub.ksA.sub.ks.sup.mC.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.ds 36 273
T.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.dsG.sub.dsG.sub.ksA.sub.es
.sup.mC.sub.ks.sup.mC.sub.esA.sub.k 1341294 1708 1723 21523 21538
CTCTGGGACCAAGGAT
.sup.mC.sub.ksT.sub.ks.sup.mC.sub.dsT.sub.dsG.sub.dsG.sub.ds 39
1908 G.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.ks
G.sub.esG.sub.ksA.sub.esT.sub.k 1341301 1777 1792 21592 21607
ATGTAATAGCCAGTAC
A.sub.ksT.sub.ksG.sub.dsT.sub.dsA.sub.dsA.sub.dsT.sub.ds 47 430
A.sub.dsG.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ksG.sub.es
T.sub.ksA.sub.es.sup.mC.sub.k 1341304 1766 1781 21581 21596
AGTACAGTTCCTTTTC
A.sub.ksG.sub.ksT.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.ds 40
1597 T.sub.dsT.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub.ksT.sub.es
T.sub.ksT.sub.es.sup.mC.sub.k 1341311 1773 1788 21588 21603
AATAGCCAGTACAGTT
A.sub.ksA.sub.ksT.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.ds 36 118
.sup.mC.sub.dsA.sub.dsG.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.ks
A.sub.esG.sub.ksT.sub.esT.sub.k 1341319 1781 1796 21596 21611
TCTTATGTAATAGCCA
T.sub.ks.sup.mC.sub.ksT.sub.dsT.sub.dsA.sub.dsT.sub.dsG.sub.ds 65
742 T.sub.dsA.sub.dsA.sub.dsT.sub.dsA.sub.ksG.sub.es.sup.mC.sub.ks
.sup.mC.sub.esA.sub.k 1341322 2254 2269 22069 22084
CAAGAGGATAGTCCAT
.sup.mC.sub.ksA.sub.ksA.sub.dsG.sub.dsA.sub.dsG.sub.dsG.sub.ds 22
510 A.sub.dsT.sub.dsA.sub.dsG.sub.dsT.sub.ks.sup.mC.sub.es
.sup.mC.sub.ksA.sub.esT.sub.k 1341326 2245 2260 22060 22075
AGTCCATGCAAAAGCA
A.sub.ksG.sub.ksT.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ds 52 120
T.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsA.sub.ksA.sub.es
G.sub.ks.sup.mC.sub.esA.sub.sk 1341327 2191 2206 22006 22021
GTCTTGATGTAGTGGG
G.sub.ksT.sub.ks.sup.MC.sub.dsT.sub.dsT.sub.dsG.sub.dsA.sub.ds 18
1132 T.sub.dsG.sub.dsT.sub.dsA.sub.dsG.sub.ksT.sub.esG.sub.ks
G.sub.esG.sub.k 1341333 N/A N/A 9518 9533 CTACACTAATATTGAG
.sup.mC.sub.ksT.sub.ksA.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ds
5 59 T.sub.dsA.sub.dsA.sub.dsT.sub.dsA.sub.dsT.sub.ksT.sub.es
G.sub.ksA.sub.esG.sub.k 1341338 2355 2370 22170 22185
TTATAACTACAAGAGG
T.sub.ksT.sub.ksA.sub.dsT.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.ds 55
1289 T.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.ksG.sub.esA.sub.ks
G.sub.esG.sub.k 1341345 N/A N/A 11853 11868 AGCAGAATTGTGAACG
A.sub.ksG.sub.ks.sup.mC.sub.dsA.sub.dsG.sub.dsA.sub.dsA.sub.ds 31
844 T.sub.dsT.sub.dsG.sub.dsT.sub.dsG.sub.ksA.sub.esA.sub.ks
.sup.mC.sub.esG.sub.k 1341357 N/A N/A 12421 12436 TGGTAACGGTGATCAA
T.sub.ksG.sub.ksG.sub.dsT.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.ds 26
67 G.sub.dsG.sub.dsT.sub.dsG.sub.dsA.sub.ksT.sub.es.sup.mC.sub.ks
A.sub.esA.sub.k 1341368 N/A N/A 16131 16146 GCTCCATAATAATAGC
G.sub.ks.sup.mC.sub.ksT.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ds
15 2665 T.sub.dsA.sub.dsA.sub.dsT.sub.dsA.sub.dsA.sub.ksT.sub.es
A.sub.ksG.sub.es.sup.mC.sub.k 1341374 N/A N/A 18099 18114
CTGAAATTGATACACC
.sup.mC.sub.ksT.sub.ksG.sub.dsA.sub.dsA.sub.dsA.sub.dsT.sub.ds 45
393 T.sub.dsG.sub.dsA.sub.dsT.sub.dsA.sub.ks.sup.mC.sub.esA.sub.ks
.sup.mC.sub.es.sup.mC.sub.k 1341378 N/A N/A 17991 18006
GTTAGTATAGTTATCT
G.sub.ksT.sub.ksT.sub.dsA.sub.dsG.sub.dsT.sub.dsA.sub.ds 51 1171
T.sub.dsA.sub.dsG.sub.dsT.sub.dsT.sub.ksA.sub.esT.sub.ks
.sup.mC.sub.esT.sub.k 1341381 N/A N/A 19911 19926 GCATCTTAAGATACCC
G.sub.ks.sup.mC.sub.ksA.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.ds 41 553
T.sub.dsA.sub.dsA.sub.dsG.sub.dsA.sub.dsT.sub.ksA.sub.es
.sup.mC.sub.k.sup.mC.sub.es.sup.mC.sub.sk 1341385 N/A N/A 19907
19922 CTTAAGATACCCAGGT
.sup.mC.sub.ksT.sub.ksT.sub.dsA.sub.dsA.sub.dsG.sub.dsA.sub.ds 34
241
T.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksA.sub.es
G.sub.ksG.sub.esT.sub.k 1341390 N/A N/A 20114 20129
GCATCAAGACATTCTA
G.sub.ks.sup.mC.sub.ksA.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ds 43
1565 A.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.ksT.sub.es
.sup.mC.sub.ksT.sub.esA.sub.k 1341398 N/A N/A 20194 20209
TTGCAGTTATTAGAAG
T.sub.ksT.sub.ksG.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.dsT.sub.ds 27
2123 T.sub.dsA.sub.dsT.sub.dsT.sub.dsA.sub.ksG.sub.esA.sub.ks
A.sub.esG.sub.k 1341403 N/A N/A 12801 12816 AGGCTGTAAGAGTCAG
A.sub.ksG.sub.ksG.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.dsT.sub.ds 38
2809 A.sub.dsA.sub.dsG.sub.dsA.sub.dsG.sub.ksT.sub.es.sup.mC.sub.ks
A.sub.esG.sub.k 1341405 N/A N/A 12501 12516 GCAGAAATTCACCTTG
G.sub.ks.sup.mC.sub.ksA.sub.dsG.sub.dsA.sub.dsA.sub.dsA.sub.ds 53
1002
T.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ks.sup.mC.sub.es
T.sub.ksT.sub.esG.sub.k 1341409 N/A N/A 20422 20437
ACAGTAAAATTATGCC
A.sub.ks.sup.mC.sub.ksA.sub.dsG.sub.dsT.sub.dsA.sub.dsA.sub.ds 28
477 A.sub.dsA.sub.dsT.sub.dsT.sub.dsA.sub.ksT.sub.esG.sub.ks
.sup.mC.sub.es.sup.mC.sub.k 1341411 N/A N/A 14194 14209
TGTGATTGAGTTCTCC
T.sub.ksG.sub.ksT.sub.dsG.sub.dsA.sub.dsT.sub.dsT.sub.ds 11 2020
G.sub.dsA.sub.dsG.sub.dsT.sub.dsT.sub.ks.sup.mC.sub.esT.sub.ks
.sup.mC.sub.es.sup.mC.sub.k 1341414 N/A N/A 14168 14183
ATAGCAAGCCAACAGA
A.sub.ksT.sub.ksA.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.ds 23
2633
G.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.ks.sup.mC.sub.es
A.sub.ksG.sub.esA.sub.k 1341528 1075 1090 20890 20905
GTGCCAAACCAATGTT
G.sub.ksT.sub.ksG.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ds 38
1042 A.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.ks
T.sub.esG.sub.ksT.sub.esT.sub.k 1341536 801 816 15682 15697
GTATTCCATCTATCAG
G.sub.ksT.sub.ksA.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ds 48 727
.sup.mC.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.ks
T.sub.es.sup.mC.sub.ksA.sub.esG.sub.k 1341537 791 806 15672 15687
TATCAGACTTCTTACG
T.sub.ksA.sub.ksT.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.dsA.sub.ds 32
103 .sup.mC.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.ksT.sub.es
A.sub.ks.sup.mC.sub.esG.sub.k 1341542 1319 1334 21134 21149
TTGAACAGTCTTAAAC
T.sub.ksT.sub.ksG.sub.dsA.sub.dsA.sub.ds.sup.MC.sub.dsA.sub.ds 37
422 G.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ksA.sub.esA.sub.ks
A.sub.es.sup.mC.sub.k 1341544 1264 1279 21079 21094
GGGAGGTAGCTTTTGT
G.sub.ic.sub.sG.sub.ic.sub.sG.sub.dsA.sub.dsG.sub.dsG.sub.ds 66 343
T.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ksT.sub.es
T.sub.ksG.sub.esT.sub.k 1341548 1384 1399 21199 21214
TAGCTGTGCACTCATT
T.sub.ksA.sub.ksG.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.dsT.sub.ds 53
1981
G.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.ks.sup.mC.sub.es
A.sub.ksT.sub.esT.sub.k 1341550 1398 1413 21213 21228
GAAACTTGATCTCTTA
G.sub.ksA.sub.ksA.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ds 54
2717 G.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.ks.sup.mC.sub.es
T.sub.ksT.sub.esA.sub.k 1341553 1346 1361 21161 21176
TGGCATGGCTACAGAT
T.sub.ksG.sub.ksG.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.dsG.sub.ds 58
423 G.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.ksA.sub.es
G.sub.ksA.sub.esT.sub.k 1341559 1488 1503 21303 21318
GTTTTGGGCTAATGAA
G.sub.ksT.sub.ksT.sub.dsT.sub.dsT.sub.dsG.sub.dsG.sub.ds 42 1204
G.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.dsA.sub.ksT.sub.esG.sub.ks
A.sub.esA.sub.k 1341562 1496 1511 21311 21326 GTTGCACCGTTTTGGG
G.sub.ksT.sub.ksT.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.ds 35 1827
.sup.mC.sub.ds.sup.mC.sub.dsG.sub.dsT.sub.dsT.sub.dsT.sub.ks
T.sub.esG.sub.ksG.sub.esG.sub.k 1341571 1717 1732 21532 21547
TCTAAACATCTCTGGG
T.sub.ks.sup.mC.sub.ksT.sub.dsA.sub.dsA.sub.dsA.sub.ds 21 2287
.sup.mC.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.ds.sup.mC.sub.ks
T.sub.esG.sub.ksG.sub.esG.sub.k 1341586 2184 2199 21999 22014
TGTAGTGGGAGTCGGA
T.sub.ksG.sub.ksT.sub.dsA.sub.dsG.sub.dsT.sub.dsG.sub.ds 27 587
G.sub.dsG.sub.dsA.sub.dsG.sub.dsT.sub.ks.sup.mC.sub.esG.sub.ks
G.sub.esA.sub.k 1341587 1726 1741 21541 21556 CTAAAATTGTCTAAAC
.sup.mC.sub.ksT.sub.ksA.sub.dsA.sub.dsA.sub.dsA.sub.dsT.sub.ds 19
