U.S. patent application number 14/645922 was filed with the patent office on 2015-08-27 for compositions and methods for inhibiting expression of a gene from the jc virus.
The applicant listed for this patent is Alnylam Pharmaceuticals, Inc.. Invention is credited to Birgit Bramlage, Dinah Sah, Pamela Tan.
Application Number | 20150240237 14/645922 |
Document ID | / |
Family ID | 38656415 |
Filed Date | 2015-08-27 |
United States Patent
Application |
20150240237 |
Kind Code |
A1 |
Tan; Pamela ; et
al. |
August 27, 2015 |
Compositions and Methods for Inhibiting Expression of a Gene from
the JC Virus
Abstract
The invention relates to a double-stranded ribonucleic acid
(dsRNA) for inhibiting the expression of a gene from the JC Virus
(JC virus genome), comprising an antisense strand having a
nucleotide sequence which is less that 30 nucleotides in length,
generally 19-25 nucleotides in length, and which is substantially
complementary to at least a part of a gene from the JC Virus. The
invention also relates to a pharmaceutical composition comprising
the dsRNA together with a pharmaceutically acceptable carrier;
methods for treating diseases caused by JC virus expression and the
expression of a gene from the JC Virus using the pharmaceutical
composition; and methods for inhibiting the expression of a gene
from the JC Virus in a cell.
Inventors: |
Tan; Pamela; (Kulmbach,
DE) ; Sah; Dinah; (Boston, MA) ; Bramlage;
Birgit; (Kulmbach, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Alnylam Pharmaceuticals, Inc. |
Cambridge |
MA |
US |
|
|
Family ID: |
38656415 |
Appl. No.: |
14/645922 |
Filed: |
March 12, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13779116 |
Feb 27, 2013 |
9012624 |
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14645922 |
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13252414 |
Oct 4, 2011 |
8410261 |
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13779116 |
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12720465 |
Mar 9, 2010 |
8058257 |
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13252414 |
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11741205 |
Apr 27, 2007 |
7691824 |
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12720465 |
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60795765 |
Apr 28, 2006 |
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Current U.S.
Class: |
514/44A ;
435/320.1; 435/366; 435/375; 536/24.5 |
Current CPC
Class: |
C12N 2310/321 20130101;
C07H 21/02 20130101; C12N 2310/14 20130101; A61P 31/12 20180101;
C12N 2310/315 20130101; A61P 25/28 20180101; A61K 48/005 20130101;
C12N 2310/321 20130101; C12N 15/1131 20130101; C12N 2310/3521
20130101; A61P 31/20 20180101 |
International
Class: |
C12N 15/113 20060101
C12N015/113 |
Claims
1. A double-stranded ribonucleic acid (dsRNA) for inhibiting the
expression of a human JC virus genome in a cell, wherein said dsRNA
comprises at least two sequences that are complementary to each
other and wherein a sense strand comprises a first sequence and an
antisense strand comprises a second sequence comprising a region of
complementarity which is substantially complementary to at least a
part of an mRNA encoding the JC virus, and wherein said region of
complementarity is less than 30 nucleotides in length and wherein
said dsRNA, upon contact with a cell expressing the JC virus,
inhibits expression of the JC virus genome.
2. The dsRNA of claim 1, wherein the first sequence is selected
from the group consisting of Tables 1a and b and the second
sequence is selected from the group consisting of Tables 1a and
b.
3. The dsRNA of claim 1, wherein the dsRNA comprises at least one
modified nucleotide.
4. The dsRNA of claim 2, wherein the dsRNA comprises at least one
modified nucleotide.
5. The dsRNA of claim 3, wherein the modified nucleotide is chosen
from the group of: a 2'-O-methyl modified nucleotide, a nucleotide
comprising a 5'-phosphorothioate group, and a terminal nucleotide
linked to a cholesteryl derivative or dodecanoic acid bisdecylamide
group.
6. The dsRNA of claim 3, wherein the modified nucleotide is chosen
from the group of: a 2'-deoxy-2'-fluoro modified nucleotide, a
2'-deoxy-modified nucleotide, a locked nucleotide, an abasic
nucleotide, 2'-amino-modified nucleotide, 2'-alkyl-modified
nucleotide, morpholino nucleotide, a phosphoramidate, and a
non-natural base comprising nucleotide.
7. The dsRNA of claim 3, wherein the first sequence is selected
from the group consisting of Tables 1a and b and said second
sequence is selected from the group consisting of Tables 1a and
b.
8. The dsRNA of claim 6, wherein the first sequence is selected
from the group consisting of Tables 1a and b and the second
sequence is selected from the group consisting of Tables 1a and
b.
9. A cell comprising the dsRNA of claim 1.
10. A pharmaceutical composition for inhibiting the expression of a
gene from the JC Virus in an organism, comprising the dsRNA of
claim 1 and a pharmaceutically acceptable carrier.
11. The pharmaceutical composition of claim 10, wherein the first
sequence of said dsRNA is selected from the group consisting of
Tables 1a and b and the second sequence of the dsRNA is selected
from the group consisting of Tables 1a and b.
12. The pharmaceutical composition of claim 10, wherein said first
sequence of the dsRNA is selected from the group consisting of
Tables 1a and b and the second sequence of said dsRNA is selected
from the group consisting of Tables 1a and b.
13. A method for inhibiting the expression of a gene from a JC
Virus in a cell, the method comprising: (a) introducing into the
cell the dsRNA of claim 1; and (b) maintaining the cell produced in
step (a) for a time sufficient to obtain degradation of the mRNA
transcript of a gene from the JC Virus, thereby inhibiting
expression of a gene from the JC Virus in the cell.
14. A method of treating or preventing pathological processes
mediated by JC virus expression comprising administering to a
patient in need of such treatment or prevention a therapeutically
or prophylactically effective amount of the dsRNA of claim 1.
15. A vector for inhibiting the expression of a gene from the JC
Virus in a cell, the vector comprising a regulatory sequence
operably linked to a nucleotide sequence that encodes at least one
strand of the dsRNA of claim 1.
16. A cell comprising the vector of claim 15.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 13/779,116, filed on Feb. 27, 2013 (allowed), which is a
continuation of U.S. application Ser. No. 13/252,414, filed on Oct.
4, 2011 (U.S. Pat. No. 8,410,261), which is a continuation of U.S.
application Ser. No. 12/720,465, filed Mar. 9, 2010 (U.S. Pat. No.
8,058,257), which is a continuation of U.S. application Ser. No.
11/741,205, filed Apr. 27, 2007 (U.S. Pat. No. 7,691,824) and
claims the benefit of U.S. Provisional Application No. 60/795,765,
filed Apr. 28, 2006. All of the prior applications are incorporated
herein by reference in their entirety.
FIELD OF THE INVENTION
[0002] This invention relates to double-stranded ribonucleic acid
(dsRNA), and its use in mediating RNA interference to inhibit the
expression of one of the genes of the JC virus and the use of the
dsRNA to treat pathological processes mediated by JC virus
infection, such as PML.
BACKGROUND OF THE INVENTION
[0003] Progressive multifocal leukoencephalopathy (PML) is a fatal
demyelinating disease of the central nervous system which results
from reactivation of the latent polyomavirus JC virus (JCV) and its
productive replication in glial cells of the human brain (Berger,
J. R. (1995) J. Neurovirol. 1:5-18). Once a rare disease primarily
seen in patients with impaired immune systems due to
lymphoproliferative and myeloproliferative disorders, PML has
become one of the major neurologic problems among patients with
AIDS (Cinque, P., (2003). J. Neurovirol. 9(Suppl. 1):88-92).
[0004] It has been reported that between 4 and 8% of AIDS patients
exhibit signs of PML, and JCV has been detected in the
cerebrospinal fluid of affected patients, suggesting that there is
active replication of the virus in the brain (Berger, J. R. (1995)
J. Neurovirol. 1:5-18, Clifford, D. B., (2001) J. Neurovirol.
4:279). In addition, PML has recently been seen in patients
undergoing experimental treatment with Tsybari, an anti VLA4
antibody, in combination with interferon. The histological
hallmarks of PML include multifocal demyelinated lesions with
enlarged eosinophilic nuclei in oligodendrocytes and enlarged
bizarre astrocytes with lobulated hyperchromatic nuclei within
white matter tracts of the brain (Cinque, P., (2003). J.
Neurovirol. 9(Suppl. 1):88-92), although in some instances atypical
features that include a unifocal pattern of demyelination and
involvement of the gray matter have been reported (Sweeney, B. J.,
(1994). J. Neurol. Neurosurg. Psychiatry 57:994-997). Earlier
observations from in vitro cell culture studies and an in vivo
evaluation of JCV in clinical samples led to early assumptions that
oligodendrocytes and astrocytes are the only cells which support
productive viral infections (Gordon, J. (1998) Int. J. Mol. Med.
1:647-655). Accordingly, molecular studies have provided evidence
for cell-type-specific transcription of the viral early genome in
cells derived from the central nervous system (Raj, G. V., (1995)
Virology 10:283-291). However, subsequent studies have shown low,
but detectable, levels of JCV gene expression in nonneural cells,
including B cells, and noticeably high levels of production of the
viral early protein in several neural and nonneural tumor cells in
humans (Gordon, J. (1998) Int. J. Mol. Med. 1:647-655, Khalili, K.,
2003. Oncogene 22:5181-5191).
[0005] Like the other polyomaviruses, JCV is a small DNA virus
whose genome can be divided into three regions that encompass the
transcription control region; the genes responsible for the
expression of the viral early protein, T antigen; and the genes
encoding the viral late proteins, VP1, VP2, and VP3. In addition,
the late genome is also responsible for production of an auxiliary
viral protein, agnoprotein. T-antigen expression is pivotal for
initiation of the viral lytic cycle, as this protein stimulates
transcription of the late genes and induces the process of viral
DNA replication. Recent studies have ascribed an important role for
agnoprotein in the transcription and replication of JCV, as
inhibition of its production significantly reduced viral gene
expression and replication (M. Safak et al., unpublished
observations). Furthermore, the agnoprotein dysregulates the cell
cycle by altering the expression of several cyclins and their
associated kinases (Darbinyan, A., (2002) Oncogene
21:5574-5581).
[0006] Thus far, there are no effective therapies for the
suppression of JCV replication and the treatment of PML. Cytosine
arabinoside (AraC) has been tested for the treatment of PML
patients, and the outcome in some instances revealed a remission of
JCV-associated demyelination (Aksamit, A. (2001) J. Neurovirol.
7:386-390). Reports from the AIDS Clinical Trial Group Organized
Trial 243, however, have suggested that there is no difference in
the survival of human immunodeficiency virus type 1
(HIV-1)-infected patients with PML and that of the control
population, although in other reports it has been suggested that
the failure of AraC in the AIDS Clinical Trial Group trial may have
been due to insufficient delivery of the AraC via the intravenous
and intrathecal routes (Levy, R. M., (2001) J. Neurovirol.
7:382-385). Based on in vitro studies showing the ability of
inhibitors of topoisomerase to suppress JCV DNA replication, the
topoisomerase inhibitor topotecan was used for the treatment of
AIDS-PML patients, and the results suggested that topotecan
treatment may be associated with a decreased lesion size and
prolonged survival (Royal, W., III, (2003) J. Neurovirol.
9:411-419).
[0007] Double-stranded RNA molecules (dsRNA) have been shown to
block gene expression in a highly conserved regulatory mechanism
known as RNA interference (RNAi). WO 99/32619 (Fire et al.)
discloses the use of a dsRNA of at least 25 nucleotides in length
to inhibit the expression of genes in C. elegans. dsRNA has also
been shown to degrade target RNA in other organisms, including
plants (see, e.g., WO 99/53050, Waterhouse et al.; and WO 99/61631,
Heifetz et al.), Drosophila (see, e.g., Yang, D., et al., Curr.
Biol. (2000) 10:1191-1200), and mammals (see WO 00/44895, Limmer;
and DE 101 00 586.5, Kreutzer et al.). This natural mechanism has
now become the focus for the development of a new class of
pharmaceutical agents for treating disorders that are caused by the
aberrant or unwanted regulation of a gene.
[0008] Recent reports have indicated that in vitro, RNAi may show
some promise in reducing JC virus replication (Radhakrishnan, S.
(2004) J. Vir. 78:7264-7269, Orba, Y. (2004) J. Vir. 78:7270-7273).
However, the RNAi agents examined were not designed against all
know JC Virus strains and were not selected for stability and other
properties need for in vivo therapeutic RNAi agents. Accordingly,
despite significant advances in the field of RNAi, there remains a
need for an agent that can selectively and efficiently silence a
gene in the JC virus using the cell's own RNAi machinery that has
both high biological activity and in vivo stability, and that can
effectively inhibit replication of the JC virus for use in treating
pathological processes mediated by JC virus infection.
SUMMARY OF THE INVENTION
[0009] The invention provides double-stranded ribonucleic acid
(dsRNA), as well as compositions and methods for inhibiting the
expression of the JC virus in a cell or mammal using such dsRNA.