2590 T.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.ksA.sub.esA.sub.ks
A.sub.es.sup.mC.sub.k 1341590 N/A N/A 9337 9352 CCTCGATCCTATATAC
.sup.mC.sub.ks.sup.mC.sub.ksT.sub.ds.sup.mC.sub.dsG.sub.dsA.sub.ds
3 2812 T.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.dsT.sub.ks
A.sub.esT.sub.ksA.sub.es.sup.mC.sub.k 1341593 N/A N/A 9961 9976
TAAGCTGAGAGTTCTA
T.sub.ksA.sub.ksA.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.ds 29
2499 A.sub.dsG.sub.dsA.sub.dsG.sub.dsT.sub.ksT.sub.es.sup.mC.sub.ks
T.sub.esA.sub.k 1341594 N/A N/A 11568 11583 TGACAATGGTTGATAG
T.sub.ksG.sub.ksA.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsT.sub.ds 37
1700 G.sub.dsG.sub.dsT.sub.dsT.sub.dsG.sub.ksA.sub.esT.sub.ks
A.sub.esG.sub.k 1341597 N/A N/A 9971 9986 TTGAGTAGTGTAAGCT
T.sub.ksT.sub.ksG.sub.dsA.sub.dsG.sub.dsT.sub.dsA.sub.ds 29 2346
G.sub.dsT.sub.dsG.sub.dsT.sub.dsA.sub.ksA.sub.esG.sub.ks
.sup.mC.sub.esT.sub.k 1341598 N/A N/A 16282 16297 TAGTCTTCAGCAAAGT
T.sub.ksA.sub.ksG.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ds 35
2632 .sup.mC.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.ksA.sub.es
A.sub.ksG.sub.esT.sub.k 1341599 N/A N/A 16377 16392
ACCAAACTTCCAGCAG
A.sub.ks.sup.mC.sub.ks.sup.mC.sub.dsA.sub.dsA.sub.dsA.sub.ds 32
1948
.sup.mC.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ks
G.sub.es.sup.mC.sub.ksA.sub.esG.sub.k 1341605 N/A N/A 15491 15506
TTAATGCCACCCTACC
T.sub.ksT.sub.ksA.sub.dsA.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.ds 11
2304
.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksT.su-
b.es A.sub.ks.sup.mC.sub.es.sup.mC.sub.k 1341606 N/A N/A 14204
14219 CAGATTATTATGTGAT
.sup.mC.sub.ksA.sub.ksG.sub.dsA.sub.dsT.sub.dsT.sub.dsA.sub.ds 31
2723 T.sub.dsT.sub.dsA.sub.dsT.sub.dsG.sub.ksT.sub.esG.sub.ks
A.sub.esT.sub.k 1341609 N/A N/A 17986 18001 TATAGTTATCTTCTCA
T.sub.ksA.sub.ksT.sub.dsA.sub.dsG.sub.dsT.sub.dsT.sub.ds 45 2295
A.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ks.sup.mC.sub.es.sup.m
T.sub.ksC.sub.esA.sub.k 1341616 N/A N/A 17996 18011
ATGAAGTTAGTATAGT
A.sub.ksT.sub.ksG.sub.dsA.sub.dsA.sub.dsG.sub.dsT.sub.ds 34 1483
T.sub.dsA.sub.dsG.sub.dsT.sub.dsA.sub.ksT.sub.esA.sub.ks
G.sub.esT.sub.k
TABLE-US-00052 TABLE 52 Inhibition of HSD17B13 RNA by modified
oligonucleotides targeting SEQ ID NO.: 1, and 2 SEQ ID SEQ ID SEQ
ID SEQ ID SEQ Compound NO: 1 NO: 1 NO: 2 NO: 2 Sequence Chemistry
Notation % ID Number Start Site Stop Site Start Site Stop Site (5'
to 3') (5' to 3') inhibition NO 1245927 N/A N/A 3433 3448
AGTAGATGGTAAGTCA
A.sub.ksG.sub.ksT.sub.ksA.sub.dsG.sub.dsA.sub.dsT.sub.dsG.sub.ds 79
121
G.sub.dsT.sub.dsA.sub.dsA.sub.dsG.sub.dsT.sub.ks.sup.mC.sub.ksA.sub.-
k 1246023 N/A N/A 5046 5061 GAGTGAATCATTCAGT
G.sub.ksA.sub.ksG.sub.ksT.sub.dsG.sub.dsA.sub.dsA.sub.dsT.sub.ds 89
1526
.sup.mC.sub.dsA.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ksG.sub.ks
T.sub.k 1341650 1264 1279 21079 21094 GGGAGGTAGCTTTTGT
G.sub.ksG.sub.ksG.sub.ksA.sub.dsG.sub.ysG.sub.dsT.sub.dsA.sub.ds 17
343
G.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsT.sub.dsT.sub.ksG.sub.ksT.sub.-
k 1341653 1316 1331 21131 21146 AACAGTCTTAAACCTT
A.sub.ksA.sub.ks.sup.mC.sub.ksA.sub.dsG.sub.ysT.sub.ds.sup.mC.sub.ds
75 188
T.sub.dsT.sub.dsA.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.ks
T.sub.ksT.sub.k 1341660 1328 1343 21143 21158 GAATGCTACTTGAACA
G.sub.ksA.sub.ksA.sub.ksT.sub.dsG.sub.ys.sup.mC.sub.dsT.sub.ds 48
1123 A.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsG.sub.dsA.sub.dsA.sub.ks
.sup.mC.sub.ksA.sub.k 1341664 1320 1335 21135 21150
CTTGAACAGTCTTAAA
.sup.mC.sub.ksT.sub.ksT.sub.ksG.sub.dsA.sub.ysA.sub.ds.sup.mC.sub.ds
49 500
A.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.ks
A.sub.ksA.sub.k 1341667 1312 1327 21127 21142 GTCTUAAACCTTCCCT
G.sub.ksT.sub.ks.sup.mC.sub.ksT.sub.dsU.sub.ysA.sub.dsA.sub.ds 35
2968
A.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ds
.sup.mC.sub.ks.sup.mC.sub.ksT.sub.k 1341670 1333 1348 21148 21163
GATTGGAATGCTACTT
G.sub.ksA.sub.ksT.sub.ksT.sub.dsG.sub.ysG.sub.dsA.sub.dsA.sub.ds 48
1435
T.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.ksT.sub.ks
T.sub.k 1341676 1324 1339 21139 21154 GCTACTTGAACAGTCT
G.sub.ks.sup.mC.sub.ksT.sub.ksA.sub.dsC.sub.ysT.sub.dsT.sub.ds 82
811 G.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.dsT.sub.ks
.sup.mC.sub.ksT.sub.k 1341678 1356 1371 21171 21186
TGATATTCTGTGGCAT
T.sub.ksG.sub.ksA.sub.ksT.sub.dsA.sub.ysT.sub.dsT.sub.ds 61 1124
.sup.mC.sub.dsT.sub.dsG.sub.dsT.sub.dsG.sub.dsG.sub.ds.sup.mC.sub.ks
A.sub.ksT.sub.k 1341680 1347 1362 21162 21177 GTGGCATGGCTACAGA
G.sub.issT.sub.ksG.sub.issG.sub.dsC.sub.ysA.sub.dsT.sub.ds 49 501
G.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.ks
G.sub.ksA.sub.k 1341683 1340 1355 21155 21170 GGCTACAGATTGGAAT
G.sub.ksG.sub.ks.sup.mC.sub.ksT.sub.dsA.sub.ys.sup.mC.sub.dsA.sub.ds
40 1980
G.sub.dsA.sub.dsT.sub.dsT.sub.dsG.sub.dsG.sub.dsA.sub.ksA.sub.ks
T.sub.k 1341690 1364 1379 21179 21194 GTTCUTGTTGATATTC
G.sub.ksT.sub.ksT.sub.ks.sup.mC.sub.dsU.sub.ysT.sub.dsG.sub.ds 70
2969
T.sub.dsT.sub.dsG.sub.dsA.sub.dsT.sub.dsA.sub.dsT.sub.ksT.sub.ks
.sup.mC.sub.k 1341696 1352 1367 21167 21182 ATTCUGTGGCATGGCT
A.sub.ksT.sub.ksT.sub.ks.sup.mC.sub.dsU.sub.ysG.sub.dsT.sub.ds 59
2970 G.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.dsG.sub.dsG.sub.ks
.sup.mC.sub.ksT.sub.k 1341699 1387 1402 21202 21217
TCTTAGCTGTGCACTC
T.sub.ks.sup.mC.sub.ksT.sub.ksT.sub.dsA.sub.ysG.sub.ds.sup.mC.sub.ds
71 190
T.sub.dsG.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ks
T.sub.ks.sup.mC.sub.k 1341705 1393 1408 21208 21223
TTGAUCTCTTAGCTGT
T.sub.ksT.sub.ksG.sub.ksA.sub.dsU.sub.ys.sup.mC.sub.dsT.sub.ds 50
2971
.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.ks
G.sub.ksT.sub.k 1341711 1420 1435 21235 21250 GGTTGAGATAAAGCTG
G.sub.ksG.sub.ksT.sub.ksT.sub.dsG.sub.ysA.sub.dsG.sub.dsA.sub.ds 57
1826
T.sub.dsA.sub.dsA.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.ksT.sub.ksG.sub.-
k 1341714 1425 1440 21240 21255 GTCCAGGTTGAGATAA
G.sub.ksT.sub.ks.sup.mC.sub.ks.sup.mC.sub.dsA.sub.ysG.sub.dsG.sub.ds
68 113
T.sub.dsT.sub.dsG.sub.dsA.sub.dsG.sub.dsA.sub.dsT.sub.ksA.sub.ks
A.sub.k 1341718 1461 1476 21276 21291 CTAGGGAAATCTTTCA
.sup.mC.sub.ksT.sub.ksA.sub.ksG.sub.dsG.sub.ysG.sub.dsA.sub.ds 19
659 A.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsT.sub.ks
.sup.mC.sub.ksA.sub.k 1341721 693 708 12111 12126 ATGAGGTTTTGATACC
A.sub.ksT.sub.ksG.sub.ksA.sub.dsG.sub.ysG.sub.dsT.sub.dsT.sub.ds 49
569 T.sub.dsT.sub.dsG.sub.dsA.sub.dsT.sub.dsA.sub.ks.sup.mC.sub.ks
.sup.mC.sub.k 1341725 1415 1430 21230 21245 AGATAAAGCTGCCTGC
A.sub.ksG.sub.ksA.sub.ksT.sub.dsA.sub.ysA.sub.dsA.sub.dsG.sub.ds 35
1515
.sup.mC.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub.ksG.-
sub.ks .sup.mC.sub.k 1341728 1489 1504 21304 21319 CGTTUTGGGCTAATGA
.sup.mc.sub.ksG.sub.ksT.sub.ksT.sub.dsU.sub.ysT.sub.dsG.sub.ds 34
2972 G.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.dsA.sub.dsT.sub.ks
G.sub.ksA.sub.k 1341731 1497 1512 21312 21327 AGTTGCACCGTTTTGG
A.sub.ksG.sub.ksT.sub.ksT.sub.dsG.sub.ys.sup.mC.sub.dsA.sub.ds 38
1905
.sup.mC.sub.ds.sup.mC.sub.dsG.sub.dsT.sub.dsT.sub.dsT.sub.dsT.sub.ks
G.sub.ksG.sub.k 1341736 1493 1508 21308 21323 GCACCGTTTTGGGCTA
G.sub.ks.sup.mC.sub.ksA.sub.ks.sup.mC.sub.dsC.sub.ysG.sub.dsT.sub.ds
67 1593
T.sub.dsT.sub.dsT.sub.dsG.sub.dsG.sub.dsG.sub.ds.sup.mC.sub.ks
T.sub.ksA.sub.k 1341738 1622 1637 21437 21452 AGAGUCGGTCACCTTT
A.sub.ksG.sub.ksA.sub.ksG.sub.dsU.sub.ys.sup.mC.sub.dsG.sub.ds 55
2973
G.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.-
sub.ks T.sub.ksT.sub.k 1341744 1504 1519 21319 21334
AGAAUAGAGTTGCACC
A.sub.ksG.sub.ksA.sub.ksA.sub.dsU.sub.ysA.sub.dsG.sub.dsA.sub.d 49
2974
.sub.sG.sub.dsT.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.ks.sup.mC.-
sub.ks .sup.mC.sub.k 1341748 1614 1629 21429 21444 TCACCTTTCATAATGT
T.sub.ks.sup.mC.sub.ksA.sub.ks.sup.mC.sub.dsC.sub.ysT.sub.dsT.sub.dsT
47 2109
.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.dsA.sub.dsA.sub.dsT.sub.ksG.sub.k-
s T.sub.k 1341754 1618 1633 21433 21448 TCGGUCACCTTTCATA