The invention also provides compositions and methods for treating
pathological conditions and diseases caused by JC viral infection,
such as PML. The dsRNA of the invention comprises an RNA strand
(the antisense strand) having a region which is less than 30
nucleotides in length, generally 19-24 nucleotides in length, and
is substantially complementary to at least part of an mRNA
transcript of a gene from the JC Virus.
[0010] In one embodiment, the invention provides double-stranded
ribonucleic acid (dsRNA) molecules for inhibiting the expression
one of the genes of the JC virus and viral replication. The dsRNA
comprises at least two sequences that are complementary to each
other. The dsRNA comprises a sense strand comprising a first
sequence and an antisense strand comprising a second sequence. The
antisense strand comprises a nucleotide sequence which is
substantially complementary to at least part of an mRNA encoded by
a gene from the JC Virus, and the region of complementarity is less
than 30 nucleotides in length, generally 19-24 nucleotides in
length. The dsRNA, upon contacting with a cell expressing infected
with the JC virus, inhibits the expression of a gene from the JC
Virus by at least 40%.
[0011] For example, the dsRNA molecules of the invention can be
comprised of a first sequence of the dsRNA that is selected from
the group consisting of the sense sequences of Tables 1a and b and
the second sequence is selected from the group consisting of the
antisense sequences of Tables 1a and b. The dsRNA molecules of the
invention can be comprised of naturally occurring nucleotides or
can be comprised of at least one modified nucleotide, such as a
2'-O-methyl modified nucleotide, a nucleotide comprising a
5'-phosphorothioate group, and a terminal nucleotide linked to a
cholesteryl derivative. Alternatively, the modified nucleotide may
be chosen from the group of: a 2'-deoxy-2'-fluoro modified
nucleotide, a 2'-deoxy-modified nucleotide, a locked nucleotide, an
abasic nucleotide, 2'-amino-modified nucleotide, 2'-alkyl-modified
nucleotide, morpholino nucleotide, a phosphoramidate, and a
non-natural base comprising nucleotide. Generally, such modified
sequence will be based on a first sequence of said dsRNA selected
from the group consisting of the sense sequences of Tables 1a and b
and a second sequence selected from the group consisting of the
antisense sequences of Tables 1a and 1b.
[0012] In another embodiment, the invention provides a cell
comprising one of the dsRNAs of the invention. The cell is
generally a mammalian cell, such as a human cell.
[0013] In another embodiment, the invention provides a
pharmaceutical composition for inhibiting the replication of the JC
virus in an organism, generally a human subject, comprising one or
more of the dsRNA of the invention and a pharmaceutically
acceptable carrier or delivery vehicle.
[0014] In another embodiment, the invention provides a method for
inhibiting the expression of a gene in the JC Virus in a cell,
comprising the following steps: [0015] (a) introducing into the
cell a double-stranded ribonucleic acid (dsRNA), wherein the dsRNA
comprises at least two sequences that are complementary to each
other. The dsRNA comprises a sense strand comprising a first
sequence and an antisense strand comprising a second sequence. The
antisense strand comprises a region of complementarity which is
substantially complementary to at least a part of a mRNA encoded by
the JC virus, and wherein the region of complementarity is less
than 30 nucleotides in length, generally 19-24 nucleotides in
length, and wherein the dsRNA, upon contact with a cell infected
with the JC virus, inhibits expression of a gene from the JC Virus
by at least 40%; and [0016] (b) maintaining the cell produced in
step (a) for a time sufficient to obtain degradation of the mRNA
transcript of a JC virus gene, thereby inhibiting expression of a
gene from the JC Virus in the cell.
[0017] In another embodiment, the invention provides methods for
treating, preventing or managing pathological processes mediated by
JC virus infection, e.g. such as PML, comprising administering to a
patient in need of such treatment, prevention or management a
therapeutically or prophylactically effective amount of one or more
of the dsRNAs of the invention.
[0018] In another embodiment, the invention provides vectors for
inhibiting the expression of a gene of the JC virus in a cell,
comprising a regulatory sequence operably linked to a nucleotide
sequence that encodes at least one strand of one of the dsRNA of
the invention.
[0019] In another embodiment, the invention provides a cell
comprising a vector for inhibiting the expression of a gene of the
JC virus in a cell. The vector comprises a regulatory sequence
operably linked to a nucleotide sequence that encodes at least one
strand of one of the dsRNA of the invention.
BRIEF DESCRIPTION OF THE FIGURES
[0020] No Figures are presented.
DETAILED DESCRIPTION OF THE INVENTION
[0021] The invention provides double-stranded ribonucleic acid
(dsRNA), as well as compositions and methods for inhibiting the
expression of a gene from the JC Virus in a cell or mammal using
the dsRNA. The invention also provides compositions and methods for
treating pathological conditions and diseases in a mammal caused by
JC virus infection using dsRNA. dsRNA directs the sequence-specific
degradation of mRNA through a process known as RNA interference
(RNAi).
[0022] The dsRNA of the invention comprises an RNA strand (the
antisense strand) having a region which is less than 30 nucleotides
in length, generally 19-24 nucleotides in length, and is
substantially complementary to at least part of an mRNA transcript
of a gene from the JC Virus. The use of these dsRNAs enables the
targeted degradation of mRNAs of genes that are implicated in
replication and or maintenance of JC virus infection and the
occurrence of PML in a subject infected with the JC virus. Using
cell-based and animal assays, the present inventors have
demonstrated that very low dosages of these dsRNA can specifically
and efficiently mediate RNAi, resulting in significant inhibition
of expression of a gene from the JC Virus. Thus, the methods and
compositions of the invention comprising these dsRNAs are useful
for treating pathological processes mediated by JC viral infection,
e.g. cancer, by targeting a gene involved in JC virus replication
and/or maintenance in a cell.
[0023] The following detailed description discloses how to make and
use the dsRNA and compositions containing dsRNA to inhibit the
expression of a gene from the JC virus, as well as compositions and
methods for treating diseases and disorders caused by the infection
with the JC virus, such as PML. The pharmaceutical compositions of
the invention comprise a dsRNA having an antisense strand
comprising a region of complementarity which is less than 30
nucleotides in length, generally 19-24 nucleotides in length, and
is substantially complementary to at least part of an RNA
transcript of a gene from the JC Virus, together with a
pharmaceutically acceptable carrier.
[0024] Accordingly, certain aspects of the invention provide
pharmaceutical compositions comprising the dsRNA of the invention
together with a pharmaceutically acceptable carrier, methods of
using the compositions to inhibit expression of a gene in a gene
from the JC Virus, and methods of using the pharmaceutical
compositions to treat diseases caused by infection with the JC
virus.
I. DEFINITIONS
[0025] For convenience, the meaning of certain terms and phrases
used in the specification, examples, and appended claims, are
provided below. If there is an apparent discrepancy between the
usage of a term in other parts of this specification and its
definition provided in this section, the definition in this section
shall prevail.
[0026] "G," "C," "A" and "U" each generally stand for a nucleotide
that contains guanine, cytosine, adenine, and uracil as a base,
respectively. However, it will be understood that the term
"ribonucleotide" or "nucleotide" can also refer to a modified
nucleotide, as further detailed below, or a surrogate replacement
moiety. The skilled person is well aware that guanine, cytosine,
adenine, and uracil may be replaced by other moieties without
substantially altering the base pairing properties of an
oligonucleotide comprising a nucleotide bearing such replacement
moiety. For example, without limitation, a nucleotide comprising
inosine as its base may base pair with nucleotides containing
adenine, cytosine, or uracil. Hence, nucleotides containing uracil,
guanine, or adenine may be replaced in the nucleotide sequences of
the invention by a nucleotide containing, for example, inosine.
Sequences comprising such replacement moieties are embodiments of
the invention.
[0027] As used herein, "JC virus" refers to the latent polyomavirus
JC Virus that has a reference sequence NC.sub.--001699. In
addition, further accession numbers of various JCVirus sequences
are AB038249.1-AB038255.1, AB048545.1-AB048582.1,
AB074575.1-AB074591.1, AB077855.1-AB077879.1,
AB081005.1-AB081030.1, AB081600.1-AB081618.1, AB081654.1,
AB092578.1-AB092587.1, AB103387.1, AB103402.1-AB103423.1,
AB104487.1, AB113118.1-AB113145.1, AB118651.1-AB118659.1,
AB126981.1-AB127027.1, AB127342.1, AB127344.1,
AB127346.1-AB127349.1, AB127352.1-AB127353.1,
AB198940.1-AB198954.1, AB220939.1-AB220943.1,
AF004349.1-AF004350.1, AF015526.1-AF015537.1, AF015684.1,
AF030085.1, AF281599.1-AF281626.1, AF295731.1-AF295739.1,
AF300945.1-AF300967.1, AF363830.1-AF363834.1,
AF396422.1-AF396435.1, AY121907.1-AY121915.1, NC.sub.--001699.1,
U61771.1, U73500.1-U73502.1.
[0028] As used herein, "target sequence" refers to a contiguous
portion of the nucleotide sequence of an mRNA molecule formed
during the transcription of a gene from the JC Virus, including
mRNA that is a product of RNA processing of a primary transcription
product.
[0029] As used herein, the term "strand comprising a sequence"
refers to an oligonucleotide comprising a chain of nucleotides that
is described by the sequence referred to using the standard
nucleotide nomenclature.
[0030] As used herein, and unless otherwise indicated, the term
"complementary," when used to describe a first nucleotide sequence
in relation to a second nucleotide sequence, refers to the ability
of an oligonucleotide or polynucleotide comprising the first
nucleotide sequence to hybridize and form a duplex structure under
certain conditions with an oligonucleotide or polynucleotide
comprising the second nucleotide sequence, as will be understood by
the skilled person. Such conditions can, for example, be stringent
conditions, where stringent conditions may include: 400 mM NaCl, 40
mM PIPES pH 6.4, 1 mM EDTA, 50.degree. C. or 70.degree. C. for
12-16 hours followed by washing. Other conditions, such as
physiologically relevant conditions as may be encountered inside an
organism, can apply. The skilled person will be able to determine
the set of conditions most appropriate for a test of
complementarity of two sequences in accordance with the ultimate
application of the hybridized nucleotides.
[0031] This includes base-pairing of the oligonucleotide or
polynucleotide comprising the first nucleotide sequence to the
oligonucleotide or polynucleotide comprising the second nucleotide
sequence over the entire length of the first and second nucleotide
sequence. Such sequences can be referred to as "fully
complementary" with respect to each other herein. However, where a
first sequence is referred to as "substantially complementary" with
respect to a second sequence herein, the two sequences can be fully
complementary, or they may form one or more, but generally not more
than 4, 3 or 2 mismatched base pairs upon hybridization, while
retaining the ability to hybridize under the conditions most
relevant to their ultimate application. However, where two
oligonucleotides are designed to form, upon hybridization, one or
more single stranded overhangs, such overhangs shall not be
regarded as mismatches with regard to the determination of
complementarity. For example, a dsRNA comprising one
oligonucleotide 21 nucleotides in length and another
oligonucleotide 23 nucleotides in length, wherein the longer
oligonucleotide comprises a sequence of 21 nucleotides that is
fully complementary to the shorter oligonucleotide, may yet be
referred to as "fully complementary" for the purposes of the
invention.
[0032] "Complementary" sequences, as used herein, may also include,
or be formed entirely from, non-Watson-Crick base pairs and/or base
pairs formed from non-natural and modified nucleotides, in as far
as the above requirements with respect to their ability to
hybridize are fulfilled.
[0033] The terms "complementary", "fully complementary" and
"substantially complementary" herein may be used with respect to
the base matching between the sense strand and the antisense strand
of a dsRNA, or between the antisense strand of a dsRNA and a target
sequence, as will be understood from the context of their use.
[0034] As used herein, a polynucleotide which is "substantially
complementary to at least part of" a messenger RNA (mRNA) refers to
a polynucleotide which is substantially complementary to a
contiguous portion of the mRNA of interest (e.g., encoding JC
virus). For example, a polynucleotide is complementary to at least
a part of a JC virus mRNA if the sequence is substantially
complementary to a non-interrupted portion of a mRNA encoding JC
virus.
[0035] The term "double-stranded RNA" or "dsRNA", as used herein,
refers to a complex of ribonucleic acid molecules, having a duplex
structure comprising two anti-parallel and substantially
complementary, as defined above, nucleic acid strands. The two
strands forming the duplex structure may be different portions of
one larger RNA molecule, or they may be separate RNA molecules.
Where the two strands are part of one larger molecule, and
therefore are connected by an uninterrupted chain of nucleotides
between the 3'-end of one strand and the 5'end of the respective
other strand forming the duplex structure, the connecting RNA chain
is referred to as a "hairpin loop". Where the two strands are
connected covalently by means other than an uninterrupted chain of
nucleotides between the 3'-end of one strand and the 5'end of the
respective other strand forming the duplex structure, the
connecting structure is referred to as a "linker". The RNA strands
may have the same or a different number of nucleotides. The maximum
number of base pairs is the number of nucleotides in the shortest
strand of the dsRNA minus any overhangs that are present in the
duplex. In addition to the duplex structure, a dsRNA may comprise
one or more nucleotide overhangs.
[0036] As used herein, a "nucleotide overhang" refers to the
unpaired nucleotide or nucleotides that protrude from the duplex
structure of a dsRNA when a 3'-end of one strand of the dsRNA
extends beyond the 5'-end of the other strand, or vice versa.
"Blunt" or "blunt end" means that there are no unpaired nucleotides
at that end of the dsRNA, i.e., no nucleotide overhang. A "blunt
ended" dsRNA is a dsRNA that is double-stranded over its entire
length, i.e., no nucleotide overhang at either end of the
molecule.
[0037] The term "antisense strand" refers to the strand of a dsRNA
which includes a region that is substantially complementary to a
target sequence. As used herein, the term "region of
complementarity" refers to the region on the antisense strand that
is substantially complementary to a sequence, for example a target
sequence, as defined herein. Where the region of complementarity is
not fully complementary to the target sequence, the mismatches are
most tolerated in the terminal regions and, if present, are
generally in a terminal region or regions, e.g., within 6, 5, 4, 3,
or 2 nucleotides of the 5' and/or 3' terminus.
[0038] The term "sense strand," as used herein, refers to the
strand of a dsRNA that includes a region that is substantially
complementary to a region of the antisense strand.
[0039] "Introducing into a cell", when referring to a dsRNA, means
facilitating uptake or absorption into the cell, as is understood
by those skilled in the art. Absorption or uptake of dsRNA can
occur through unaided diffusive or active cellular processes, or by
auxiliary agents or devices. The meaning of this term is not
limited to cells in vitro; a dsRNA may also be "introduced into a
cell", wherein the cell is part of a living organism. In such
instance, introduction into the cell will include the delivery to
the organism. For example, for in vivo delivery, dsRNA can be
injected into a tissue site or administered systemically. In vitro
introduction into a cell includes methods known in the art such as
electroporation and lipofection.
[0040] The terms "silence" and "inhibit the expression of", in as
far as they refer to a gene from the JC Virus, herein refer to the
at least partial suppression of the expression of a gene from the
JC Virus, as manifested by a reduction of the amount of mRNA
transcribed from a gene from the JC Virus which may be isolated
from a first cell or group of cells in which a gene from the JC
Virus is transcribed and which has or have been treated such that
the expression of a gene from the JC Virus is inhibited, as
compared to a second cell or group of cells substantially identical
to the first cell or group of cells but which has or have not been
so treated (control cells). The degree of inhibition is usually
expressed in terms of
( mRNA in control cells ) - ( mRNA in treated cells ) ( mRNA in
control cells ) 100 % ##EQU00001##
[0041] Alternatively, the degree of inhibition may be given in
terms of a reduction of a parameter that is functionally linked to
JC virus genome transcription, e.g. the amount of protein encoded
by a gene from the JC Virus, or the number of cells displaying a
certain phenotype, e.g. infection with the JC Virus. In principle,
JC virus genome silencing may be determined in any cell expressing
the target, either constitutively or by genomic engineering, and by
any appropriate assay. However, when a reference is needed in order
to determine whether a given dsRNA inhibits the expression of a
gene from the JC Virus by a certain degree and therefore is
encompassed by the instant invention, the assay provided in the
Examples below shall serve as such reference.
[0042] For example, in certain instances, expression of a gene from
the JC Virus is suppressed by at least about 20%, 25%, 35%, or 50%
by administration of the double-stranded oligonucleotide of the
invention. In some embodiment, a gene from the JC Virus is
suppressed by at least about 60%, 70%, or 80% by administration of
the double-stranded oligonucleotide of the invention. In some
embodiments, a gene from the JC Virus is suppressed by at least
about 85%, 90%, or 95% by administration of the double-stranded
oligonucleotide of the invention.
[0043] As used herein in the context of JC virus expression, the
terms "treat", "treatment", and the like, refer to relief from or
alleviation of pathological processes mediated by JC virus
infection. In the context of the present invention insofar as it
relates to any of the other conditions recited herein below (other
than pathological processes mediated by JC virus expression), the
terms "treat", "treatment", and the like mean to relieve or
alleviate at least one symptom associated with such condition, or
to slow or reverse the progression of such condition.
[0044] As used herein, the phrases "therapeutically effective
amount" and "prophylactically effective amount" refer to an amount
that provides a therapeutic benefit in the treatment, prevention,
or management of pathological processes mediated by JC virus
infection or an overt symptom of pathological processes mediated by
JC virus expression. The specific amount that is therapeutically
effective can be readily determined by ordinary medical
practitioner, and may vary depending on factors known in the art,
such as, e.g. the type of pathological processes mediated by JC
virus infection, the patient's history and age, the stage of
pathological processes mediated by JC virus infection, and the
administration of other anti-pathological processes mediated by JC
virus infection.
[0045] As used herein, a "pharmaceutical composition" comprises a
pharmacologically effective amount of a dsRNA and a
pharmaceutically acceptable carrier. As used herein,
"pharmacologically effective amount," "therapeutically effective
amount" or simply "effective amount" refers to that amount of an
RNA effective to produce the intended pharmacological, therapeutic
or preventive result. For example, if a given clinical treatment is
considered effective when there is at least a 25% reduction in a
measurable parameter associated with a disease or disorder, a
therapeutically effective amount of a drug for the treatment of
that disease or disorder is the amount necessary to effect at least
a 25% reduction in that parameter.
[0046] The term "pharmaceutically acceptable carrier" refers to a
carrier for administration of a therapeutic agent. Such carriers
include, but are not limited to, saline, buffered saline, dextrose,
water, glycerol, ethanol, and combinations thereof. The term
specifically excludes cell culture medium. For drugs administered
orally, pharmaceutically acceptable carriers include, but are not
limited to pharmaceutically acceptable excipients such as inert
diluents, disintegrating agents, binding agents, lubricating
agents, sweetening agents, flavoring agents, coloring agents and
preservatives. Suitable inert diluents include sodium and calcium
carbonate, sodium and calcium phosphate, and lactose, while corn
starch and alginic acid are suitable disintegrating agents. Binding
agents may include starch and gelatin, while the lubricating agent,
if present, will generally be magnesium stearate, stearic acid or
talc. If desired, the tablets may be coated with a material such as
glyceryl monostearate or glyceryl distearate, to delay absorption
in the gastrointestinal tract.
[0047] As used herein, a "transformed cell" is a cell into which a
vector has been introduced from which a dsRNA molecule may be
expressed.
II. Double-Stranded Ribonucleic Acid (dsRNA)
[0048] In one embodiment, the invention provides double-stranded
ribonucleic acid (dsRNA) molecules for inhibiting the expression of
a gene from the JC Virus in a cell or mammal, wherein the dsRNA
comprises an antisense strand comprising a region of
complementarity which is complementary to at least a part of an
mRNA formed in the expression of a gene from the JC Virus, and
wherein the region of complementarity is less than 30 nucleotides
in length, generally 19-24 nucleotides in length, and wherein said
dsRNA, upon contact with a cell expressing the gene from the JC
virus, inhibits the expression of the JC virus gene by at least
40%.
[0049] The dsRNA comprises two RNA strands that are sufficiently
complementary to hybridize to form a duplex structure. One strand
of the dsRNA (the antisense strand) comprises a region of
complementarity that is substantially complementary, and generally
fully complementary, to a target sequence, derived from the
sequence of an mRNA formed during the expression of a gene from the
JC Virus, the other strand (the sense strand) comprises a region
which is complementary to the antisense strand, such that the two
strands hybridize and form a duplex structure when combined under
suitable conditions. Generally, the duplex structure is between 15
and 30, more generally between 18 and 25, yet more generally
between 19 and 24, and most generally between 19 and 21 base pairs
in length. Similarly, the region of complementarity to the target
sequence is between 15 and 30, more generally between 18 and 25,
yet more generally between 19 and 24, and most generally between 19
and 21 nucleotides in length. The dsRNA of the invention may
further comprise one or more single-stranded nucleotide
overhang(s).
[0050] The dsRNA can be synthesized by standard methods known in
the art as further discussed below, e.g., by use of an automated
DNA synthesizer, such as are commercially available from, for
example, Biosearch, Applied Biosystems, Inc. In a preferred
embodiment, a gene from the JC Virus is the human JC virus genome.
In specific embodiments, the antisense strand of the dsRNA
comprises the sense sequences of Tables 1a and b and the second
sequence is selected from the group consisting of the antisense
sequences of Tables 1a and b. Alternative antisense agents that
target elsewhere in the target sequence provided in Tables 1a and b
can readily be determined using the target sequence and the
flanking JC virus sequence.
[0051] In further embodiments, the dsRNA comprises at least one
nucleotide sequence selected from the groups of sequences provided
in Tables 1a and b. In other embodiments, the dsRNA comprises at
least two sequences selected from this group, wherein one of the at
least two sequences is complementary to another of the at least two
sequences, and one of the at least two sequences is substantially
complementary to a sequence of an mRNA generated in the expression
of a gene from the JC Virus. Generally, the dsRNA comprises two
oligonucleotides, wherein one oligonucleotide is described as the
sense strand in Tables 1a and b and the second oligonucleotide is
described as the antisense strand in Tables 1a and b
[0052] The skilled person is well aware that dsRNAs comprising a
duplex structure of between 20 and 23, but specifically 21, base
pairs have been hailed as particularly effective in inducing RNA
interference (Elbashir et al., EMBO 2001, 20:6877-6888). However,
others have found that shorter or longer dsRNAs can be effective as
well. In the embodiments described above, by virtue of the nature
of the oligonucleotide sequences provided in Tables 1a and b, the
dsRNAs of the invention can comprise at least one strand of a
length of minimally 21 nt. It can be reasonably expected that
shorter dsRNAs comprising one of the sequences of Tables 1a and b
minus only a few nucleotides on one or both ends may be similarly
effective as compared to the dsRNAs described above. Hence, dsRNAs
comprising a partial sequence of at least 15, 16, 17, 18, 19, 20,
or more contiguous nucleotides from one of the sequences of Tables
1a and b, and differing in their ability to inhibit the expression
of a gene from the JC Virus in a FACS assay as described herein
below by not more than 5, 10, 15, 20, 25, or 30% inhibition from a
dsRNA comprising the full sequence, are contemplated by the
invention. Further dsRNAs that cleave within the target sequence
provided in Tables 1a and b can readily be made using the JC virus
sequence and the target sequence provided.
[0053] In addition, the RNAi agents provided in Tables 1a and b
identify a site in the JC virus mRNA that is susceptible to RNAi
based cleavage. As such the present invention further includes RNAi
agents that target within the sequence targeted by one of the
agents of the present invention. As used herein a second RNAi agent
is said to target within the sequence of a first RNAi agent if the
second RNAi agent cleaves the message anywhere within the mRNA that
is complementary to the antisense strand of the first RNAi agent.
Such a second agent will generally consist of at least 15
contiguous nucleotides from one of the sequences provided in Tables
1a and b coupled to additional nucleotide sequences taken from the
region contiguous to the selected sequence in a gene from the JC
Virus. For example, the last 15 nucleotides of SEQ ID NO:1 combined
with the next 6 nucleotides from the target JC virus genome
produces a single strand agent of 21 nucleotides that is based on
one of the sequences provided in Tables 1a and b.
[0054] The dsRNA of the invention can contain one or more
mismatches to the target sequence. In a preferred embodiment, the
dsRNA of the invention contains no more than 3 mismatches. If the
antisense strand of the dsRNA contains mismatches to a target
sequence, it is preferable that the area of mismatch not be located
in the center of the region of complementarity. If the antisense
strand of the dsRNA contains mismatches to the target sequence, it
is preferable that the mismatch be restricted to 5 nucleotides from
either end, for example 5, 4, 3, 2, or 1 nucleotide from either the
5' or 3' end of the region of complementarity. For example, for a
23 nucleotide dsRNA strand which is complementary to a region of a
gene from the JC Virus, the dsRNA generally does not contain any
mismatch within the central 13 nucleotides. The methods described
within the invention can be used to determine whether a dsRNA
containing a mismatch to a target sequence is effective in
inhibiting the expression of a gene from the JC Virus.
Consideration of the efficacy of dsRNAs with mismatches in
inhibiting expression of a gene from the JC Virus is important,
especially if the particular region of complementarity in a gene
from the JC Virus is known to have polymorphic sequence variation
within the population.