T.sub.ks.sup.mC.sub.ksG.sub.ksG.sub.dsU.sub.ys.sup.mC.sub.dsA.sub.ds
21 2975
.sup.mC.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsA.-
sub.ks T.sub.ksA.sub.k 1341761 1630 1645 21445 21460
TTTAAAATAGAGTCGG
T.sub.ksT.sub.ksT.sub.ksA.sub.dsA.sub.ysA.sub.dsA.sub.dsT.sub.ds 77
1051
A.sub.dsG.sub.dsA.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.ksG.sub.ksG.sub.-
k 1341764 1626 1641 21441 21456 AAATAGAGTCGGTCAC
A.sub.ksA.sub.ksA.sub.ksT.sub.dsA.sub.ysG.sub.dsA.sub.dsG.sub.ds 63
740
T.sub.ds.sup.mC.sub.dsG.sub.dsG.sub.dsT.sub.ds.sup.mC.sub.ksA.sub.ks
.sup.mC.sub.k 1341767 1714 1729 21529 21544 AAACATCTCTGGGACC
A.sub.ksA.sub.ksA.sub.ks.sup.mC.sub.dsA.sub.ysT.sub.ds.sup.mC.sub.ds
66 2129
T.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.dsG.sub.dsG.sub.dsA.sub.ks
.sup.mC.sub.ks.sup.mC.sub.k 1341768 1710 1725 21525 21540
ATCTCTGGGACCAAGG
A.sub.ksT.sub.ks.sup.mC.sub.ksT.sub.dsC.sub.ysT.sub.dsG.sub.ds 52
37
G.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.ks
G.sub.ksG.sub.k 1341773 1718 1733 21533 21548 GTCTAAACATCTCTGG
G.sub.ksT.sub.ks.sup.mC.sub.ksT.sub.dsA.sub.ysA.sub.dsA.sub.ds 47
429
.sup.mC.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.ds.sup.mC.sub.dsT.-
sub.ks G.sub.ksG.sub.k 1341781 1768 1783 21583 21598
CCAGUACAGTTCCTTT
.sup.mC.sub.ks.sup.mC.sub.ksA.sub.ksG.sub.dsU.sub.ysA.sub.ds.sup.mC.sub.d-
s 51 2976
A.sub.dsG.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsT.sub.ks
T.sub.ksT.sub.k 1341783 1750 1765 21565 21580 CTGTGTTAGCTTTAAT
.sup.mC.sub.ksT.sub.ksG.sub.ksT.sub.dsG.sub.ysT.sub.dsT.sub.ds 41
1286 A.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsT.sub.dsA.sub.ks
A.sub.ksT.sub.k 1341787 794 809 15675 15690 ATCTATCAGACTTCTT
A.sub.ksT.sub.ks.sup.mC.sub.ksT.sub.dsA.sub.ysT.sub.ds.sup.mC.sub.ds
34 2728
A.sub.dsG.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ks
T.sub.ksT.sub.k 1341789 1778 1793 21593 21608 TATGUAATAGCCAGTA
T.sub.ksA.sub.ksT.sub.ksG.sub.dsU.sub.ysA.sub.dsA.sub.dsT.sub.ds 43
2977
A.sub.dsG.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsG.sub.ksT.sub.ks
A.sub.k 1341792 1774 1789 21589 21604 TAATAGCCAGTACAGT
T.sub.ksA.sub.ksA.sub.ksT.sub.dsA.sub.ysG.sub.ds.sup.mC.sub.ds 51
196
.sup.mC.sub.dsA.sub.dsG.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.ks
G.sub.ksT.sub.k 1341801 2186 2201 22001 22016 GATGUAGTGGGAGTCG
G.sub.ksA.sub.ksT.sub.ksG.sub.dsU.sub.ysA.sub.dsG.sub.dsT.sub.ds 35
2978
G.sub.dsG.sub.dsG.sub.dsA.sub.dsG.sub.dsT.sub.ks.sup.mC.sub.ksG.sub.-
k 1341806 2193 2208 22008 22023 TAGTCTTGATGTAGTG
T.sub.ksA.sub.ksG.sub.ksT.sub.dsC.sub.ysT.sub.dsT.sub.dsG.sub.ds 56
1288
A.sub.dsT.sub.dsG.sub.dsT.sub.dsA.sub.dsG.sub.ksT.sub.ksG.sub.k
1341807 1782 1797 21597 21612 TTCTUATGTAATAGCC
T.sub.ksT.sub.ks.sup.mC.sub.ksT.sub.dsU.sub.ysA.sub.dsT.sub.ds 66
2979 G.sub.dsT.sub.dsA.sub.dsA.sub.dsT.sub.dsA.sub.dsG.sub.ks
.sup.mC.sub.ks.sup.mC.sub.k 1341816 2257 2272 22072 22087
AAACAAGAGGATAGTC
A.sub.ksA.sub.ksA.sub.ks.sup.mC.sub.dsA.sub.ysA.sub.dsG.sub.ds 53
744
A.sub.dsG.sub.dsG.sub.dsA.sub.dsT.sub.dsA.sub.dsG.sub.ksT.sub.ks
.sup.mC.sub.k
1341817 2247 2262 22062 22077 ATAGUCCATGCAAAAG
A.sub.ksT.sub.ksA.sub.ksG.sub.dsU.sub.ys.sup.mC.sub.ds.sup.mC.sub.ds
57 2980
A.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsA.sub.ks
A.sub.ksG.sub.k 1341820 N/A N/A 9511 9526 AATAUTGAGGCACTGG
A.sub.ksA.sub.ksT.sub.ksA.sub.dsU.sub.ysT.sub.dsG.sub.dsA.sub.ds 48
2981
G.sub.dsG.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.ksG.sub.ks
G.sub.k 1341827 N/A N/A 9330 9345 CCTAUATACATCCAAG
.sup.mC.sub.ks.sup.mC.sub.ksT.sub.ksA.sub.dsU.sub.ysA.sub.dsT.sub.ds
39 2982
A.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.-
sub.ks A.sub.ksG.sub.k 1341830 N/A N/A 9598 9613 ATGTGAAGAGCTGGTA
A.sub.ksT.sub.ksG.sub.ksT.sub.dsG.sub.ysA.sub.dsA.sub.dsG.sub.ds 26
527
A.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsG.sub.dsG.sub.ksT.sub.ksA.sub.-
k 1341832 N/A N/A 9964 9979 GTGTAAGCTGAGAGTT
G.sub.ksT.sub.ksG.sub.ksT.sub.dsA.sub.ysA.sub.dsG.sub.ds 55 2760
.sup.mC.sub.dsT.sub.dsG.sub.dsA.sub.dsG.sub.dsA.sub.dsG.sub.ks
T.sub.ksT.sub.k 1341840 N/A N/A 11543 11558 TGACAATGGTTGCCAC
T.sub.ksG.sub.ksA.sub.ks.sup.mC.sub.dsA.sub.ysA.sub.dsT.sub.ds 55
1233
G.sub.dsG.sub.dsT.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.ds.sup.mC.sub.ks
A.sub.ks.sup.mC.sub.k 1341842 N/A N/A 11548 11563 TCTCUTGACAATGGTT
T.sub.ks.sup.mC.sub.ksT.sub.ks.sup.mC.sub.dsU.sub.ysT.sub.dsG.sub.ds
62 2983 11573 11588
A.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsT.sub.dsG.sub.dsG.sub.ks
T.sub.ksT.sub.k 1341845 N/A N/A 11858 11873 GATTAAGCAGAATTGT
G.sub.ksA.sub.ksT.sub.ksT.sub.dsA.sub.ysA.sub.dsG.sub.ds 28 1156
.sup.mC.sub.dsA.sub.dsG.sub.dsA.sub.dsA.sub.dsT.sub.dsT.sub.ks
G.sub.ksT.sub.k 1341847 805 820 15686 15701 GTAAGTATTCCATCTA
G.sub.ksT.sub.ksA.sub.ksA.sub.dsG.sub.ysT.sub.dsA.sub.dsT.sub.ds 43
1038
T.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.ds.sup.mC.sub.ksT.-
sub.ks A.sub.k 1341851 N/A N/A 14196 14211 TATGUGATTGAGTTCT
T.sub.ksA.sub.ksT.sub.ksG.sub.dsU.sub.ysG.sub.dsA.sub.dsT.sub.ds 21
2984
T.sub.dsG.sub.dsA.sub.dsG.sub.dsT.sub.dsT.sub.ks.sup.mC.sub.ksT.sub.-
k 1341853 N/A N/A 12416 12431 ACGGUGATCAAATGTA
A.sub.ks.sup.mC.sub.ksG.sub.ksG.sub.dsU.sub.ysG.sub.dsA.sub.dsT 18
2985
.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsA.sub.dsT.sub.dsG.sub.ksT.sub.k-
s A.sub.k 1341855 N/A N/A 12426 12441 CAGGGTGGTAACGGTG
.sup.mC.sub.ksA.sub.ksG.sub.ksG.sub.dsG.sub.ysT.sub.dsG.sub.ds 29
2729 G.sub.dsT.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.dsG.sub.dsG.sub.ks
T.sub.ksG.sub.k 1341860 N/A N/A 16134 16149 GATGCTCCATAATAAT
G.sub.ksA.sub.ksT.sub.ksG.sub.dsC.sub.ysT.sub.ds.sup.mC.sub.ds 24
2049 .sup.mC.sub.dsA.sub.dsT.sub.dsA.sub.dsA.sub.dsT.sub.dsA.sub.ks
A.sub.ksT.sub.k 1341861 N/A N/A 14914 14929 ACATUAGCAAGCTAAG
A.sub.ks.sup.mC.sub.ksA.sub.ksT.sub.dsU.sub.ysA.sub.dsG.sub.ds 23
2986
.sup.mC.sub.dsA.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.ks
A.sub.ksG.sub.k 1341862 N/A N/A 15494 15509 GCATUAATGCCACCCT
G.sub.ks.sup.mC.sub.ksA.sub.ksT.sub.dsU.sub.ysA.sub.dsA.sub.ds 32
2987
T.sub.dsG.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ds
.sup.mC.sub.ks.sup.mC.sub.ksT.sub.k 1341870 N/A N/A 16287 16302
TAGAATAGTCTTCAGC
T.sub.ksA.sub.ksG.sub.ksA.sub.dsA.sub.ysT.sub.dsA.sub.dsG.sub.ds 30
1403
T.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ksG.sub.ks
.sup.mC.sub.k 1341877 N/A N/A 16124 16139 AATAATAGCTCTATTG
A.sub.ksA.sub.ksT.sub.ksA.sub.dsA.sub.ysT.sub.dsA.sub.dsG.sub.ds 16
2410
.sup.mC.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.dsT.sub.ksT.sub.ks
G.sub.k 1341882 N/A N/A 17992 18007 AGTTAGTATAGTTATC
AG.sub.ksT.sub.ksT.sub.dsA.sub.ysG.sub.dsT.sub.dsA.sub.ds 42 1249
T.sub.dsA.sub.dSG.sub.dsT.sub.dsT.sub.dsA.sub.ksT.sub.ks.sup.mC.sub.-
k 1341887 N/A N/A 16380 16395 CCAACCAAACTTCCAG
.sup.mC.sub.ks.sup.mC.sub.ksA.sub.ksA.sub.dsC.sub.ys.sup.mC.sub.dsA.sub.d-
s 30 2539
A.sub.dsA.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ds.sup.mC.-
sub.ks A.sub.ksG.sub.k 1341889 N/A N/A 17987 18002 GTATAGTTATCTTCTC
G.sub.ksT.sub.ksA.sub.ksT.sub.dsA.sub.ysG.sub.dsT.sub.dsT.sub.ds 54
937
A.sub.dsT.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.ksT.sub.ks
.sup.mC.sub.k 1341890 1082 1097 20897 20912 GCTGCTAGTGCCAAAC
G.sub.ks.sup.mC.sub.ksT.sub.ksG.sub.dsC.sub.ysT.sub.dsA.sub.ds 39
1587
G.sub.dsT.sub.dsG.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.ks
A.sub.ks.sup.mC.sub.k 1341895 N/A N/A 18099 18114 CTGAAATTGATACACC
.sup.mC.sub.ksT.sub.ksG.sub.ksA.sub.dsA.sub.ysA.sub.dsT.sub.ds 71
393 T.sub.dsG.sub.dsA.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.dsA.sub.ks
.sup.mC.sub.ks.sup.mC.sub.k 1341896 N/A N/A 17997 18012
TATGAAGTTAGTATAG
T.sub.ksA.sub.ksT.sub.ksG.sub.dsA.sub.ysA.sub.dsG.sub.dsT.sub.ds 27
1560
T.sub.dsA.sub.dsG.sub.dsT.sub.dsA.sub.dsT.sub.ksA.sub.ksG.sub.k
1341900 N/A N/A 19911 19926 GCATCTTAAGATACCC
G.sub.ks.sup.mC.sub.ksA.sub.ksT.sub.dsC.sub.ysT.sub.dsT.sub.ds 65
553 A.sub.dsA.sub.dsG.sub.dsA.sub.dsT.sub.dsA.sub.ds.sup.mC.sub.ks
.sup.mC.sub.ks.sup.mC.sub.k 1341907 N/A N/A 18697 18712
CAAAAGACTTTGAGAC
.sup.mC.sub.ksA.sub.ksA.sub.ksA.sub.dsA.sub.ysG.sub.dsA.sub.ds 25
2186 .sup.mC.sub.dsT.sub.dsT.sub.dsT.sub.dsG.sub.dsA.sub.dsG.sub.ks
A.sub.ks.sup.mC.sub.k 1341908 N/A N/A 19915 19930 GAGTGCATCTTAAGAT
G.sub.ksA.sub.ksG.sub.ksT.sub.dsG.sub.ys.sup.mC.sub.dsA.sub.ds 7
2256 T.sub.ds.sup.mC.sub.dsT.sub.dsT.sub.dsA.sub.dsA.sub.dsG.sub.ks
A.sub.ksT.sub.k 1341914 N/A N/A 19907 19922 CTTAAGATACCCAGGT
.sup.mC.sub.ksT.sub.ksT.sub.ksA.sub.dsA.sub.ysG.sub.dsA.sub.ds 50
241
T.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.ds.sup.mC.sub.dsA.sub.ds
G.sub.ksG.sub.ksT.sub.k 1341919 N/A N/A 20109 20124
AAGACATTCTAGCCTG
A.sub.ksA.sub.ksG.sub.ksA.sub.dsC.sub.ysA.sub.dsT.sub.dsT.sub.ds 54
2744
.sup.mC.sub.dsT.sub.dsA.sub.dsG.sub.ds.sup.mC.sub.ds.sup.mC.sub.ksT.-
sub.ks G.sub.k 1341923 N/A N/A 20119 20134 TTACAGCATCAAGACA
T.sub.ksT.sub.ksA.sub.ks.sup.mC.sub.dsA.sub.ysG.sub.ds.sup.mC.sub.ds
46 2409
A.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsG.sub.dsA.sub.ks
.sup.mC.sub.ksA.sub.k 1341924 1078 1093 20893 20908
CTAGUGCCAAACCAAT
.sup.mC.sub.ksT.sub.ksA.sub.ksG.sub.dsU.sub.ysG.sub.ds.sup.mC.sub.ds
45 2988
.sup.mC.sub.dsA.sub.dsA.sub.dsA.sub.ds.sup.mC.sub.ds.sup.mC.sub.ds
A.sub.ksA.sub.ksT.sub.k 1341928 N/A N/A 20194 20209
TTGCAGTTATTAGAAG
T.sub.ksT.sub.ksG.sub.ks.sup.mC.sub.dsA.sub.ysG.sub.dsT.sub.ds 17
2123 T.sub.dsA.sub.dsT.sub.dsT.sub.dsA.sub.dsG.sub.dsA.sub.ks
A.sub.ksG.sub.k 1341930 N/A N/A 20383 20398 GTAAUCACAAGTAAGG
G.sub.ksT.sub.ksA.sub.ksA.sub.dsU.sub.ys.sup.mC.sub.dsA.sub.ds 20
2989 .sup.mC.sub.dsA.sub.dsA.sub.dsG.sub.dsT.sub.dsA.sub.dsA.sub.ks
G.sub.ksG.sub.k 1341941 N/A N/A 20489 20504 CATAACTTCATAGTGG
.sup.mC.sub.ksA.sub.ksT.sub.ksA.sub.dsA.sub.ys.sup.mC.sub.dsT.sub.ds
38 866
T.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.dsA.sub.dsG.sub.dsT.sub.ks
G.sub.ksG.sub.k 1341942 1074 1089 20889 20904 TGCCAAACCAATGTTT
T.sub.ksG.sub.ks.sup.mC.sub.ks.sup.mC.sub.dsA.sub.ysA.sub.dsA.sub.ds
35 2673
.sup.mC.sub.ds.sup.mC.sub.dsA.sub.dsA.sub.dsT.sub.dsG.sub.dsT.sub.ks
T.sub.ksT.sub.k 1341948 N/A N/A 12503 12518 TTGCAGAAATTCACCT
T.sub.ksT.sub.ksG.sub.ks.sup.mC.sub.dsA.sub.ysG.sub.dsA.sub.ds 29
2528
A.sub.dsA.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.ds.sup.mC.sub.ks
.sup.mC.sub.ksT.sub.k 1341953 1086 1101 20901 20916
GACTGCTGCTAGTGCC
G.sub.ksA.sub.ks.sup.mC.sub.ksT.sub.dsG.sub.ys.sup.mC.sub.dsT.sub.ds
60 1899
G.sub.ds.sup.mC.sub.dsT.sub.dsA.sub.dsG.sub.dsT.sub.dsG.sub.ks.sup.m
C.sub.ks.sup.mC.sub.k 1341957 N/A N/A 20479 20494 TAGTGGACTTCATTAG
T.sub.ksA.sub.ksG.sub.ksT.sub.dsG.sub.ysG.sub.dsA.sub.ds 34 2351
.sup.mC.sub.dsT.sub.dsT.sub.ds.sup.mC.sub.dsA.sub.dsT.sub.dsT.sub.ks
A.sub.ksG.sub.k
Example 5: Dose-Dependent Inhibition of Human HSD17B13 in HepaRG
Cells by Modified Oligonucleotides
[0526] Certain modified oligonucleotides described in the studies
above exhibiting significant in vitro inhibition of HSD17B13 RNA
were selected and tested at various doses in HepaRG cells.
[0527] The modified oligonucleotides were tested in a series of
experiments using the same culture conditions. The results for each
experiment are presented in separate tables shown below. Cultured
HepaRG cells at a density of 30,000-35,000 cells per well were
transfected using electroporation with modified oligonucleotides
diluted to different concentrations as specified in the tables
below. After a treatment period of approximately 24 hours, HSD17B13
RNA levels were measured as previously described using the Human
HSD17B13 primer-probe set RTS43553. HSD17B13 RNA levels were
normalized to total RNA content, as measured by human GAPDH.
Results are presented in the tables below as percent inhibition of
HSD17B13, relative to untreated control cells. Data indicated as
"N.D." (no data) means that no data is available for that treatment
with that compound.
[0528] The half maximal inhibitory concentration (IC.sub.50) of
each modified oligonucleotide was calculated using a linear
regression on a log/linear plot of the data in excel and is also
presented in the Tables below.
TABLE-US-00053 TABLE 53 Multi-dose assay of modified
oligonucleotides in HepaRG cells % inhibition HSD17B13 ION
IC.sub.50 No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (.mu.M) 1245094 0
5 75 68 N.D. 0.3 1245641 5 16 52 75 80 0.4 1245744 5 11 40 81 87
0.4 1245822 0 0 57 78 93 0.1 1245901 1 14 38 55 78 0.8 1245927 8 42
76 83 92 0.2 1245952 25 34 51 70 86 0.2 1245979 4 0 38 64 75 0.8
1246005 1 14 60 64 78 0.5 1246134 0 50 75 79 N.D. 0.2 1246135 10 10
42 68 88 0.5 1246161 18 20 63 75 86 0.3 1246550 14 28 58 76 88 0.3
1246706 60 69 68 76 N.D. 0.02
TABLE-US-00054 TABLE 54 Multi-dose assay of modified
oligonucleotides in HepaRG cells % inhibition HSD17B13 ION
IC.sub.50 No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (.mu.M) 1245096 3
17 70 85 N.D. 0.2 1245097 4 40 75 80 76 0.2 1245565 2 0 26 56 65
1.5 1245798 16 37 57 82 90 0.2 1245825 0 11 44 64 81 0.6 1245851 0
9 45 69 84 0.6 1245927 0 25 56 79 82 0.4 1245928 7 42 67 89 95 0.2
1245980 12 43 94 84 N.D. 0.1 1246059 1 15 44 68 81 0.5 1246084 4 18
69 89 93 0.2 1246110 10 41 71 90 N.D. 0.1 1246111 0 22 44 79 83 0.4
1246162 33 31 71 88 94 0.1 1246163 1 17 42 73 92 0.4
TABLE-US-00055 TABLE 55 Multi-dose assay of modified
oligonucleotides in HepaRG cells % inhibition HSD17B13 ION
IC.sub.50 No. 19 nM 78 nM 313 nM 1250 nM 5000 nM (.mu.M) 1245098 25
27 71 80 71 0.2 1245463 0 0 20 63 78 0.9 1245696 15 30 52 74 89 0.3
1245800 0 30 55 82 82 0.3 1245904 12 19 51 73 97 0.3 1245927 3 11
48 68 76 0.6 1245930 7 26 58 77 89 0.3 1245957 0 0 54 75 86 0.5
1245982 7 25 45 78 92 0.3 1245983 0 18 42 67 90 0.5 1246035 0 2 51
73 75 0.6 1246113 12 0 47 75 84 0.6 1247023 0 23 46 75 90 0.4
1247048 9 22 41 74 84 0.4 1247075 0 0 4 50 68 2.0
TABLE-US-00056 TABLE 56 Multi-dose assay of modified
oligonucleotides in HepaRG cells % inhibition HSD17B13 ION
IC.sub.50 No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (.mu.M) 1245075 20
50 62 75 86 0.1 1245829 18 33 58 83 94 0.2 1245855 16 21 59 78 89
0.3 1245927 0 21 54 69 76 0.5 1245932 22 24 56 90 94 0.2 1245933 23
24 63 76 89 0.2 1245958 12 31 43 87 84 0.3 1245959 1 10 46 65 90
0.5 1245984 9 37 62 76 93 0.2 1246036 15 33 65 80 95 0.2 1246063 16
29 53 84 85 0.2 1246115 0 38 66 88 92 0.2 1246140 20 2 54 75 86 0.5
1246192 0 17 52 72 89 0.5 1247024 16 45 82 89 97 0.1
TABLE-US-00057 TABLE 57 Multi-dose assay of modified
oligonucleotides in HepaRG cells % inhibition HSD17B13 ION
IC.sub.50 No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (.mu.M) 1245076 0
0 32 66 83 0.6 1245415 0 0 22 65 88 0.9 1245649 8 23 49 79 97 0.3
1245857 0 2 35 74 91 0.6 1245927 4 25 57 82 86 0.3 1245960 14 34 54
78 88 0.2 1245986 2 2 30 78 95 0.4 1245987 26 32 58 82 91 0.2
1246013 0 0 27 68 83 0.8 1246064 19 36 63 74 92 0.2 1246116 17 41
75 92 95 0.1 1246169 0 0 30 55 86 1.0 1246195 0 0 26 63 82 0.9
1246610 5 0 2 57 82 1.3 1247078 3 4 28 66 93 0.6
TABLE-US-00058 TABLE 58 Multi-dose assay of modified
oligonucleotides in HepaRG cells % inhibition HSD17B13 ION
IC.sub.50 No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (.mu.M) 1245105 0
0 24 61 88 0.8 1245651 3 22 49 78 89 0.3 1245676 0 0 34 67 91 0.7
1245806 28 27 51 69 91 0.2 1245807 1 9 47 80 90 0.4 1245858 16 39
66 86 96 0.2 1245927 0 22 46 79 89 0.4 1245988 8 26 40 65 85 0.5
1246066 26 41 63 86 94 0.1 1246067 0 0 40 51 85 0.9 1246093 0 0 24
64 86 0.7 1246144 5 30 43 78 86 0.3 1246145 0 3 40 72 85 0.6
1246248 28 32 62 86 92 0.1 1247029 0 0 11 36 73 1.9
TABLE-US-00059 TABLE 59 Multi-dose assay of modified
oligonucleotides in HepaRG cells % inhibition HSD17B13 ION
IC.sub.50 No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (.mu.M) 1245080 7
13 39 70 87 0.5 1245081 4 28 44 72 85 0.4 1245106 0 28 46 80 81 0.4
1245809 0 0 1 48 77 1.6 1245886 0 4 21 62 80 0.9 1245927 16 29 64
84 90 0.2 1245964 16 22 48 72 95 0.3 1245990 15 4 29 61 86 0.7
1245991 0 9 26 63 83 0.8 1246068 14 31 49 73 92 0.3 1246095 10 16
46 69 88 0.4 1246121 0 18 37 76 86 0.5 1246173 3 26 58 83 89 0.3
1246562 5 19 26 70 88 0.5
TABLE-US-00060 TABLE 60 Multi-dose assay of modified
oligonucleotides in HepaRG cells % inhibition HSD17B13 ION