[0055] In one embodiment, at least one end of the dsRNA has a
single-stranded nucleotide overhang of 1 to 4, generally 1 or 2
nucleotides. dsRNAs having at least one nucleotide overhang have
unexpectedly superior inhibitory properties than their blunt-ended
counterparts. Moreover, the present inventors have discovered that
the presence of only one nucleotide overhang strengthens the
interference activity of the dsRNA, without affecting its overall
stability. dsRNA having only one overhang has proven particularly
stable and effective in vivo, as well as in a variety of cells,
cell culture mediums, blood, and serum. Generally, the
single-stranded overhang is located at the 3'-terminal end of the
antisense strand or, alternatively, at the 3'-terminal end of the
sense strand. The dsRNA may also have a blunt end, generally
located at the 5'-end of the antisense strand. Such dsRNAs have
improved stability and inhibitory activity, thus allowing
administration at low dosages, i.e., less than 5 mg/kg body weight
of the recipient per day. Generally, the antisense strand of the
dsRNA has a nucleotide overhang at the 3'-end, and the 5'-end is
blunt. In another embodiment, one or more of the nucleotides in the
overhang is replaced with a nucleoside thiophosphate.
[0056] In yet another embodiment, the dsRNA is chemically modified
to enhance stability. The nucleic acids of the invention may be
synthesized and/or modified by methods well established in the art,
such as those described in "Current protocols in nucleic acid
chemistry", Beaucage, S. L. et al. (Edrs.), John Wiley & Sons,
Inc., New York, N.Y., USA, which is hereby incorporated herein by
reference. Specific examples of preferred dsRNA compounds useful in
this invention include dsRNAs containing modified backbones or no
natural internucleoside linkages. As defined in this specification,
dsRNAs having modified backbones include those that retain a
phosphorus atom in the backbone and those that do not have a
phosphorus atom in the backbone. For the purposes of this
specification, and as sometimes referenced in the art, modified
dsRNAs that do not have a phosphorus atom in their internucleoside
backbone can also be considered to be oligonucleosides.
[0057] Preferred modified dsRNA backbones include, for example,
phosphorothioates, chiral phosphorothioates, phosphorodithioates,
phosphotriesters, aminoalkylphosphotriesters, methyl and other
alkyl phosphonates including 3'-alkylene phosphonates and chiral
phosphonates, phosphinates, phosphoramidates including 3'-amino
phosphoramidate and aminoalkylphosphoramidates,
thionophosphoramidates, thionoalkylphosphonates,
thionoalkylphosphotriesters, and boranophosphates having normal
3'-5' linkages, 2'-5' linked analogs of these, and those) having
inverted polarity wherein the adjacent pairs of nucleoside units
are linked 3'-5' to 5'-3' or 2'-5' to 5'-2'. Various salts, mixed
salts and free acid forms are also included.
[0058] Representative U.S. patents that teach the preparation of
the above phosphorus-containing linkages include, but are not
limited to, U.S. Pat. Nos. 3,687,808; 4,469,863; 4,476,301;
5,023,243; 5,177,195; 5,188,897; 5,264,423; 5,276,019; 5,278,302;
5,286,717; 5,321,131; 5,399,676; 5,405,939; 5,453,496; 5,455,233;
5,466,677; 5,476,925; 5,519,126; 5,536,821; 5,541,316; 5,550,111;
5,563,253; 5,571,799; 5,587,361; and 5,625,050, each of which is
herein incorporated by reference
[0059] Preferred modified dsRNA backbones that do not include a
phosphorus atom therein have backbones that are formed by short
chain alkyl or cycloalkyl internucleoside linkages, mixed
heteroatoms and alkyl or cycloalkyl internucleoside linkages, or
ore or more short chain heteroatomic or heterocyclic
internucleoside linkages. These include those having morpholino
linkages (formed in part from the sugar portion of a nucleoside);
siloxane backbones; sulfide, sulfoxide and sulfone backbones;
formacetyl and thioformacetyl backbones; methylene formacetyl and
thioformacetyl backbones; alkene containing backbones; sulfamate
backbones; methyleneimino and methylenehydrazino backbones;
sulfonate and sulfonamide backbones; amide backbones; and others
having mixed N, O, S and CH2 component parts.
[0060] Representative U.S. patents that teach the preparation of
the above oligonucleosides include, but are not limited to, U.S.
Pat. Nos. 5,034,506; 5,166,315; 5,185,444; 5,214,134; 5,216,141;
5,235,033; 5,64,562; 5,264,564; 5,405,938; 5,434,257; 5,466,677;
5,470,967; 5,489,677; 5,541,307; 5,561,225; 5,596,086; 5,602,240;
5,608,046; 5,610,289; 5,618,704; 5,623,070; 5,663,312; 5,633,360;
5,677,437; and, 5,677,439, each of which is herein incorporated by
reference.
[0061] In other preferred dsRNA mimetics, both the sugar and the
internucleoside linkage, i.e., the backbone, of the nucleotide
units are replaced with novel groups. The base units are maintained
for hybridization with an appropriate nucleic acid target compound.
One such oligomeric compound, an dsRNA mimetic that has been shown
to have excellent hybridization properties, is referred to as a
peptide nucleic acid (PNA). In PNA compounds, the sugar backbone of
an dsRNA is replaced with an amide containing backbone, in
particular an aminoethylglycine backbone. The nucleobases are
retained and are bound directly or indirectly to aza nitrogen atoms
of the amide portion of the backbone. Representative U.S. patents
that teach the preparation of PNA compounds include, but are not
limited to, U.S. Pat. Nos. 5,539,082; 5,714,331; and 5,719,262,
each of which is herein incorporated by reference. Further teaching
of PNA compounds can be found in Nielsen et al., Science, 1991,
254, 1497-1500.
[0062] Most preferred embodiments of the invention are dsRNAs with
phosphorothioate backbones and oligonucleosides with heteroatom
backbones, and in particular --CH.sub.2--NH--CH.sub.2--,
--CH.sub.2--N(CH.sub.3)--O--CH.sub.2-- [known as a methylene
(methylimino) or MMI backbone],
--CH.sub.2--O--N(CH.sub.3)--CH.sub.2--,
--CH.sub.2--N(CH.sub.3)--N(CH.sub.3)--CH.sub.2-- and
--N(CH.sub.3)--CH.sub.2--CH.sub.2-- [wherein the native
phosphodiester backbone is represented as --O--P--O--CH.sub.2-- ]
of the above-referenced U.S. Pat. No. 5,489,677, and the amide
backbones of the above-referenced U.S. Pat. No. 5,602,240. Also
preferred are dsRNAs having morpholino backbone structures of the
above-referenced U.S. Pat. No. 5,034,506.
[0063] Modified dsRNAs may also contain one or more substituted
sugar moieties. Preferred dsRNAs comprise one of the following at
the 2' position: OH; F; O-, S-, or N-alkyl; O-, S-, or N-alkenyl;
O-, S- or N-alkynyl; or O-alkyl-O-alkyl, wherein the alkyl, alkenyl
and alkynyl may be substituted or unsubstituted C.sub.1 to C.sub.10
alkyl or C.sub.2 to C.sub.10 alkenyl and alkynyl. Particularly
preferred are O[(CH.sub.2).sub.nO].sub.mCH.sub.3,
O(CH.sub.2).sub.nOCH.sub.3, O(CH.sub.2).sub.nNH.sub.2,
O(CH.sub.2).sub.nCH.sub.3, O(CH.sub.2).sub.nONH.sub.2, and
O(CH.sub.2).sub.nON[(CH.sub.2).sub.nCH.sub.3)].sub.2, where n and m
are from 1 to about 10. Other preferred dsRNAs comprise one of the
following at the 2' position: C.sub.1 to C.sub.10 lower alkyl,
substituted lower alkyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl,
SH, SCH.sub.3, OCN, Cl, Br, CN, CF.sub.3, OCF.sub.3, SOCH.sub.3,
SO.sub.2CH.sub.3, ONO.sub.2, NO.sub.2, N.sub.3, NH.sub.2,
heterocycloalkyl, heterocycloalkaryl, aminoalkylamino,
polyalkylamino, substituted silyl, an RNA cleaving group, a
reporter group, an intercalator, a group for improving the
pharmacokinetic properties of an dsRNA, or a group for improving
the pharmacodynamic properties of an dsRNA, and other substituents
having similar properties. A preferred modification includes
2'-methoxyethoxy (2'-O--CH.sub.2CH.sub.2OCH.sub.3, also known as
2'-O-(2-methoxyethyl) or 2'-MOE) (Martin et al., Helv. Chim. Acta,
1995, 78, 486-504) i.e., an alkoxy-alkoxy group. A further
preferred modification includes 2'-dimethylaminooxyethoxy, i.e., a
O(CH.sub.2).sub.2ON(CH.sub.3).sub.2 group, also known as 2'-DMAOE,
as described in examples herein below, and
2'-dimethylaminoethoxyethoxy (also known in the art as
2'-O-dimethylaminoethoxyethyl or 2'-DMAEOE), i.e.,
2'-O--CH.sub.2--O--CH.sub.2--N(CH.sub.2).sub.2, also described in
examples herein below.
[0064] Other preferred modifications include 2'-methoxy
(2'-OCH.sub.3), 2'-aminopropoxy
(2'-OCH.sub.2CH.sub.2CH.sub.2NH.sub.2) and 2'-fluoro (2'-F).
Similar modifications may also be made at other positions on the
dsRNA, particularly the 3' position of the sugar on the 3' terminal
nucleotide or in 2'-5' linked dsRNAs and the 5' position of 5'
terminal nucleotide. dsRNAs may also have sugar mimetics such as
cyclobutyl moieties in place of the pentofuranosyl sugar.
Representative U.S. patents that teach the preparation of such
modified sugar structures include, but are not limited to, U.S.
Pat. Nos. 4,981,957; 5,118,800; 5,319,080; 5,359,044; 5,393,878;
5,446,137; 5,466,786; 5,514,785; 5,519,134; 5,567,811; 5,576,427;
5,591,722; 5,597,909; 5,610,300; 5,627,053; 5,639,873; 5,646,265;
5,658,873; 5,670,633; and 5,700,920, certain of which are commonly
owned with the instant application, and each of which is herein
incorporated by reference in its entirety.
[0065] dsRNAs may also include nucleobase (often referred to in the
art simply as "base") modifications or substitutions. As used
herein, "unmodified" or "natural" nucleobases include the purine
bases adenine (A) and guanine (G), and the pyrimidine bases thymine
(T), cytosine (C) and uracil (U). Modified nucleobases include
other synthetic and natural nucleobases such as 5-methylcytosine
(5-me-C), 5-hydroxymethyl cytosine, xanthine, hypoxanthine,
2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and
guanine, 2-propyl and other alkyl derivatives of adenine and
guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine,
5-halouracil and cytosine, 5-propynyl uracil and cytosine, 6-azo
uracil, cytosine and thymine, 5-uracil (pseudouracil),
4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl
anal other 8-substituted adenines and guanines, 5-halo,
particularly 5-bromo, 5-trifluoromethyl and other 5-substituted
uracils and cytosines, 7-methylguanine and 7-methyladenine,
8-azaguanine and 8-azaadenine, 7-deazaguanine and 7-daazaadenine
and 3-deazaguanine and 3-deazaadenine. Further nucleobases include
those disclosed in U.S. Pat. No. 3,687,808, those disclosed in The
Concise Encyclopedia Of Polymer Science And Engineering, pages
858-859, Kroschwitz, J. L, ed. John Wiley & Sons, 1990, these
disclosed by Englisch et al., Angewandte Chemie, International
Edition, 1991, 30, 613, and those disclosed by Sanghvi, Y S.,
Chapter 15, DsRNA Research and Applications, pages 289-302, Crooke,
S. T. and Lebleu, B., Ed., CRC Press, 1993. Certain of these
nucleobases are particularly useful for increasing the binding
affinity of the oligomeric compounds of the invention. These
include 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6
and 0-6 substituted purines, including 2-aminopropyladenine,
5-propynyluracil and 5-propynylcytosine. 5-methylcytosine
substitutions have been shown to increase nucleic acid duplex
stability by 0.6-1.2.degree. C. (Sanghvi, Y. S., Crooke, S. T. and
Lebleu, B., Eds., DsRNA Research and Applications, CRC Press, Boca
Raton, 1993, pp. 276-278) and are presently preferred base
substitutions, even more particularly when combined with
2'-O-methoxyethyl sugar modifications.
[0066] Representative U.S. patents that teach the preparation of
certain of the above noted modified nucleobases as well as other
modified nucleobases include, but are not limited to, the above
noted U.S. Pat. No. 3,687,808, as well as U.S. Pat. Nos. 4,845,205;
5,130,30; 5,134,066; 5,175,273; 5,367,066; 5,432,272; 5,457,187;
5,459,255; 5,484,908; 5,502,177; 5,525,711; 5,552,540; 5,587,469;
5,594,121, 5,596,091; 5,614,617; and 5,681,941, each of which is
herein incorporated by reference, and U.S. Pat. No. 5,750,692, also
herein incorporated by reference.