IC.sub.50 No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (.mu.M) 1245212 3
1 43 63 88 0.6 1245680 0 0 22 64 82 0.9 1245681 0 17 58 80 94 0.3
1245888 17 22 41 72 87 0.4 1245927 0 16 52 78 93 0.4 1245967 0 9 41
62 89 0.6 1246019 17 26 62 92 91 0.2 1246070 7 31 46 74 94 0.3
1246123 0 16 37 58 83 0.7 1246226 12 30 56 86 89 0.2 1246227 0 6 0
55 78 1.4 1246824 0 0 17 40 81 1.5 1246902 0 17 40 74 86 0.5
1246903 35 35 60 68 84 0.2 1246929 0 18 40 65 87 0.6
TABLE-US-00061 TABLE 61 Multi-dose assay of modified
oligonucleotides in HepaRG cells % inhibition HSD17B13 ION
IC.sub.50 No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (.mu.M) 1245085 18
21 49 79 95 0.3 1245162 19 5 41 78 97 0.4 1245579 0 8 39 65 87 0.6
1245656 20 33 47 80 83 0.3 1245682 23 42 53 87 93 0.2 1245838 9 0
28 77 92 0.5 1245916 1 25 26 60 82 0.7 1245927 14 36 76 77 86 0.2
1245968 24 43 69 88 88 0.1 1245969 0 9 32 67 74 0.9 1246124 7 12 31
76 90 0.5 1246203 0 0 21 58 87 1.0 1246489 2 14 44 86 86 0.4
1246853 0 0 16 52 77 1.3 1247061 0 12 32 70 93 0.5
TABLE-US-00062 TABLE 62 Multi-dose assay of modified
oligonucleotides in HepaRG cells % inhibition HSD17B13 ION
IC.sub.50 No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (.mu.M) 1245580 3
9 49 58 89 0.5 1245607 0 16 33 77 87 0.5 1245684 35 51 77 92 96 0.1
1245685 13 25 59 80 93 0.2 1245736 0 0 45 81 95 0.6 1245737 13 23
53 83 94 0.3 1245919 0 0 0 72 90 1.0 1245927 0 9 37 84 77 0.4
1245996 29 53 74 91 97 0.1 1245997 16 31 54 79 90 0.2 1246022 49 54
80 93 94 0.0 1246023 0 40 89 86 95 0.2 1246048 12 0 73 73 97 0.3
1246074 7 43 73 84 94 0.2 1246075 0 0 41 70 88 0.7
TABLE-US-00063 TABLE 63 Multi-dose assay of modified
oligonucleotides in HepaRG cells % inhibition HSD17B13 ION
IC.sub.50 No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (.mu.M) 1245141 12
30 57 84 90 0.2 1245374 29 7 43 65 85 0.4 1245660 7 12 36 73 94 0.4
1245738 36 38 61 80 88 0.1 1245790 50 61 68 87 95 <0.2 1245927 0
23 58 85 90 0.3 1245972 24 39 58 79 90 0.2 1245973 0 26 41 66 75
0.5 1245998 12 10 43 78 89 0.4 1245999 0 19 60 87 88 0.3 1246025 35
54 84 94 89 0.0 1246051 4 26 54 78 92 0.3 1246128 37 38 58 84 92
0.1 1246701 0 4 12 20 40 5.0 1246909 0 17 27 66 86 0.7
TABLE-US-00064 TABLE 64 Multi-dose assay of modified
oligonucleotides in HepaRG cells % inhibition HSD17B13 ION
IC.sub.50 No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (.mu.M) 1245142 0
9 40 64 78 0.8 1245246 15 32 33 74 91 0.3 1245610 28 44 61 82 97
0.1 1245715 0 0 37 65 86 0.9 1245844 38 37 53 75 89 0.1 1245927 11
27 64 75 81 0.3 1245975 0 11 48 71 82 0.5 1246027 0 2 15 71 85 0.8
1246052 36 41 57 79 85 0.1 1246053 0 0 9 56 74 1.5 1246104 21 40 64
77 91 0.2 1246105 0 0 3 47 73 1.8 1246130 35 13 54 78 91 0.2
1246157 44 37 62 78 91 0.1 1246391 0 0 2 48 83 1.5
TABLE-US-00065 TABLE 65 Multi-dose assay of modified
oligonucleotides in HepaRG cells % inhibition HSD17B13 ION
IC.sub.50 No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (.mu.M) 1245092 9
20 39 68 89 0.4 1245639 0 0 21 65 85 0.8 1245716 20 27 40 69 86 0.4
1245927 0 0 25 74 64 1.2 1245976 9 29 57 77 86 0.3 1245977 0 21 44
76 94 0.4 1246002 38 51 64 79 91 0.1 1246028 0 0 19 56 80 1.2
1246029 0 18 50 73 86 0.4 1246081 5 19 48 75 88 0.4 1246185 13 15
43 62 79 0.6 1246314 3 8 36 72 92 0.5 1246340 28 32 37 58 85 0.4
1246705 1 14 20 42 70 1.8 1246861 0 0 7 25 63 5.0
TABLE-US-00066 TABLE 66 Multi-dose assay of modified
oligonucleotides in HepaRG cells % inhibition HSD17B13 ION
IC.sub.50 No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (.mu.M) 1246023 9
21 57 83 87 0.3 1340071 0 0 0 56 88 1.3 1340085 0 0 27 68 91 0.8
1340154 0 20 48 80 90 0.4 1340360 0 0 0 51 42 3.8 1340385 4 35 69
82 72 0.3 1340448 0 0 27 78 74 0.9 1340543 5 15 62 78 86 0.3
1340546 0 12 40 65 56 1.2 1340549 0 4 50 78 92 0.4 1340601 0 0 31
54 81 1.1 1340684 0 0 31 58 84 0.9 1340704 0 8 25 69 83 0.8 1340762
0 13 41 71 79 0.7 1340878 1 1 30 79 85 0.6
TABLE-US-00067 TABLE 67 Multi-dose assay of modified
oligonucleotides in HepaRG cells % inhibition HSD17B13 ION
IC.sub.50 No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (.mu.M) 1246023 0
20 55 82 88 0.4 1340206 0 22 55 71 90 0.4 1340208 12 12 51 69 92
0.4 1340226 0 0 43 73 96 0.6 1340260 0 0 33 56 78 1.0 1340268 0 0
35 55 90 0.9 1340334 0 5 30 67 86 0.8 1340397 0 0 49 73 88 0.7
1340555 1 13 41 63 76 0.7 1340585 0 13 47 77 74 0.6 1340603 18 16
47 69 85 0.4 1340647 14 35 76 83 94 0.2 1340789 10 14 32 73 83 0.5
1340834 14 18 48 74 79 0.4 1340895 0 19 32 65 87 0.6
TABLE-US-00068 TABLE 68 Multi-dose assay of modified
oligonucleotides in HepaRG cells % inhibition HSD17B13 ION
IC.sub.50 No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (.mu.M) 1246023 0
25 47 76 85 0.4 1340168 6 0 32 80 90 0.6 1340401 4 11 50 78 79 0.4
1340449 26 8 59 81 93 0.3 1340548 0 17 51 78 92 0.4 1340626 0 5 45
80 90 0.5 1340646 6 31 57 67 58 0.6 1340653 2 0 38 69 77 0.8
1340780 6 23 36 73 83 0.5 1340820 20 35 55 84 88 0.2 1340821 0 0 21
40 60 2.7 1340847 9 20 45 60 88 0.5 1340857 0 0 11 46 66 2.3
1340859 14 32 47 71 84 0.3 1340908 16 33 60 84 92 0.2
TABLE-US-00069 TABLE 69 Multi-dose assay of modified
oligonucleotides in HepaRG cells % inhibition HSD17B13 ION
IC.sub.50 No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (.mu.M) 1246023 0
16 42 80 87 0.5 1340153 0 18 38 75 82 0.5 1340227 0 21 57 70 90 0.4
1340435 14 27 57 78 90 0.3 1340441 6 14 32 70 74 0.7 1340493 13 23
54 70 88 0.3 1340510 11 13 27 66 87 0.6 1340511 0 0 7 52 74 1.6
1340572 19 23 53 75 89 0.3 1340630 20 25 42 75 87 0.3 1340670 16 24
51 74 93 0.3 1340782 0 26 54 77 92 0.3 1340840 0 3 23 43 67 1.9
1340848 0 0 30 71 91 0.7 1340861 22 34 47 74 90 0.2
TABLE-US-00070 TABLE 70 Multi-dose assay of modified
oligonucleotides in HepaRG cells % inhibition HSD17B13 ION
IC.sub.50 No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (.mu.M) 1246023 3
22 55 79 84 0.3 1340159 10 13 49 83 80 0.4 1340481 0 0 34 64 82 0.8
1340502 0 4 37 71 87 0.6 1340564 5 10 34 72 85 0.5 1340635 7 21 40
79 82 0.4 1340649 0 0 42 69 89 0.6 1340672 0 20 47 72 76 0.6
1340743 12 18 46 80 90 0.3 1340779 5 7 39 68 40 0.6 1340793 3 24 66
86 91 0.2 1340796 0 19 61 88 84 0.3 1340799 16 34 72 86 89 0.2
1340827 16 31 48 72 81 0.3 1340881 10 28 52 59 79 0.4
TABLE-US-00071 TABLE 71 Multi-dose assay of modified
oligonucleotides in HepaRG cells % inhibition HSD17B13 ION
IC.sub.50 No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (.mu.M) 1246023 0
20 42 58 79 0.7 1341183 11 18 27 53 57 2.0 1341190 0 3 29 53 48 2.4
1341193 11 27 53 63 68 0.5 1341195 15 13 12 61 71 1.2 1341239 16 0
27 62 83 0.7 1341262 0 4 36 52 78 0.9 1341273 6 18 38 63 81 0.6
1341303 29 21 44 61 90 0.3 1341313 9 33 58 67 85 0.3 1341315 8 28
52 79 82 0.3 1341342 24 25 37 51 81 0.6 1341348 15 25 43 71 70 0.5
1341391 0 2 35 49 70 1.3 1341547 13 2 40 61 83 0.6
TABLE-US-00072 TABLE 72 Multi-dose assay of modified
oligonucleotides in HepaRG cells % inhibition HSD17B13 ION
IC.sub.50 No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (.mu.M) 1246023 19
1 38 77 89 0.4 1341026 10 20 43 73 83 0.4 1341032 0 13 14 74 92 0.6
1341035 5 0 36 62 74 1.0 1341036 23 28 53 78 93 0.2 1341038 17 25
57 76 85 0.3 1341052 6 13 52 69 79 0.5 1341062 0 23 47 66 79 0.5
1341095 0 17 51 61 81 0.6 1341108 28 34 58 81 83 0.2 1341146 6 0 39
66 70 0.9 1341206 28 25 45 81 87 0.2 1341260 23 24 37 66 78 0.5
1341283 8 23 40 67 90 0.4 1341308 18 29 54 71 86 0.3
TABLE-US-00073 TABLE 73 Multi-dose assay of modified
oligonucleotides in HepaRG cells % inhibition HSD17B13 ION
IC.sub.50 No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (.mu.M) 1246023 0
0 47 66 89 0.6 1340983 0 0 26 55 45 3.1 1340995 1 17 37 66 62 0.9
1341011 0 0 34 50 81 1.0 1341043 0 3 40 50 44 2.2 1341050 0 7 39 55
76 0.9 1341057 6 9 39 57 78 0.8 1341068 0 0 11 46 79 1.5 1341075 0
0 0 39 55 3.1 1341118 0 8 13 31 74 2.2 1341145 0 17 37 69 83 0.6
1341154 0 0 47 43 79 1.0 1341244 10 0 21 55 68 1.5 1341335 0 0 25
51 55 2.4 1341510 4 17 34 57 66 1.0
TABLE-US-00074 TABLE 74 Multi-dose assay of modified
oligonucleotides in HepaRG cells % inhibition HSD17B13 ION
IC.sub.50 No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (.mu.M) 1246023 1
20 59 67 88 0.4 1340992 0 0 0 51 76 1.8 1341004 0 12 31 55 77 0.9
1341022 15 18 25 65 84 0.6 1341048 1 15 43 74 85 0.5 1341077 8 16
38 54 71 0.9 1341104 0 23 38 64 79 0.6 1341140 12 17 41 64 82 0.5
1341151 13 31 52 71 80 0.3 1341271 8 0 43 65 80 0.7 1341318 23 17
49 61 55 1.0 1341436 0 23 46 64 77 0.6 1341437 3 0 16 60 88 0.9
1341654 0 24 53 66 69 0.6 1341668 7 25 42 56 82 0.6
TABLE-US-00075 TABLE 75 Multi-dose assay of modified
oligonucleotides in HepaRG cells % inhibition HSD17B13 ION
IC.sub.50 No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (.mu.M) 1246023 2
24 40 70 92 0.4 1341651 19 35 41 67 85 0.3 1341655 0 0 13 70 89 0.9
1341671 13 27 35 66 91 0.4 1341675 9 22 46 77 76 0.4 1341686 2 2 31
61 78 0.9 1341703 16 14 33 52 58 1.8 1341735 12 32 54 71 84 0.3
1341742 13 26 39 66 84 0.4 1341797 0 0 34 65 91 0.6 1341815 0 21 20
65 75 0.9 1341839 25 16 39 60 87 0.5 1341899 14 28 42 66 77 0.5
1341911 7 29 46 67 90 0.4 1341913 0 2 0 48 59 3.2
TABLE-US-00076 TABLE 76 Multi-dose assay of modified
oligonucleotides in HepaRG cells % inhibition HSD17B13 ION
IC.sub.50 No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (.mu.M) 1246023 0
7 18 81 92 0.6 1341531 18 21 38 62 76 0.6 1341561 26 22 39 75 70
0.4 1341644 0 11 60 82 90 0.4 1341645 0 20 0 39 79 1.8 1341646 3 0
8 57 76 1.3 1341968 0 0 10 72 90 0.8 1341980 8 9 26 54 78 1.0
Example 6: Design of Human HSD17B13 Modified Oligonucleotides
[0529] Certain modified oligonucleotides described above were
further modified by conjugating at the 5'-end with a LICA-1 moiety.
The resulting compounds and their unconjugated counterparts are
listed in the table below. The compounds have identical sequence
and oligonucleotide chemistry as the "parent compounds" described
above.
TABLE-US-00077 TABLE 77 Design of 5'-LICA-1-conjugated modified
oligonucleotides targeting human HSD17B13 GalNac Conjugated Parent
SEQ Compound Compound Sequence ID No. No. (5' to 3') NO 1310535
1246163 CAACTATGTAATAGGC 286 1371966 1245806 AAAATAGAGTCGGTCA 817
1371968 1246068 AGCATAAGTTACCAGA 983 1371969 1246115
AAATTATACTTTTCCG 596 1371971 1246063 GTTTTATAACTGAGCT 594 1371973
1246019 GAATTTTTGAGGTTGG 1215 1371974 1245987 TCTCAAGGAGTACTTC 747
1371976 1245952 GTCATAAAAATCGCTG 43 1371978 1245930
AAGATAAGTAGATGGT 355 1371979 1245972 GCACTAAAGGTTTCTG 1602 1371981
1245980 ATACTAATGTCCAAGG 201 1373086 1245649 CTACTTGAACAGTCTT 734
1373087 1246903 AGTTAGTATAGTTATC 1249 1373089 1246134
CTCATTTATGTACCAA 51 1373090 1246162 ACTATGTAATAGGCAG 208 1373097
1245984 ACAATTTTTCCAATCC 513 1373098 1246022 AGTGAATCATTCAGTA 1449
1373099 1245996 CATTCGAATTTCTTCA 1448 1373101 1245790
GTATCTTATAAGACTA 1595 1394140 1341675 CTACUTGAACAGTCTT 2868 1394141
1340820 GTAGATGGTAAGTCAA 2567 1394142 1341283 TGATATTCTGTGGCAT 1124
1394143 1341313 TATGTAATAGCCAGTA 508 1394144 1341742
GTATCTTATAAGACTA 1595 1394145 1341038 TTCTTATGTAATAGCC 819 1394146
1341735 CACCGTTTTGGGCTAA 1516 1394147 1341032 TTATGTAATAGCCAGT 586
1394148 1341108 GCATCTTAAGATACCC 553 1394149 1340435
TAGAACTGTGTTGCTT 2535 1394150 1340908 TAGAGTGAATCATTCA 2420 1394151
1340208 GAGTAGTGTAAGCTGA 2204 1394152 1340782 GAGATTTGAAGGTTAG 2561
1371970 1246157 GCAGTAAAGTGCTAAG 1843 1371972 1246025
AGCCTTAGAGTGAATC 1682 1373094 1246036 TGAAAACTCAGCCAGC 515 1373096
1245968 GTAATTTTCAGATCCC 1291 1373100 1245682 GTTGATATTCTGTGGC
1280
Example 7: Dose-Dependent Ex-Vivo Inhibition of Human HSD17B13 in
Transgenic Mouse Hepatocytes
[0530] The conjugated modified oligonucleotides described above
were tested for inhibition of HSD17B13 RNA at various doses in
primary mouse hepatocytes extracted from transgenic mice.
[0531] A transgenic mouse model was developed in-house using a
Fosmid containing the human HSD17B13 gene (NCBI Clone DB ID:
ABC8-43206400A10). The clone was digested at Not1 restriction sites
(2 different sites) to produce a fragment containing 19,118 bp of
the human HSD17B13 gene, including 12,175 bp upstream and 7,553 bp
downstream regions. That gene fragment was introduced into
fertilized eggs from C57/BL/6NTac strain mice by pronuclear
injection to produce huHSD 17469 and 17470 founder lines.
Transgenic mice derived from Founder Line 17469 was used in the
experiments described herein. Human HSD17B13 RNA expression is
found in the liver in this model. Mice were sacrified and
hepatocytes were collected for use in experiments testing
conjugated modified oligonucleotides.
[0532] The conjugated modified oligonucleotides were tested in a
series of experiments using the same culture conditions. The
results for each experiment are presented in separate tables shown
below. Primary mouse transgenic hepatocytes described above were
plated at a density of 20,000 cells per well and were treated by
free uptake with conjugated modified oligonucleotides diluted to
different concentrations as specified in the tables below. After an
overnight incubation, HSD17B13 RNA levels were measured as
previously described herein using the Human HSD17B13 primer-probe
set RTS43553. HSD17B13 RNA levels were normalized to total GAPDH
content. Results are presented in the tables below as percent
inhibition of HSD17B13, relative to untreated control cells. The
half maximal inhibitory concentration (IC.sub.50) of each modified
oligonucleotide was calculated using a linear regression on a
log/linear plot of the data in excel and is also presented in the
Tables below.
TABLE-US-00078 TABLE 78 Multi-dose assay of modified
oligonucleotides in primary mouse hepatocytes % Inhibition ION 1.95
7.81 31.25 125 500 2000 IC.sub.50 No. nM nM nM nM nM nM (nM)
1310535 38 53 80 87 85 90 3.2 1371966 41 52 87 88 91 89 4.1 1371968
39 56 84 94 91 90 4.1 1371969 23 60 81 88 88 92 5.2 1371971 6 45 54
70 85 76 34.1 1371973 38 61 84 93 94 96 2.2 1371974 4 31 65 74 74
82 38.6 1371976 16 62 79 87 90 93 7.3 1371978 0 39 84 92 89 88 18.4
1371979 10 38 70 82 85 87 21.0 1371981 33 68 86 94 93 95 1.9
TABLE-US-00079 TABLE 79 Multi-dose assay of modified
oligonucleotides in primary mouse hepatocytes % Inhibition ION 1.95
7.81 31.25 125 500 2000 IC.sub.50 No. nM nM nM nM nM nM (nM)
1373086 24 49 78 83 86 84 8.9 1373087 23 20 67 70 64 65 22.6
1373089 36 62 84 92 91 92 4.0 1373090 43 49 69 81 80 82 5.4 1373097
41 64 84 89 92 91 1.3 1373098 43 69 80 87 89 89 2.3 1373099 19 37
68 84 83 86 13.8 1373101 9 41 66 83 85 92 20.5 1394140 5 42 80 78
85 88 19.6 1394142 5 49 73 87 89 91 16.4 1371966 4 55 77 88 88 87
11.5
TABLE-US-00080 TABLE 80 Multi-dose assay of modified
oligonucleotides in primary mouse hepatocytes % Inhibition ION 1.95
7.81 31.25 125 500 2000 IC.sub.50 No. nM nM nM nM nM nM (nM)
1394143 19 45 80 83 89 89 10.6 1394144 16 21 54 70 75 80 48.1
1394145 37 44 83 91 88 88 6.2 1394146 3 30 67 74 82 77 38.2 1394147
30 71 85 94 94 93 4.0 1394148 41 80 88 90 87 91 1.7 1394149 1 26 56
72 78 82 50.9 1394150 14 45 80 84 88 85 12.8 1394151 0 37 63 81 83
85 42.5 1394152 8 35 63 82 81 87 28.1 1371966 0 61 72 82 89 88
16.7
Example 8: Tolerability of Modified Oligonucleotides Complementary
to Human HSD17B13 in CD-1 Mice
[0533] CD-1 mice are a multipurpose mouse model frequently utilized
for safety and efficacy testing. In this study, CD-1 mice were
treated with conjugated modified oligonucleotides selected from
studies described above and evaluated for changes in the levels of
various plasma chemistry markers.
Treatment
[0534] Groups of 6- to 8-week-old male CD-1 mice were injected
subcutaneously once a week for six weeks (for a total of 7
treatments) with 25 mg/kg of conjugated modified oligonucleotides.
One group of male CD-1 mice was injected with PBS. Mice were
euthanized 48 hours following the final administration.
Study 1
Plasma Chemistry Markers
[0535] To evaluate the effect of conjugated modified
oligonucleotides on liver function, plasma levels of blood urea
nitrogen (BUN), albumin, alanine aminotransferase (ALT), aspartate
aminotransferase (AST), and creatinine (CREA) were measured using
an automated clinical chemistry analyzer (Hitachi Olympus AU400c,
Melville, N.Y.). The results are presented in the table below.