[0067] Another modification of the dsRNAs of the invention involves
chemically linking to the dsRNA one or more moieties or conjugates
which enhance the activity, cellular distribution or cellular
uptake of the dsRNA. Such moieties include but are not limited to
lipid moieties such as a cholesterol moiety (Letsinger et al.,
Proc. Natl. Acid. Sci. USA, 199, 86, 6553-6556), cholic acid
(Manoharan et al., Biorg. Med. Chem. Let., 1994 4 1053-1060), a
thioether, e.g., beryl-S-tritylthiol (Manoharan et al., Ann. N.Y.
Acad. Sci., 1992, 660, 306-309; Manoharan et al., Biorg. Med. Chem.
Let., 1993, 3, 2765-2770), a thiocholesterol (Oberhauser et al.,
Nucl. Acids Res., 1992, 20, 533-538), an aliphatic chain, e.g.,
dodecandiol 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-Hphosphonate (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 (Manoharan et al., Tetrahedron
Lett., 1995, 36, 3651-3654), a palmityl moiety (Mishra et al.,
Biochim. Biophys. Acta, 1995, 1264, 229-237), or an octadecylamine
or hexylamino-carbonyloxycholesterol moiety (Crooke et al., J.
Pharmacol. Exp. Ther., 1996, 277, 923-937).
[0068] Representative U.S. patents that teach the preparation of
such dsRNA conjugates include, but are not limited to, U.S. Pat.
Nos. 4,828,979; 4,948,882; 5,218,105; 5,525,465; 5,541,313;
5,545,730; 5,552,538; 5,578,717, 5,580,731; 5,591,584; 5,109,124;
5,118,802; 5,138,045; 5,414,077; 5,486,603; 5,512,439; 5,578,718;
5,608,046; 4,587,044; 4,605,735; 4,667,025; 4,762,779; 4,789,737;
4,824,941; 4,835,263; 4,876,335; 4,904,582; 4,958,013; 5,082,830;
5,112,963; 5,214,136; 5,082,830; 5,112,963; 5,214,136; 5,245,022;
5,254,469; 5,258,506; 5,262,536; 5,272,250; 5,292,873; 5,317,098;
5,371,241, 5,391,723; 5,416,203, 5,451,463; 5,510,475; 5,512,667;
5,514,785; 5,565,552; 5,567,810; 5,574,142; 5,585,481; 5,587,371;
5,595,726; 5,597,696; 5,599,923; 5,599,928 and 5,688,941, each of
which is herein incorporated by reference.
[0069] It is not necessary for all positions in a given compound to
be uniformly modified, and in fact more than one of the
aforementioned modifications may be incorporated in a single
compound or even at a single nucleoside within an dsRNA. The
present invention also includes dsRNA compounds which are chimeric
compounds. "Chimeric" dsRNA compounds or "chimeras," in the context
of this invention, are dsRNA compounds, particularly dsRNAs, which
contain two or more chemically distinct regions, each made up of at
least one monomer unit, i.e., a nucleotide in the case of an dsRNA
compound. These dsRNAs typically contain at least one region
wherein the dsRNA is modified so as to confer upon the dsRNA
increased resistance to nuclease degradation, increased cellular
uptake, and/or increased binding affinity for the target nucleic
acid. An additional region of the dsRNA may serve as a substrate
for enzymes capable of cleaving RNA:DNA or RNA:RNA hybrids. By way
of example, RNase H is a cellular endonuclease which cleaves the
RNA strand of an RNA:DNA duplex. Activation of RNase H, therefore,
results in cleavage of the RNA target, thereby greatly enhancing
the efficiency of dsRNA inhibition of gene expression.
Consequently, comparable results can often be obtained with shorter
dsRNAs when chimeric dsRNAs are used, compared to phosphorothioate
deoxydsRNAs hybridizing to the same target region. Cleavage of the
RNA target can be routinely detected by gel electrophoresis and, if
necessary, associated nucleic acid hybridization techniques known
in the art.
[0070] In certain instances, the dsRNA may be modified by a
non-ligand group. A number of non-ligand molecules have been
conjugated to dsRNAs in order to enhance the activity, cellular
distribution or cellular uptake of the dsRNA, and procedures for
performing such conjugations are available in the scientific
literature. Such non-ligand moieties have included lipid moieties,
such as cholesterol (Letsinger et al., Proc. Natl. Acad. Sci. USA,
1989, 86:6553), cholic acid (Manoharan et al., Bioorg. Med. Chem.
Lett., 1994, 4:1053), a thioether, e.g., hexyl-S-tritylthiol
(Manoharan et al., Ann. N.Y. Acad. Sci., 1992, 660:306; Manoharan
et al., Bioorg. Med. Chem. Let., 1993, 3:2765), a thiocholesterol
(Oberhauser et al., Nucl. Acids Res., 1992, 20:533), an aliphatic
chain, e.g., dodecandiol or undecyl residues (Saison-Behmoaras et
al., EMBO J., 1991, 10:111; Kabanov et al., FEBS Lett., 1990,
259:327; Svinarchuk et al., Biochimie, 1993, 75:49), a
phospholipid, e.g., di-hexadecyl-rac-glycerol or triethylammonium
1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate (Manoharan et al.,
Tetrahedron Lett., 1995, 36:3651; Shea et al., Nucl. Acids Res.,
1990, 18:3777), a polyamine or a polyethylene glycol chain
(Manoharan et al., Nucleosides & Nucleotides, 1995, 14:969), or
adamantane acetic acid (Manoharan et al., Tetrahedron Lett., 1995,
36:3651), a palmityl moiety (Mishra et al., Biochim. Biophys. Acta,
1995, 1264:229), or an octadecylamine or
hexylamino-carbonyl-oxycholesterol moiety (Crooke et al., J.
Pharmacol. Exp. Ther., 1996, 277:923). Representative United States
patents that teach the preparation of such dsRNA conjugates have
been listed above. Typical conjugation protocols involve the
synthesis of dsRNAs bearing an aminolinker at one or more positions
of the sequence. The amino group is then reacted with the molecule
being conjugated using appropriate coupling or activating reagents.
The conjugation reaction may be performed either with the dsRNA
still bound to the solid support or following cleavage of the dsRNA
in solution phase. Purification of the dsRNA conjugate by HPLC
typically affords the pure conjugate.
[0071] Vector Encoded RNAi Agents
[0072] The dsRNA of the invention can also be expressed from
recombinant viral vectors intracellularly in vivo. The recombinant
viral vectors of the invention comprise sequences encoding the
dsRNA of the invention and any suitable promoter for expressing the
dsRNA sequences. Suitable promoters include, for example, the U6 or
H1 RNA pol III promoter sequences and the cytomegalovirus promoter.
Selection of other suitable promoters is within the skill in the
art. The recombinant viral vectors of the invention can also
comprise inducible or regulatable promoters for expression of the
dsRNA in a particular tissue or in a particular intracellular
environment. The use of recombinant viral vectors to deliver dsRNA
of the invention to cells in vivo is discussed in more detail
below.
[0073] dsRNA of the invention can be expressed from a recombinant
viral vector either as two separate, complementary RNA molecules,
or as a single RNA molecule with two complementary regions.
[0074] Any viral vector capable of accepting the coding sequences
for the dsRNA molecule(s) to be expressed can be used, for example
vectors derived from adenovirus (AV); adeno-associated virus (AAV);
retroviruses (e.g., lentiviruses (LV), Rhabdoviruses, murine
leukemia virus); herpes virus, and the like. The tropism of viral
vectors can be modified by pseudotyping the vectors with envelope
proteins or other surface antigens from other viruses, or by
substituting different viral capsid proteins, as appropriate.
[0075] For example, lentiviral vectors of the invention can be
pseudotyped with surface proteins from vesicular stomatitis virus
(VSV), rabies, Ebola, Mokola, and the like. AAV vectors of the
invention can be made to target different cells by engineering the
vectors to express different capsid protein serotypes. For example,
an AAV vector expressing a serotype 2 capsid on a serotype 2 genome
is called AAV 2/2. This serotype 2 capsid gene in the AAV 2/2
vector can be replaced by a serotype 5 capsid gene to produce an
AAV 2/5 vector. Techniques for constructing AAV vectors which
express different capsid protein serotypes are within the skill in
the art; see, e.g., Rabinowitz J E et al. (2002), J Virol
76:791-801, the entire disclosure of which is herein incorporated
by reference.
[0076] Selection of recombinant viral vectors suitable for use in
the invention, methods for inserting nucleic acid sequences for
expressing the dsRNA into the vector, and methods of delivering the
viral vector to the cells of interest are within the skill in the
art. See, for example, Dornburg R (1995), Gene Therap. 2: 301-310;
Eglitis M A (1988), Biotechniques 6: 608-614; Miller A D (1990),
Hum Gene Therap. 1: 5-14; Anderson W F (1998), Nature 392: 25-30;
and Rubinson D A et al., Nat. Genet. 33: 401-406, the entire
disclosures of which are herein incorporated by reference.
[0077] Preferred viral vectors are those derived from AV and AAV.
In a particularly preferred embodiment, the dsRNA of the invention
is expressed as two separate, complementary single-stranded RNA
molecules from a recombinant AAV vector comprising, for example,
either the U6 or H1 RNA promoters, or the cytomegalovirus (CMV)
promoter.
[0078] A suitable AV vector for expressing the dsRNA of the
invention, a method for constructing the recombinant AV vector, and
a method for delivering the vector into target cells, are described
in Xia H et al. (2002), Nat. Biotech. 20: 1006-1010.
[0079] Suitable AAV vectors for expressing the dsRNA of the
invention, methods for constructing the recombinant AV vector, and
methods for delivering the vectors into target cells are described
in Samulski R et al. (1987), J. Virol. 61: 3096-3101; Fisher K J et
al. (1996), J. Virol, 70: 520-532; Samulski R et al. (1989), J.
Virol. 63: 3822-3826; U.S. Pat. No. 5,252,479; U.S. Pat. No.
5,139,941; International Patent Application No. WO 94/13788; and
International Patent Application No. WO 93/24641, the entire
disclosures of which are herein incorporated by reference.
III. Pharmaceutical Compositions Comprising dsRNA
[0080] In one embodiment, the invention provides pharmaceutical
compositions comprising a dsRNA, as described herein, and a
pharmaceutically acceptable carrier. The pharmaceutical composition
comprising the dsRNA is useful for treating a disease or disorder
associated with the expression or activity of a gene from the JC
Virus and/or viral infection, such as PML. Such pharmaceutical
compositions are formulated based on the mode of delivery. One
example is compositions that are formulated for systemic
administration via parenteral delivery.
[0081] The pharmaceutical compositions of the invention are
administered in dosages sufficient to inhibit expression of a gene
from the JC Virus. The present inventors have found that, because
of their improved efficiency, compositions comprising the dsRNA of
the invention can be administered at surprisingly low dosages. A
maximum dosage of 5 mg dsRNA per kilogram body weight of recipient
per day is sufficient to inhibit or completely suppress expression
of a gene from the JC Virus.
[0082] In general, a suitable dose of dsRNA will be in the range of
0.01 to 5.0 milligrams per kilogram body weight of the recipient
per day, generally in the range of 1 microgram to 1 mg per kilogram
body weight per day. The pharmaceutical composition may be
administered once daily, or the dsRNA may be administered as two,
three, or more sub-doses at appropriate intervals throughout the
day or even using continuous infusion or delivery through a
controlled release formulation. In that case, the dsRNA contained
in each sub-dose must be correspondingly smaller in order to
achieve the total daily dosage. The dosage unit can also be
compounded for delivery over several days, e.g., using a
conventional sustained release formulation which provides sustained
release of the dsRNA over a several day period. In this embodiment,
the dosage unit contains a corresponding multiple of the daily
dose.
[0083] The skilled artisan will appreciate that certain factors may
influence the dosage and timing required to effectively treat a
subject, including but not limited to the severity of the disease
or disorder, previous treatments, the general health and/or age of
the subject, and other diseases present. Moreover, treatment of a
subject with a therapeutically effective amount of a composition
can include a single treatment or a series of treatments. Estimates
of effective dosages and in vivo half-lives for the individual
dsRNAs encompassed by the invention can be made using conventional
methodologies or on the basis of in vivo testing using an
appropriate animal model, as described elsewhere herein.
[0084] Advances in mouse genetics have generated a number of mouse
models for the study of various human diseases, such as
pathological processes mediated by JC virus expression. Such models
are used for in vivo testing of dsRNA, as well as for determining a
therapeutically effective dose.
[0085] The present invention also includes pharmaceutical
compositions and formulations which include the dsRNA compounds of
the invention. The pharmaceutical compositions of the present
invention may be administered in a number of ways depending upon
whether local or systemic treatment is desired and upon the area to
be treated. Administration may be topical, pulmonary, e.g., by
inhalation or insufflation of powders or aerosols, including by
nebulizer; intratracheal, intranasal, epidermal and transdermal),
oral or parenteral. Parenteral administration includes intravenous,
intraarterial, subcutaneous, intraperitoneal or intramuscular
injection or infusion; or intracranial, e.g., intrathecal or
intraventricular, administration.