TABLE-US-00081 TABLE 81 Plasma chemistry markers in male CD-1 mice
ION Albumin ALT AST CREA BUN NO. (g/dL) (IU/L) (IU/L) (mg/dL)
(mg/dL) PBS 2.5 25 52 0.2 23 1310535 2.6 32 44 0.2 24 1371966 2.7
31 40 0.2 23 1371968 2.7 26 42 0.2 23 1371969 2.6 28 59 0.2 24
1371970 2.6 277 225 0.2 24 1371971 2.8 41 74 0.2 24 1371972 2.4 810
568 0.2 24 1371973 2.3 50 78 0.2 22 1371974 2.7 60 61 0.2 25
1371976 2.7 32 61 0.2 22 1371978 2.7 51 59 0.2 21 1371979 2.7 32 70
0.2 23
Body and Organ Weights
[0536] Body weights of CD-1 mice were measured at days 1 and 44,
and the average body weight for each group is presented in the
table below. Liver, kidney and spleen weights were measured at the
end of the study and are presented in the table below.
TABLE-US-00082 TABLE 82 Body and organ weights (in grams) ION Body
Weight (g) Liver Kidney Spleen No. Day 1 Day 44 (g) (g) (g) PBS 34
42 2.4 0.5 0.1 1310535 33 42 2.4 0.6 0.1 1371966 32 39 2.2 0.6 0.1
1371968 30 38 2.1 0.5 0.1 1371969 33 43 2.4 0.5 0.1 1371970 29 36
2.1 0.5 0.1 1371971 33 41 2.5 0.6 0.2 1371972 33 40 3.1 0.7 0.2
1371973 31 38 1.7 0.5 0.1 1371974 34 40 2.4 0.6 0.1 1371976 32 40
2.4 0.6 0.1 1371978 32 38 2.4 0.5 0.1 1371979 33 38 2.3 0.6 0.1
Hematology Assays
[0537] Blood obtained from mouse groups at week 6 and was sent to
IDEXX BioResearch for measurement of hematocrit (HCT), and platelet
counts (PLT). The results are presented in the table below.
TABLE-US-00083 TABLE 83 Blood cell counts in male CD-1 mice ION NO.
HCT (%) PLT (10.sup.9/L) PBS 46 1155 1310535 50 1389 1371966 46
1415 1371968 47 1372 1371969 45 1059 1371970 48 1395 1371971 46
1244 1371972 44 1360 1371973 47 968 1371974 45 1362 1371976 49 1199
1371978 47 1417 1371979 48 1190
Study 2
Plasma Chemistry Markers
[0538] To evaluate the effect of modified oligonucleotides on liver
function, plasma levels of blood urea nitrogen (BUN), albumin,
alanine aminotransferase (ALT), aspartate aminotransferase (AST),
and creatinine (CREA) were measured using an automated clinical
chemistry analyzer (Hitachi Olympus AU400c, Melville, N.Y.). The
results are presented in the table below.
TABLE-US-00084 TABLE 84 Plasma chemistry markers in male CD-1 mice
ION Albumin ALT AST CREA BUN NO. (g/dL) (IU/L) (IU/L) (mg/dL)
(mg/dL) PBS 2.8 36 57 0.11 19 1371981 2.7 26 39 0.14 24 1373086 2.6
39 59 0.12 24 1373087 2.6 31 54 0.13 23 1373089 2.5 107 88 0.12 24
1373090 2.5 27 45 0.11 25 1373094 2.8 687 532 0.15 23 1373096 2.7
57 87 0.13 23 1373097 2.4 67 71 0.13 23 1373098 2.5 67 73 0.12 24
1373099 2.7 43 75 0.12 22 1373100 2.7 373 365 0.12 25 1373101 2.5
153 179 0.14 23
Body and Organ Weights
[0539] Body weights of CD-1 mice were measured at days 1 and 42,
and the average body weight for each group is presented in the
table below. Liver, kidney and spleen weights were measured at the
end of the study and are presented in the table below.
TABLE-US-00085 TABLE 85 Body and organ weights (in grams) ION Body
Weight (g) Liver Kidney Spleen No. Day 1 Day 42 (g) (g) (g) PBS 27
38 1.9 0.6 0.1 1371981 27 39 2.5 0.6 0.1 1373086 27 38 2.1 0.5 0.1
1373087 27 40 2.4 0.6 0.1 1373089 26 39 2.8 0.5 0.1 1373090 27 38
2.4 0.5 0.2 1373094 28 41 2.9 0.6 0.2 1373096 27 42 2.5 0.6 0.2
1373097 27 42 2.52 0.49 0.17 1373098 27 39 2.48 0.51 0.13 1373099
27 39 2.44 0.61 0.14 1373100 26 37 2.11 0.52 0.16 1373101 29 45
2.68 0.63 0.20
Hematology Assays
[0540] Blood obtained from mouse groups at week 6 and was sent to
IDEXX BioResearch for measurement of hematocrit (HCT), platelet
counts (PLT), neutrophil counts (NEU), reticulocyte counts (RET)
and lymphocyte counts (LYM). The results are presented in the table
below.
TABLE-US-00086 TABLE 86 Blood cell counts in male CD-1 mice ION HCT
PLT NEU RET LYM NO. (%) (10.sup.3/.mu.L) (%) (%) (%) PBS 45 1150 19
3 77 1371981 46 1398 18 3 76 1373086 44 1415 17 3 74 1373087 42
1343 21 3 73 1373089 43 1216 21 3 72 1373090 42 1332 21 3 52
1373094 44 1307 24 3 68 1373096 47 1161 19 3 69 1373097 42 1394 25
3 67 1373098 44 1432 24 4 68 1373099 44 1201 20 3 75 1373100 41
1031 16 3 77 1373101 45 1236 28 4 65
Study 3
Plasma Chemistry Markers
[0541] To evaluate the effect of modified oligonucleotides on liver
function, plasma levels of blood urea nitrogen (BUN), albumin,
alanine aminotransferase (ALT), aspartate aminotransferase (AST),
total bilirubin (TBIL) and creatinine (CREA) were measured using an
automated clinical chemistry analyzer (Hitachi Olympus AU400c,
Melville, N.Y.). The results are presented in the table below.
TABLE-US-00087 TABLE 87 Plasma chemistry markers in male CD-I mice
ION Albumin ALT AST CREA BUN TBIL NO. (g/dL) (IU/L) (IU/L) (mg/dL)
(mg/dL) (mg/dL) PBS 2.8 25 56 0.1 26 0.2 1394140 2.9 38 72 0.2 24
0.2 1394142 2.5 67 92 0.1 23 0.2 1394143 2.7 30 55 0.1 22 0.2
1394144 2.7 37 69 0.1 24 0.2 1394145 2.7 50 67 0.1 25 0.1 1394146
2.8 142 203 0.1 24 0.2 1394147 2.5 63 80 0.1 25 0.1 1394148 3.1 219
193 0.1 23 0.2 1394149 2.9 746 757 0.2 25 0.3 1394150 2.7 608 451
0.1 22 0.2
Body and Organ Weights
[0542] Body weights of CD-1 mice were measured at days 1 and 39,
and the average body weight for each group is presented in the
table below. Liver, kidney and spleen weights were measured at the
end of the study and are presented in the table below.
TABLE-US-00088 TABLE 88 Body and organ weights (in grams) ION Body
Weight (g) Liver Kidney Spleen No. Day 1 Day 39 (g) (g) (g) PBS 29
36 1.8 0.5 0.1 1394140 28 36 2.0 0.5 0.1 1394142 30 38 1.8 0.5 0.2
1394143 29 37 2.1 0.5 0.1 1394144 29 37 2.1 0.5 0.1 1394145 30 38
2.4 0.5 0.2 1394146 29 37 2.1 0.5 0.1 1394147 31 38 2.5 0.5 0.2
1394148 29 37 2.6 0.5 0.2 1394149 27 35 2.3 0.4 0.1 1394150 27 35
2.3 0.5 0.2
Hematology Assays
[0543] Blood obtained from mouse groups at week 6 were sent to
IDEXX BioResearch for measurement of hematocrit (HCT), platelet
counts (PLT), neutrophil counts (NEU), reticulocyte counts (RET)
and lymphocyte counts (LYM). The results are presented in the table
below.
TABLE-US-00089 TABLE 89 Blood cell counts in male CD-1 mice ION HCT
PLT NEU RET LYM NO. (%) (10.sup.3/.mu.L) (%) (%) (%) PBS 53 1271 17
3 74 1394140 52 1221 20 3 72 1394142 50 1249 28 3 64 1394143 50
1165 17 3 76 1394144 49 1090 18 3 75 1394145 52 1292 21 3 73
1394146 50 1382 27 3 66 1394147 52 1343 22 3 69 1394148 52 1286 27
3 64 1394149 46 1613 26 3 66 1394150 47 1444 13 2 79
Example 9: Tolerability of Modified Oligonucleotides Targeting
Human HSD17B13 in Sprague-Dawley Rats
[0544] Sprague-Dawley rats are a multipurpose model used for safety
and efficacy evaluations. In this study, the rats were treated with
Ionis conjugated modified oligonucleotides from the studies
described in the Examples above and evaluated for changes in the
levels of various plasma chemistry markers.
Treatment
[0545] Male Sprague-Dawley rats were maintained on a 12-hour
light/dark cycle and fed ad libitum with Purina normal rat chow.
Groups of 4 Sprague-Dawley rats each were weekly injected
subcutaneously with 25 mg/kg of conjugated modified oligonucleotide
for 6 weeks (total 7 doses). 72 hours after the last dose, rats
were euthanized; and organs, urine and plasma were harvested for
further analysis.
Study 1
Plasma Chemistry Markers
[0546] To evaluate the effect of the conjugated modified
oligonucleotides on hepatic function, plasma levels of
transaminases were measured using an automated clinical chemistry
analyzer (Hitachi Olympus AU400c, Melville, N.Y.). Plasma levels of
ALT (alanine transaminase) and AST (aspartate transaminase) were
measured and the results are presented in the Table below expressed
in IU/L. Plasma levels of creatinine (CREA), albumin, and Blood
Urea Nitrogen (BUN) were also measured using the same clinical
chemistry analyzer and the results are also presented in the table
below.
TABLE-US-00090 TABLE 90 Plasma chemistry markers in Sprague-Dawley
rats ION Albumin ALT AST CREA BUN NO. (g/dL) (IU/L) (IU/L) (mg/dL)
(mg/dL) PBS 3.4 34 53 0.3 13 1310535 3.2 35 68 0.3 14 1371966 3.5
33 66 0.3 16 1371968 3.8 36 57 0.4 16 1371969 3.0 25 68 0.3 16
1371970 3.4 48 101 0.3 15 1371971 3.6 34 72 0.3 16 1371972 3.5 51
76 0.4 15 1371973 3.6 36 62 0.3 14 1371974 3.3 37 76 0.4 15 1371976
3.4 31 55 0.3 15 1371978 3.4 37 67 0.3 15 1371979 3.5 117 122 0.3
12
Hematology Assays
[0547] Blood obtained from mouse groups at week 6 and was sent to
IDEXX BioResearch for measurement of hematocrit (HCT), and platelet
counts (PLT). The results are presented in the table below.
TABLE-US-00091 TABLE 91 Blood Cell Count in Sprague-Dawley Rats ION
NO. HCT (%) PLT (10.sup.9/L) PBS 47 849 1310535 43 954 1371966 46
844 1371968 47 1010 1371969 43 810 1371970 48 1016 1371971 46 893
1371972 46 1019 1371973 44 857 1371974 46 930 1371976 45 843
1371978 45 900 1371979 47 1077
Kidney Function
[0548] To evaluate the effect of the conjugated modified
oligonucleotides on kidney function, urinary levels of total
protein and creatinine were measured using an automated clinical
chemistry analyzer (Hitachi Olympus AU400c, Melville, N.Y.). The
ratios of total protein to creatinine (P/C ratio) are presented in
the table below.