[0086] Compositions and formulations for oral administration
include powders or granules, microparticulates, nanoparticulates,
suspensions or solutions in water or non-aqueous media, capsules,
gel capsules, sachets, tablets or minitablets. Thickeners,
flavoring agents, diluents, emulsifiers, dispersing aids or binders
may be desirable.
[0087] Compositions and formulations for parenteral, intrathecal or
intraventricular administration may include sterile aqueous
solutions which may also contain buffers, diluents and other
suitable additives such as, but not limited to, penetration
enhancers, carrier compounds and other pharmaceutically acceptable
carriers or excipients.
[0088] Pharmaceutical compositions of the present invention
include, but are not limited to, solutions, emulsions, and
liposome-containing formulations. These compositions may be
generated from a variety of components that include, but are not
limited to, preformed liquids, self-emulsifying solids and
self-emulsifying semisolids.
[0089] The pharmaceutical formulations of the present invention,
which may conveniently be presented in unit dosage form, may be
prepared according to conventional techniques well known in the
pharmaceutical industry. Such techniques include the step of
bringing into association the active ingredients with the
pharmaceutical carrier(s) or excipient(s). In general, the
formulations are prepared by uniformly and intimately bringing into
association the active ingredients with liquid carriers or finely
divided solid carriers or both, and then, if necessary, shaping the
product.
[0090] Liposomes
[0091] There are many organized surfactant structures besides
microemulsions that have been studied and used for the formulation
of drugs. These include monolayers, micelles, bilayers and
vesicles. Vesicles, such as liposomes, have attracted great
interest because of their specificity and the duration of action
they offer from the standpoint of drug delivery. As used in the
present invention, the term "liposome" means a vesicle composed of
amphiphilic lipids arranged in a spherical bilayer or bilayers.
[0092] Liposomes are unilamellar or multilamellar vesicles which
have a membrane formed from a lipophilic material and an aqueous
interior. The aqueous portion contains the composition to be
delivered. Cationic liposomes possess the advantage of being able
to fuse to the cell wall. Non-cationic liposomes, although not able
to fuse as efficiently with the cell wall, are taken up by
macrophages in vivo.
[0093] In order to cross intact mammalian skin, lipid vesicles must
pass through a series of fine pores, each with a diameter less than
50 nm, under the influence of a suitable transdermal gradient.
Therefore, it is desirable to use a liposome which is highly
deformable and able to pass through such fine pores.
[0094] Further advantages of liposomes include; liposomes obtained
from natural phospholipids are biocompatible and biodegradable;
liposomes can incorporate a wide range of water and lipid soluble
drugs; liposomes can protect encapsulated drugs in their internal
compartments from metabolism and degradation (Rosoff, in
Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.),
1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 245).
Important considerations in the preparation of liposome
formulations are the lipid surface charge, vesicle size and the
aqueous volume of the liposomes.
[0095] Liposomes are useful for the transfer and delivery of active
ingredients to the site of action. Because the liposomal membrane
is structurally similar to biological membranes, when liposomes are
applied to a tissue, the liposomes start to merge with the cellular
membranes and as the merging of the liposome and cell progresses,
the liposomal contents are emptied into the cell where the active
agent may act.
[0096] Liposomal formulations have been the focus of extensive
investigation as the mode of delivery for many drugs. There is
growing evidence that for topical administration, liposomes present
several advantages over other formulations. Such advantages include
reduced side-effects related to high systemic absorption of the
administered drug, increased accumulation of the administered drug
at the desired target, and the ability to administer a wide variety
of drugs, both hydrophilic and hydrophobic, into the skin.
[0097] Several reports have detailed the ability of liposomes to
deliver agents including high-molecular weight DNA into the skin.
Compounds including analgesics, antibodies, hormones and
high-molecular weight DNAs have been administered to the skin. The
majority of applications resulted in the targeting of the upper
epidermis
[0098] Liposomes fall into two broad classes. Cationic liposomes
are positively charged liposomes which interact with the negatively
charged DNA molecules to form a stable complex. The positively
charged DNA/liposome complex binds to the negatively charged cell
surface and is internalized in an endosome. Due to the acidic pH
within the endosome, the liposomes are ruptured, releasing their
contents into the cell cytoplasm (Wang et al., Biochem. Biophys.
Res. Commun., 1987, 147, 980-985).
[0099] Liposomes which are pH-sensitive or negatively-charged,
entrap DNA rather than complex with it. Since both the DNA and the
lipid are similarly charged, repulsion rather than complex
formation occurs. Nevertheless, some DNA is entrapped within the
aqueous interior of these liposomes. pH-sensitive liposomes have
been used to deliver DNA encoding the thymidine kinase gene to cell
monolayers in culture. Expression of the exogenous gene was
detected in the target cells (Zhou et al., Journal of Controlled
Release, 1992, 19, 269-274).
[0100] One major type of liposomal composition includes
phospholipids other than naturally-derived phosphatidylcholine.
Neutral liposome compositions, for example, can be formed from
dimyristoyl phosphatidylcholine (DMPC) or dipalmitoyl
phosphatidylcholine (DPPC). Anionic liposome compositions generally
are formed from dimyristoyl phosphatidylglycerol, while anionic
fusogenic liposomes are formed primarily from dioleoyl
phosphatidylethanolamine (DOPE). Another type of liposomal
composition is formed from phosphatidylcholine (PC) such as, for
example, soybean PC, and egg PC. Another type is formed from
mixtures of phospholipid and/or phosphatidylcholine and/or
cholesterol.
[0101] Several studies have assessed the topical delivery of
liposomal drug formulations to the skin. Application of liposomes
containing interferon to guinea pig skin resulted in a reduction of
skin herpes sores while delivery of interferon via other means
(e.g. as a solution or as an emulsion) were ineffective (Weiner et
al., Journal of Drug Targeting, 1992, 2, 405-410). Further, an
additional study tested the efficacy of interferon administered as
part of a liposomal formulation to the administration of interferon
using an aqueous system, and concluded that the liposomal
formulation was superior to aqueous administration (du Plessis et
al., Antiviral Research, 1992, 18, 259-265).
[0102] Non-ionic liposomal systems have also been examined to
determine their utility in the delivery of drugs to the skin, in
particular systems comprising non-ionic surfactant and cholesterol.
Non-ionic liposomal formulations comprising Novasome.TM. I
(glyceryl dilaurate/cholesterol/po-lyoxyethylene-10-stearyl ether)
and Novasome.TM. II (glyceryl
distearate/cholesterol/polyoxyethylene-10-stearyl ether) were used
to deliver cyclosporin-A into the dermis of mouse skin. Results
indicated that such non-ionic liposomal systems were effective in
facilitating the deposition of cyclosporin-A into different layers
of the skin (Hu et al. S.T.P.Pharma. Sci., 1994, 4, 6, 466).
[0103] Liposomes also include "sterically stabilized" liposomes, a
term which, as used herein, refers to liposomes comprising one or
more specialized lipids that, when incorporated into liposomes,
result in enhanced circulation lifetimes relative to liposomes
lacking such specialized lipids. Examples of sterically stabilized
liposomes are those in which part of the vesicle-forming lipid
portion of the liposome (A) comprises one or more glycolipids, such
as monosialoganglioside G.sub.M1, or (B) is derivatized with one or
more hydrophilic polymers, such as a polyethylene glycol (PEG)
moiety. While not wishing to be bound by any particular theory, it
is thought in the art that, at least for sterically stabilized
liposomes containing gangliosides, sphingomyelin, or
PEG-derivatized lipids, the enhanced circulation half-life of these
sterically stabilized liposomes derives from a reduced uptake into
cells of the reticuloendothelial system (RES) (Allen et al., FEBS
Letters, 1987, 223, 42; Wu et al., Cancer Research, 1993, 53,
3765).
[0104] Various liposomes comprising one or more glycolipids are
known in the art. Papahadjopoulos et al. (Ann. N.Y. Acad. Sci.,
1987, 507, 64) reported the ability of monosialoganglioside
G.sub.M1, galactocerebroside sulfate and phosphatidylinositol to
improve blood half-lives of liposomes. These findings were
expounded upon by Gabizon et al. (Proc. Natl. Acad. Sci. U.S.A.,
1988, 85, 6949). U.S. Pat. No. 4,837,028 and WO 88/04924, both to
Allen et al., disclose liposomes comprising (1) sphingomyelin and
(2) the ganglioside G.sub.M1 or a galactocerebroside sulfate ester.
U.S. Pat. No. 5,543,152 (Webb et al.) discloses liposomes
comprising sphingomyelin. Liposomes comprising
1,2-sn-dimyristoylphosphat-idylcholine are disclosed in WO 97/13499
(Lim et al).
[0105] Many liposomes comprising lipids derivatized with one or
more hydrophilic polymers, and methods of preparation thereof, are
known in the art. Sunamoto et al. (Bull. Chem. Soc. Jpn., 1980, 53,
2778) described liposomes comprising a nonionic detergent,
2C.sub.1215G, that contains a PEG moiety. Illum et al. (FEBS Lett.,
1984, 167, 79) noted that hydrophilic coating of polystyrene
particles with polymeric glycols results in significantly enhanced
blood half-lives. Synthetic phospholipids modified by the
attachment of carboxylic groups of polyalkylene glycols (e.g., PEG)
are described by Sears (U.S. Pat. Nos. 4,426,330 and 4,534,899).
Klibanov et al. (FEBS Lett., 1990, 268, 235) described experiments
demonstrating that liposomes comprising phosphatidylethanolamine
(PE) derivatized with PEG or PEG stearate have significant
increases in blood circulation half-lives. Blume et al. (Biochimica
et Biophysica Acta, 1990, 1029, 91) extended such observations to
other PEG-derivatized phospholipids, e.g., DSPE-PEG, formed from
the combination of distearoylphosphatidylethanolamine (DSPE) and
PEG. Liposomes having covalently bound PEG moieties on their
external surface are described in European Patent No. EP 0 445 131
B1 and WO 90/04384 to Fisher. Liposome compositions containing 1-20
mole percent of PE derivatized with PEG, and methods of use
thereof, are described by Woodle et al. (U.S. Pat. Nos. 5,013,556
and 5,356,633) and Martin et al. (U.S. Pat. No. 5,213,804 and
European Patent No. EP 0 496 813 B1). Liposomes comprising a number
of other lipid-polymer conjugates are disclosed in WO 91/05545 and
U.S. Pat. No. 5,225,212 (both to Martin et al.) and in WO 94/20073
(Zalipsky et al.). Liposomes comprising PEG-modified ceramide
lipids are described in WO 96/10391 (Choi et al). U.S. Pat. No.
5,540,935 (Miyazaki et al.) and U.S. Pat. No. 5,556,948 (Tagawa et
al.) describe PEG-containing liposomes that can be further
derivatized with functional moieties on their surfaces.
[0106] A limited number of liposomes comprising nucleic acids are
known in the art. WO 96/40062 to Thierry et al. discloses methods
for encapsulating high molecular weight nucleic acids in liposomes.
U.S. Pat. No. 5,264,221 to Tagawa et al. discloses protein-bonded
liposomes and asserts that the contents of such liposomes may
include an dsRNA RNA. U.S. Pat. No. 5,665,710 to Rahman et al.
describes certain methods of encapsulating oligodeoxynucleotides in
liposomes. WO 97/04787 to Love et al. discloses liposomes
comprising dsRNA dsRNAs targeted to the raf gene.
[0107] Transfersomes are yet another type of liposomes, and are
highly deformable lipid aggregates which are attractive candidates
for drug delivery vehicles. Transfersomes may be described as lipid
droplets which are so highly deformable that they are easily able
to penetrate through pores which are smaller than the droplet.
Transfersomes are adaptable to the environment in which they are
used, e.g. they are self-optimizing (adaptive to the shape of pores
in the skin), self-repairing, frequently reach their targets
without fragmenting, and often self-loading. To make transfersomes
it is possible to add surface edge-activators, usually surfactants,
to a standard liposomal composition. Transfersomes have been used
to deliver serum albumin to the skin. The transfersome-mediated
delivery of serum albumin has been shown to be as effective as
subcutaneous injection of a solution containing serum albumin.
[0108] Surfactants find wide application in formulations such as
emulsions (including microemulsions) and liposomes. The most common
way of classifying and ranking the properties of the many different
types of surfactants, both natural and synthetic, is by the use of
the hydrophile/lipophile balance (HLB). The nature of the
hydrophilic group (also known as the "head") provides the most
useful means for categorizing the different surfactants used in
formulations (Rieger, in Pharmaceutical Dosage Forms, Marcel
Dekker, Inc., New York, N.Y., 1988, p. 285).
[0109] If the surfactant molecule is not ionized, it is classified
as a nonionic surfactant. Nonionic surfactants find wide
application in pharmaceutical and cosmetic products and are usable
over a wide range of pH values. In general their HLB values range
from 2 to about 18 depending on their structure. Nonionic
surfactants include nonionic esters such as ethylene glycol esters,
propylene glycol esters, glyceryl esters, polyglyceryl esters,
sorbitan esters, sucrose esters, and ethoxylated esters. Nonionic
alkanolamides and ethers such as fatty alcohol ethoxylates,
propoxylated alcohols, and ethoxylated/propoxylated block polymers
are also included in this class. The polyoxyethylene surfactants
are the most popular members of the nonionic surfactant class.
[0110] If the surfactant molecule carries a negative charge when it
is dissolved or dispersed in water, the surfactant is classified as
anionic. Anionic surfactants include carboxylates such as soaps,
acyl lactylates, acyl amides of amino acids, esters of sulfuric
acid such as alkyl sulfates and ethoxylated alkyl sulfates,
sulfonates such as alkyl benzene sulfonates, acyl isethionates,
acyl taurates and sulfosuccinates, and phosphates. The most
important members of the anionic surfactant class are the alkyl
sulfates and the soaps.
[0111] If the surfactant molecule carries a positive charge when it
is dissolved or dispersed in water, the surfactant is classified as
cationic. Cationic surfactants include quaternary ammonium salts
and ethoxylated amines. The quaternary ammonium salts are the most
used members of this class.
[0112] If the surfactant molecule has the ability to carry either a
positive or negative charge, the surfactant is classified as
amphoteric. Amphoteric surfactants include acrylic acid
derivatives, substituted alkylamides, N-alkylbetaines and
phosphatides.
[0113] The use of surfactants in drug products, formulations and in
emulsions has been reviewed (Rieger, in Pharmaceutical Dosage
Forms, Marcel Dekker, Inc., New York, N.Y., 1988, p. 285).
[0114] Agents that enhance uptake of dsRNAs at the cellular level
may also be added to the pharmaceutical and other compositions of
the present invention. For example, cationic lipids, such as
lipofectin (Junichi et al, U.S. Pat. No. 5,705,188), cationic
glycerol derivatives, and polycationic molecules, such as
polylysine (Lollo et al., PCT Application WO 97/30731), are also
known to enhance the cellular uptake of dsRNAs.
[0115] Other agents may be utilized to enhance the penetration of
the administered nucleic acids, including glycols such as ethylene
glycol and propylene glycol, pyrrols such as 2-pyrrol, azones, and
terpenes such as limonene and menthone.
[0116] Carriers
[0117] Certain compositions of the present invention also
incorporate carrier compounds in the formulation. As used herein,
"carrier compound" or "carrier" can refer to a nucleic acid, or
analog thereof, which is inert (i.e., does not possess biological
activity per se) but is recognized as a nucleic acid by in vivo
processes that reduce the bioavailability of a nucleic acid having
biological activity by, for example, degrading the biologically
active nucleic acid or promoting its removal from circulation. The
coadministration of a nucleic acid and a carrier compound,
typically with an excess of the latter substance, can result in a
substantial reduction of the amount of nucleic acid recovered in
the liver, kidney or other extracirculatory reservoirs, presumably
due to competition between the carrier compound and the nucleic
acid for a common receptor. For example, the recovery of a
partially phosphorothioate dsRNA in hepatic tissue can be reduced
when it is coadministered with polyinosinic acid, dextran sulfate,
polycytidic acid or
4-acetamido-4'isothiocyano-stilbene-2,2'-disulfonic acid (Miyao et
al., DsRNA Res. Dev., 1995, 5, 115-121; Takakura et al., DsRNA
& Nucl. Acid Drug Dev., 1996, 6, 177-183.
[0118] Excipients
[0119] In contrast to a carrier compound, a "pharmaceutical
carrier" or "excipient" is a pharmaceutically acceptable solvent,
suspending agent or any other pharmacologically inert vehicle for
delivering one or more nucleic acids to an animal. The excipient
may be liquid or solid and is selected, with the planned manner of
administration in mind, so as to provide for the desired bulk,
consistency, etc., when combined with a nucleic acid and the other
components of a given pharmaceutical composition. Typical
pharmaceutical carriers include, but are not limited to, binding
agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or
hydroxypropyl methylcellulose, etc.); fillers (e.g., lactose and
other sugars, microcrystalline cellulose, pectin, gelatin, calcium
sulfate, ethyl cellulose, polyacrylates or calcium hydrogen
phosphate, etc.); lubricants (e.g., magnesium stearate, talc,
silica, colloidal silicon dioxide, stearic acid, metallic
stearates, hydrogenated vegetable oils, corn starch, polyethylene
glycols, sodium benzoate, sodium acetate, etc.); disintegrants
(e.g., starch, sodium starch glycolate, etc.); and wetting agents
(e.g., sodium lauryl sulphate, etc).
[0120] Pharmaceutically acceptable organic or inorganic excipient
suitable for non-parenteral administration which do not
deleteriously react with nucleic acids can also be used to
formulate the compositions of the present invention. Suitable
pharmaceutically acceptable carriers include, but are not limited
to, water, salt solutions, alcohols, polyethylene glycols, gelatin,
lactose, amylose, magnesium stearate, talc, silicic acid, viscous
paraffin, hydroxymethylcellulose, polyvinylpyrrolidone and the
like.
[0121] Suitable pharmaceutically acceptable excipients include, but
are not limited to, water, salt solutions, alcohol, polyethylene
glycols, gelatin, lactose, amylose, magnesium stearate, talc,
silicic acid, viscous paraffin, hydroxymethylcellulose,
polyvinylpyrrolidone and the like.
[0122] Other Components
[0123] The compositions of the present invention may additionally
contain other adjunct components conventionally found in
pharmaceutical compositions, at their art-established usage levels.
Thus, for example, the compositions may contain additional,
compatible, pharmaceutically-active materials such as, for example,
antipruritics, astringents, local anesthetics or anti-inflammatory
agents, or may contain additional materials useful in physically
formulating various dosage forms of the compositions of the present
invention, such as dyes, flavoring agents, preservatives,
antioxidants, opacifiers, thickening agents and stabilizers.
However, such materials, when added, should not unduly interfere
with the biological activities of the components of the
compositions of the present invention. The formulations can be
sterilized and, if desired, mixed with auxiliary agents, e.g.,
lubricants, preservatives, stabilizers, wetting agents,
emulsifiers, salts for influencing osmotic pressure, buffers,
colorings, flavorings and/or aromatic substances and the like which
do not deleteriously interact with the nucleic acid(s) of the
formulation.
[0124] Aqueous suspensions may contain substances which increase
the viscosity of the suspension including, for example, sodium
carboxymethylcellulose, sorbitol and/or dextran. The suspension may
also contain stabilizers.
[0125] Certain embodiments of the invention provide pharmaceutical
compositions containing (a) one or more antisense compounds and (b)
one or more other chemotherapeutic agents which function by a
non-antisense mechanism. Examples of such chemotherapeutic agents
include but are not limited to daunorubicin, daunomycin,
dactinomycin, doxorubicin, epirubicin, idarubicin, esorubicin,
bleomycin, mafosfamide, ifosfamide, cytosine arabinoside,
bis-chloroethylnitrosurea, busulfan, mitomycin C, actinomycin D,
mithramycin, prednisone, hydroxyprogesterone, testosterone,
tamoxifen, dacarbazine, procarbazine, hexamethylmelamine,
pentamethylmelamine, mitoxantrone, amsacrine, chlorambucil,
methylcyclohexylnitrosurea, nitrogen mustards, melphalan,
cyclophosphamide, 6-mercaptopurine, 6-thioguanine, cytarabine,
5-azacytidine, hydroxyurea, deoxycoformycin,
4-hydroxyperoxycyclophosphor-amide, 5-fluorouracil (5-FU),
5-fluorodeoxyuridine (5-FUdR), methotrexate (MTX), colchicine,
taxol, vincristine, vinblastine, etoposide (VP-16), trimetrexate,
irinotecan, topotecan, gemcitabine, teniposide, cisplatin and
diethylstilbestrol (DES). See, generally, The Merck Manual of
Diagnosis and Therapy, 15th Ed. 1987, pp. 1206-1228, Berkow et al.,
eds., Rahway, N.J. When used with the compounds of the invention,
such chemotherapeutic agents may be used individually (e.g., 5-FU
and oligonucleotide), sequentially (e.g., 5-FU and oligonucleotide
for a period of time followed by MTX and oligonucleotide), or in
combination with one or more other such chemotherapeutic agents
(e.g., 5-FU, MTX and oligonucleotide, or 5-FU, radiotherapy and
oligonucleotide). Anti-inflammatory drugs, including but not
limited to nonsteroidal anti-inflammatory drugs and
corticosteroids, and antiviral drugs, including but not limited to
ribivirin, vidarabine, acyclovir and ganciclovir, may also be
combined in compositions of the invention. See, generally, The
Merck Manual of Diagnosis and Therapy, 15th Ed., Berkow et al.,
eds., 1987, Rahway, N.J., pages 2499-2506 and 46-49, respectively).
Other non-antisense chemotherapeutic agents are also within the
scope of this invention. Two or more combined compounds may be used
together or sequentially.
[0126] Toxicity and therapeutic efficacy of such compounds can be
determined by standard pharmaceutical procedures in cell cultures
or experimental animals, e.g., for determining the LD50 (the dose
lethal to 50% of the population) and the ED50 (the dose
therapeutically effective in 50% of the population). The dose ratio
between toxic and therapeutic effects is the therapeutic index and
it can be expressed as the ratio LD50/ED50. Compounds which exhibit
high therapeutic indices are preferred.
[0127] The data obtained from cell culture assays and animal
studies can be used in formulation a range of dosage for use in
humans. The dosage of compositions of the invention lies generally
within a range of circulating concentrations that include the ED50
with little or no toxicity. The dosage may vary within this range
depending upon the dosage form employed and the route of
administration utilized. For any compound used in the method of the
invention, the therapeutically effective dose can be estimated
initially from cell culture assays. A dose may be formulated in
animal models to achieve a circulating plasma concentration range
of the compound or, when appropriate, of the polypeptide product of
a target sequence (e.g., achieving a decreased concentration of the
polypeptide) that includes the IC50 (i.e., the concentration of the
test compound which achieves a half-maximal inhibition of symptoms)
as determined in cell culture. Such information can be used to more
accurately determine useful doses in humans. Levels in plasma may
be measured, for example, by high performance liquid
chromatography.
[0128] In addition to their administration individually or as a
plurality, as discussed above, the dsRNAs of the invention can be
administered in combination with other known agents effective in
treatment of pathological processes mediated by JC virus
expression. In any event, the administering physician can adjust
the amount and timing of dsRNA administration on the basis of
results observed using standard measures of efficacy known in the
art or described herein.
[0129] Methods for Treating Diseases Caused by Expression of a Gene
from the JC Virus
[0130] The invention relates in particular to the use of a dsRNA or
a pharmaceutical composition prepared therefrom for the treatment
or prevention of pathological conditions associated with JC Virus
infection, e.g., PML. Owing to the inhibitory effect on JC virus
expression, an dsRNA according to the invention or a pharmaceutical
composition prepared therefrom can enhance the quality of life,
particularly in a patient being treated with an anti-VLA4 antibody
as part of treatment for MS.
[0131] The invention furthermore relates to the use of an dsRNA or
a pharmaceutical composition thereof for treating PML in
combination with other pharmaceuticals and/or other therapeutic
methods, e.g., with known pharmaceuticals and/or known therapeutic
methods, such as, for example, those which are currently employed
for treating cancer and/or for preventing tumor metastasis.
Preference is given to a combination with radiation therapy and
chemotherapeutic agents, such as cisplatin, cyclophosphamide,
5-fluorouracil, adriamycin, daunorubicin or tamoxifen.
[0132] The invention can also be practiced by including with a
specific RNAi agent, in combination with another anti-cancer
chemotherapeutic agent, such as any conventional chemotherapeutic
agent. The combination of a specific binding agent with such other
agents can potentiate the chemotherapeutic protocol. Numerous
chemotherapeutic protocols will present themselves in the mind of
the skilled practitioner as being capable of incorporation into the
method of the invention. Any chemotherapeutic agent can be used,
including alkylating agents, antimetabolites, hormones and
antagonists, radioisotopes, as well as natural products. For
example, the compound of the invention can be administered with
antibiotics such as doxorubicin and other anthracycline analogs,
nitrogen mustards such as cyclophosphamide, pyrimidine analogs such
as 5-fluorouracil, cisplatin, hydroxyurea, taxol and its natural
and synthetic derivatives, and the like. As another example, in the
case of mixed tumors, such as adenocarcinoma of the breast, where
the tumors include gonadotropin-dependent and
gonadotropin-independent cells, the compound can be administered in
conjunction with leuprolide or goserelin (synthetic peptide analogs
of LH-RH). Other antineoplastic protocols include the use of a
tetracycline compound with another treatment modality, e.g.,
surgery, radiation, etc., also referred to herein as "adjunct
antineoplastic modalities." Thus, the method of the invention can
be employed with such conventional regimens with the benefit of
reducing side effects and enhancing efficacy.
[0133] Methods for Inhibiting Expression of a Gene from the JC
Virus
[0134] In yet another aspect, the invention provides a method for
inhibiting the expression of a gene from the JC Virus in a mammal.