TABLE-US-00092 TABLE 92 Total protein to creatinine ratio in
Sprague-Dawley rats ION NO. Urine P/C Ratio PBS 0.5 1310535 0.4
1371966 0.8 1371968 0.7 1371969 0.6 1371970 0.6 1371971 1.1 1371972
0.4 1371973 0.7 1371974 0.8 1371976 0.7 1371978 0.5 1371979 0.8
Body and Organ Weights
[0549] Body weights of Sprague-Dawley rats were measured at days 1
and 40, and the average body weight for each group is presented in
the table below. Liver, heart, spleen and kidney weights were
measured at the end of the study and are presented in the table
below.
TABLE-US-00093 TABLE 93 Body and Organ weights In Sprague-Dawley
rats (g) ION Body Weight (g) Kidney Spleen No. Day 1 Day 40 Liver
(g) (g) (g) PBS 140 464 18 3.2 1.1 1310535 152 476 20 3.7 1.5
1371966 150 437 17 3.1 1.0 1371968 147 419 15 2.9 1.0 1371969 151
423 16 3.5 2.0 1371970 151 440 16 2.9 1.1 1371971 138 406 17 3.1
1.4 1371972 144 424 12 2.7 1.0 1371973 141 401 14 3.0 1.3 1371974
143 443 16 3.0 1.1 1371976 126 412 16 2.8 1.0 1371978 155 452 17
3.3 1.3 1371979 148 458 19 3.1 1.3
Study 2
Plasma Chemistry Markers
[0550] To evaluate the effect of the conjugated modified
oligonucleotides on hepatic function, plasma levels of
transaminases were measured using an automated clinical chemistry
analyzer (Hitachi Olympus AU400c, Melville, N.Y.). Plasma levels of
ALT (alanine transaminase) and AST (aspartate transaminase) were
measured and the results are presented in the Table below expressed
in IU/L. Plasma levels of creatinine (CREA), albumin, and Blood
Urea Nitrogen (BUN) were also measured using the same clinical
chemistry analyzer and the results are also presented in the table
below.
TABLE-US-00094 TABLE 94 Plasma chemistry markers in Sprague-Dawley
rats ION Albumin ALT AST CREA BUN NO. (g/dL) (IU/L) (IU/L) (mg/dL)
(mg/dL) PBS 3.6 33 56 0.3 16 1371981 3.7 35 57 0.3 17 1373086 3.7
35 87 0.4 19 1373087 3.3 33 64 0.4 18 1373089 3.7 92 129 0.3 18
1373090 3.5 38 72 0.4 18 1373094 3.7 187 311 0.4 16 1373096 3.3 69
171 0.3 18 1373097 3.2 40 86 0.3 17 1373098 3.8 37 74 0.3 17
1373099 3.6 33 60 0.4 16 1373100 3.1 39 115 0.3 20 1373101 3.4 37
80 0.3 14
Hematology Assays
[0551] Blood obtained from mouse groups at week 6 were sent to
IDEXX BioResearch for measurement of hematocrit (HCT), and platelet
counts (PLT), neutrophil counts (NEU), reticulocyte counts (RET)
and lymphocyte counts (LYM). The results are presented in the table
below.
TABLE-US-00095 TABLE 95 Blood Cell Count in Sprague-Dawley Rats ION
HCT PLT NEU RET LYM NO. (%) (10.sup.3/.mu.L) (%) (%) (%) PBS 51 709
14 3 72 1371981 52 769 11 2 84 1373086 47 921 8 2 88 1373087 50 764
6 3 89 1373089 49 1217 7 3 88 1373090 50 766 10 4 85 1373094 53 943
14 2 81 1373096 61 376 6 3 89 1373097 49 746 5 3 90 1373098 49 929
10 3 85 1373099 47 717 8 3 85 1373100 42 823 6 4 87 1373101 48 693
7 3 87
Kidney Function
[0552] To evaluate the effect of Ionis oligonucleotides on kidney
function, urinary levels of total protein and creatinine were
measured using an automated clinical chemistry analyzer (Hitachi
Olympus AU400c, Melville, N.Y.). The ratios of total protein to
creatinine (P/C ratio) are presented in the table below.
TABLE-US-00096 TABLE 96 Total protein to creatinine ratio in
Sprague-Dawley rats ION NO. Urine P/C Ratio PBS 1.0 1371981 1.7
1373086 1.5 1373087 1.7 1373089 1.5 1373090 1.3 1373094 3.3 1373096
1.5 1373097 1.3 1373098 1.2 1373099 1.9 1373100 0.9 1373101 1.7
Body and Organ Weights
[0553] Body weights of Sprague-Dawley rats were measured at days 1
and 44, and the average body weight for each group is presented in
the table below. Liver, heart, spleen and kidney weights were
measured at the end of the study and are presented in the table
below.
TABLE-US-00097 TABLE 97 Body and Organ weights In Sprague-Dawley
rats (g) ION Body Weight (g) Liver Kidney Spleen No. Day 1 Day 44
(g) (g) (g) PBS 146 458 19 3.1 1.0 1371981 141 424 21 3.4 1.1
1373086 151 434 19 3.0 1.8 1373087 143 433 19 3.3 1.3 1373089 149
431 21 3.5 2.1 1373090 142 453 19 3.2 1.3 1373094 142 449 19 3.2
1.4 1373096 149 460 23 3.6 3.2 1373097 136 400 17 3.3 2.2 1373098
130 389 20 2.9 1.5 1373099 152 421 16 2.9 1.6 1373100 146 453 19
4.2 2.3 1373101 140 412 17 2.9 1.5
Study 3
Plasma Chemistry Markers
[0554] To evaluate the effect of the conjugated modified
oligonucleotides on hepatic function, plasma levels of
transaminases were measured using an automated clinical chemistry
analyzer (Hitachi Olympus AU400c, Melville, N.Y.). Plasma levels of
ALT (alanine transaminase) and AST (aspartate transaminase) were
measured and the results are presented in the Table below expressed
in IU/L. Plasma levels of creatinine (CREA), albumin, total
bilirubin (TBIL) and Blood Urea Nitrogen (BUN) were also measured
using the same clinical chemistry analyzer and the results are also
presented in the table below.
TABLE-US-00098 TABLE 98 Plasma chemistry markers in Sprague-Dawley
rats ION Albumin ALT AST CREA BUN TBIL NO. (g/dL) (IU/L) (IU/L)
(mg/dL) (mg/dL) (mg/dL) PBS 3.2 41 62 0.3 18 0.2 1394140 3.6 48 123
0.4 20 0.3 1394142 3.0 57 136 0.4 23 0.2 1394143 3.3 122 201 0.3 19
0.4 1394144 3.2 38 73 0.4 18 0.1 1394145 3.6 112 187 0.4 17 0.2
1394146 3.4 54 98 0.4 20 0.2 1394147 3.1 53 110 0.3 18 0.2 1394148
3.5 45 57 0.4 19 0.3 1394149 3.7 94 102 0.5 27 0.3 1394150 3.8 60
83 0.4 19 0.2
Hematology Assays
[0555] Blood obtained from mouse groups at week 6 and was sent to
IDEXX BioResearch for measurement of hematocrit (HCT), and platelet
counts (PLT), neutrophil counts (NEU), reticulocyte counts (RET)
and lymphocyte counts (LYM). The results are presented in the table
below.
TABLE-US-00099 TABLE 99 Blood Cell Count in Sprague-Dawley Rats ION
HCT PLT NEU RET LYM NO. (%) (K/.mu.L) (%) (%) (%) PBS 52 795 12 3
84 1394140 45 876 8 3 88 1394142 47 768 4 3 90 1394143 59 1277 11 2
80 1394144 51 574 6 3 87 1394145 51 806 12 2 82 1394146 48 1052 11
2 81 1394147 49 922 8 3 85 1394148 49 1134 12 3 84 1394149 46 1816
14 3 80 1394150 52 1094 12 3 83
Kidney Function
[0556] To evaluate the effect of Ionis oligonucleotides on kidney
function, urinary levels of total protein and creatinine were
measured using an automated clinical chemistry analyzer (Hitachi
Olympus AU400c, Melville, N.Y.). The ratios of total protein to
creatinine (P/C ratio) are presented in the table below.
TABLE-US-00100 TABLE 100 Total protein to creatinine ratio in
Sprague-Dawley rats ION NO. Urine P/C Ratio PBS 0.8 1394140 1.6
1394142 1.1 1394143 1.3 1394144 1.3 1394145 1.1 1394146 1.8 1394147
1.5 1394148 1.0 1394149 1.1 1394150 1.9
Body and Organ Weights
[0557] Body weights of Sprague-Dawley rats were measured at days 1
and 42, and the average body weight for each group is presented in
the table below. Liver, heart, spleen and kidney weights were
measured at the end of the study and are presented in the table
below.
TABLE-US-00101 TABLE 101 Body and Organ weights In Sprague-Dawley
rats (g) ION Body Weight (g) Liver Kidney Spleen No. Day 1 Day 42
(g) (g) (g) PBS 270 503 19 3.0 0.9 1394140 263 440 19 3.0 1.5
1394142 258 370 13 2.9 1.5 1394143 257 393 16 2.9 1.1 1394144 254
461 18 3.2 1.5 1394145 266 475 21 3.4 1.4 1394146 268 444 17 3.1
1.7 1394147 258 401 17 3.2 2.0 1394148 267 447 21 3.0 1.5 1394149
261 422 20 5.8 1.4 1394150 251 423 18 3.0 1.2
Example 10: Measurement of Viscosity of Modified Oligonucleotides
Targeting Human HSD17B13
[0558] The viscosity of select conjugated modified oligonucleotides
from the studies described above was measured.
[0559] Conjugated modified oligonucleotides (within a range of
32-38 mg) were placed into separate glass vials; approximately 100
.mu.L of water was added to each vial, and the conjugated modified
oligonucleotides were dissolved into solution by heating the vials
to 55.degree. C. A 75 .mu.L portion of the pre-heated sample was
pipetted to a micro-viscometer (PAC Cambridge Viscosity
Viscometer). The temperature of the micro-viscometer was set to
25.degree. C. and the viscosity of the sample was measured. The 75
uL portion of each sample was then combined with the remaining
portion of the original sample, which was then diluted for UV
reading at 260 nM (Cary UV instrument). The data is presented in
the Table below. Compounds having viscosity of less that 40 cP in
this assay are generally suitable for use in therapy.
TABLE-US-00102 TABLE 102 Viscosity of modified oligonucleotides
Concentration Concentration Compound by weight by UV Viscocity ID
(mg/mL) (mg/mL) (cP) 1310535 300 206 6 1371966 300 223 10 1371974
300 207 8 1371976 300 254 64 1371978 300 219 7 1371979 300 244 10
1373086 300 215 7 1373087 300 219 9 1373090 300 191 8 1373097 300
222 6 1373098 300 203 5 1373099 300 242 6 1373101 300 205 11
1394140 300 197 10 1394141 300 225 9 1394142 300 271 24 1394143 300
250 11 1394144 300 257 32 1394145 300 263 10 1394146 300 289 11
1394147 300 246 15 1394148 300 205 9 1394149 300 304 14 1394150 300
202 16 1394151 300 223 8 1394152 300 225 24 1371976 200 151 16
Sequence CWU 0 SQTB SEQUENCE LISTING The patent application
contains a lengthy "Sequence Listing" section. A copy of the
"Sequence Listing" is available in electronic form from the USPTO
web site
(https://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20220273691A1).
An electronic copy of the "Sequence Listing" will also be available
from the USPTO upon request and payment of the fee set forth in 37
CFR 1.19(b)(3).
0 SQTB SEQUENCE LISTING The patent application contains a lengthy
"Sequence Listing" section. A copy of the "Sequence Listing" is
available in electronic form from the USPTO web site
(https://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20220273691A1).
An electronic copy of the "Sequence Listing" will also be available
from the USPTO upon request and payment of the fee set forth in 37
CFR 1.19(b)(3).
* * * * *
References