The method comprises administering a composition of the invention
to the mammal such that expression of the target JC virus genome is
silenced. Because of their high specificity, the dsRNAs of the
invention specifically target RNAs (primary or processed) of the
target JC virus gene. Compositions and methods for inhibiting the
expression of these JC virus genes using dsRNAs can be performed as
described elsewhere herein.
[0135] In one embodiment, the method comprises administering a
composition comprising a dsRNA, wherein the dsRNA comprises a
nucleotide sequence which is complementary to at least a part of an
RNA transcript of a gene from the JC Virus, to the mammal to be
treated. When the organism to be treated is a mammal such as a
human, the composition may be administered by any means known in
the art including, but not limited to oral or parenteral routes,
including intravenous, intramuscular, subcutaneous, transdermal,
airway (aerosol), nasal, administration. In preferred embodiments,
the compositions are administered by intravenous infusion or
injection.
[0136] Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. Although
methods and materials similar or equivalent to those described
herein can be used in the practice or testing of the invention,
suitable methods and materials are described below. All
publications, patent applications, patents, and other references
mentioned herein are incorporated by reference in their entirety.
In case of conflict, the present specification, including
definitions, will control. In addition, the materials, methods, and
examples are illustrative only and not intended to be limiting.
EXAMPLES
Design of JCV siRNAs
[0137] Full-length genome sequences to JC virus available on Apr.
10, 2006, were obtained, resulting in a target pool of 388
sequences (accession numbers: AB038249.1-AB038255.1;
AB048545.1-AB048582.1; AB074575.1-AB074591.1;
AB077855.1-AB077879.1; AB081005.1-AB081030.1;
AB081600.1-AB081618.1; AB081654.1; AB092578.1-AB092587.1;
AB103387.1; AB103402.1-AB103423.1; AB104487.1;
AB113118.1-AB113145.1; AB118651.1-AB118659.1;
AB126981.1-AB127027.1; AB127342.1; AB127344.1;
AB127346.1-AB127349.1; AB127352.1-AB127353.1;
AB198940.1-AB198954.1; AB220939.1-AB220943.1;
AF004349.1-AF004350.1; AF015526.1-AF015537.1; AF015684.1;
AF030085.1; AF281599.1-AF281626.1; AF295731.1-AF295739.1;
AF300945.1-AF300967.1; AF363830.1-AF363834.1;
AF396422.1-AF396435.1; AY121907.1-AY121915.1; NC.sub.--001699.1;
U61771.1; U73500.1-U73502.1). NC.sub.--001699 was defined as
reference sequence.
[0138] The siRNA selection process was run as follows: ClustalW
multiple alignment was used to generate a global alignment of all
sequences from the target pool. An IUPAC consensus sequence was
then generated.
[0139] All conserved 19 mer target sequences from the IUPAC
consensus represented by stretches containing only A, T, C or G
bases, which are therefore present in all sequences of the target
pool were selected. In order to only select siRNAs that target
transcribed sequence parts of the JC virus, candidate target
sequences were selected out of the pool of conserved 19 mer target
sequences. For this, candidate target sequences covering regions
between nucleotide 163-2594 and between 2527-5115 relative to
reference sequence were extracted for late and early genes,
respectively. Further, as sequences for early genes are in reverse
complement orientation compared with genomic sequences, candidate
target sequences of these genes were transferred to reverse
complement sequences and replaced the former pool of candidate
target sequences.
[0140] In order to rank candidate target sequences and their
respective siRNAs and select appropriate ones, their predicted
potential for interacting with irrelevant targets (off-target
potential) was taken as a ranking parameter. siRNAs with low
off-target potential were defined as preferable and assumed to be
more specific in vivo.
[0141] For predicting siRNA-specific off-target potential, the
following assumptions were made: [0142] 1) positions 2 to 9
(counting 5' to 3') of a strand (seed region) may contribute more
to off-target potential than rest of sequence (non-seed and
cleavage site region) [0143] 2) positions 10 and 11 (counting 5' to
3') of a strand (cleavage site region) may contribute more to
off-target potential than non-seed region [0144] 3) an off-target
score can be calculated for each hit, based on identity to siRNA
sequence and position of mismatches [0145] 4) assuming potential
abortion of sense strand activity by internal modifications
introduced, only off-target potential of antisense strand will be
relevant
[0146] To identify potential off-target genes, 19 mer input
sequences were subjected to a homology search against publically
available human mRNA sequences.
[0147] To this purpose, fastA (version 3.4) searches were performed
with all 19 mer candidate target sequences against a human RefSeq
database (downloaded available version from
ftp://ftp.ncbi.nih.gov/refseq/on Nov. 7, 2006). FastA searches were
executed with parameters-values-pairs -f 50 -g 50 in order to take
into account the homology over the full length of the 19 mer
without any gaps. In order to ensure the listing of all relevant
off-target hits in the fastA output file the parameter -E 30000 was
used in addition. A scoring matrix was applied for the run that
assessed every nucleotide match with a score of 13 and every
mismatch with a score of -7. The search resulted in a list of
potential off-targets for each candidate siRNA.
[0148] To sort the resulting list of potential off-targets for each
siRNA, fastA output files were analyzed to identify the best
off-target and its off-target score. The following off-target
properties for each 19 mer input sequence were extracted for each
off-target to calculate the off-target score:
[0149] Number of mismatches in non-seed region
[0150] Number of mismatches in seed region
[0151] Number of mismatches in cleavage site region
[0152] The off-target score was calculated for considering
assumption 1 to 3 as follows:
Off - target score = number of seed mismatches * 10 + number of
cleavage site mismatches * 1.2 + number of non - seed mismatches *
1 ##EQU00002##
[0153] The most relevant off-target gene for input each 19 mer
input sequences was defined as the gene with the lowest off-target
score. Accordingly, the lowest off-target score was defined as the
relevant off-target score for the corresponding siRNA.
[0154] In order to generate a ranking for siRNAs, calculated
relevant off-target scores were transferred into a result table.
All siRNAs were sorted according to the off-target score
(descending).
[0155] An off-target score of 2.2 was defined as cut-off for siRNA
selection (specificity criterion). In addition, all sequences with
only one mismatch in the seed region were eliminated from the
screening set. The selection procedure resulted in a set of 93 JCV
specific siRNAs (Table 1a).
[0156] An expanded screening was generated by re-calculating the
predicted specificity based on the newly available human RefSeq
database (Human mRNA sequences in RefSeq release version 21
(downloaded Jan. 12, 2007)) and selecting only 208 siRNAs that did
not contain more than 3 G's in a row and had an off-target score of
at least 2 for the antisense strand (Table 1b).
[0157] Synthesis of JCV siRNAs
[0158] All siRNAs were synthesized in 0.2 .mu.mole synthesis scale
on an ABI3900 DNA synthesizer according to standard procedures.
[0159] For the initial screening set (93 different siRNA
sequences), 4 different strategies of chemical modification were
used:
[0160] a) exo/endo light (EEL): [0161] sense strand: 2'-O-methyl @
all pyrimidines, PTO between nucleotides 20 and 21 (counting from
5'-end), dTdT at 3'-end (nucleotides 20 and 21) [0162] antisense
strand: 2'-O-methyl at pyrimidines in 5'-UA-3' and 5'-CA-3'
motives, PTO between nucleotides 20 and 21 (counting from 5'-end),
dTdT at 3'-end (nucleotides 20 and 21)
[0163] b) EEL plus 2'-O-methyl in position 2 of antisense strand
(only if no 5'-UA-3' and 5'-CA-3' at 5'-end, otherwise already
covered by EEL)
[0164] c) EEL plus 2'-O-methyl in position 2 of sense strand (only
if no pyrimidine in position 2, otherwise already covered by
EEL)
[0165] d) EEL plus 2'-O-methyl in position 2 of sense and antisense
strand (only if not already covered by a, b, and c) (Table 1a)
[0166] For the expanded screening set (208 different siRNA
sequences), siRNAs were composed of unmodified RNA oligonucleotides
with dT/dT overhangs (dTdT at 3'-end (nucleotides 20 and 21) of
antisense and sense strands) (Table 1b).
[0167] Screening of JCV siRNAs
[0168] Construction of Reporter-Systems Encoding JCV
Transcripts
[0169] The sequence of the early JCV transcript (E) was synthesized
at GENEART (Regensburg, Germany) and cloned into GENEART standard
vectors. The sequence of the late JCV transcript was subdivided in
a first approach into two fragments: L1, including the transcript
sequence of the VP1 protein, and LA23, including the sequences of
VP2, VP3 and the Agnoprotein. Due to cloning problems with fragment
LA23, this sequence was subdivided in a second approach into two
fragments (LA23 1-700 and LA23 701-1438). All sequences were
synthesized at GENEART and cloned into GENEART standard vectors.
All fragments (E, L1, LA23 1-700 and LA23 701-1438) were subcloned
into psiCheck-2 (Promega, Mannheim, Germany) via XhoI and NotI
(both NEB, Frankfurt, Germany), resulting in constructs with the
JCV sequences between the stop-codon and the polyA-signal of
Renilla luciferase.
[0170] L1
TABLE-US-00001 (SEQ ID NO: 931)
CTCGAGACTTTTAGGGTTGTACGGGACTGTAACACCTGCTCTTG
AAGCATATGAAGATGGCCCCAACAAAAAGAAAAGGAGAAAGGAA
GGACCCCGTGCAAGTTCCAAAACTTCTTATAAGAGGAGGAGTAG
AAGTTCTAGAAGTTAAAACTGGGGTTGACTCAATTACAGAGGTA
GAATGCTTTTTAACTCCAGAAATGGGTGACCCAGATGAGCATCT
TAGGGGTTTTAGTAAGTCAATTTCTATATCAGATACATTTGAAA
GTGACTCCCCAAATAAGGACATGCTTCCTTGTTACAGTGTGGCC
AGAATTCCACTACCCAATCTAAATGAGGATCTAACCTGTGGAAA
TATACTAATGTGGGAGGCTGTGACCTTAAAAACTGAGGTTCTAG
GGGTGACAACTTTGATGAATGTGCACTCTAATGGTCAAGCAACT
CATGACAATGGTGCAGGAAAGCCAGTGCAGGGCACCAGCTTTCA
TTTTTTTTCTGTTGGCGGGGAGGCTTTAGAATTACAGGGGGTGG
TTTTTAATTACAGAACAAAGTACCCAGATGGAACAATTTTTCCA
AAGAATGCAACAGTGCAATCTCAAGTAATGAACACAGAGCACAA
GGCGTACCTAGATAAGAACAAAGCATATCCTGTTGAATGTTGGG
TTCCTGATCCCACCAGAAATGAAAACACAAGATATTTTGGGACA
CTAACAGGAGGAGAAAATGTTCCTCCAGTTCTTCATATAACAAA
CACTGCCACAACAGTGCTGCTTGATGAATTTGGTGTTGGGCCAC
TTTGCAAAGGTGACAACTTGTATTTGTCAGCTGTTGATGTTTGT
GGAATGTTTACTAACAGATCTGGTTCCCAGCAGTGGAGAGGACT
GTCCAGATATTTTAAGGTTCAGCTCAGAAAAAGGAGGGTTAAAA
ACCCCTACCCAATTTCTTTCCTTCTTACTGATTTGATTAACAGA
AGGACCCCTAGAGTTGATGGGCAACCTATGTATGGTATGGATGC
TCAGGTAGAGGAGGTTAGAGTTTTTGAGGGGACAGAGGAACTTC
CAGGGGACCCAGACATGATGAGATATGTTGACAGATATGGACAG
TTGCAAACAAAGATGCTGTAATCAAAATCCTTTATTGTAATATG
CAGTACATTTTAATAAAGTATAACCAGCTTTACTTTACAGTTGC AGTCATGCGGCCGC
[0171] E
TABLE-US-00002 (SEQ ID NO: 932)
CTCGAGCCGCCTCCAAGCTTACTCAGAAGTAGTAAGGGC
GTGGAGGCTTTTTAGGAGGCCAGGGAAATTCCCTTGTTTTTCCC
TTTTTTGCAGTAATTTTTTGCTGCAAAAAGCTAAAATGGACAAA
GTGCTGAATAGGGAGGAATCCATGGAGCTTATGGATTTATTAGG
CCTTGATAGGTCTGCATGGGGGAACATTCCTGTCATGAGAAAAG
CTTATCTGAAAAAATGCAAAGAACTCCACCCTGATAAAGGTGGG
GACGAAGACAAGATGAAGAGAATGAATTTTTTATATAAAAAAAT
GGAACAAGGTGTAAAAGTTGCTCATCAGCCTGATTTTGGTACAT
GGAATAGTTCAGAGGTTGGTTGTGATTTTCCTCCTAATTCTGAT
ACCCTTTATTGCAAGGAATGGCCTAACTGTGCCACTAATCCTTC
AGTGCATTGCCCCTGTTTAATGTGCATGCTAAAATTAAGGCATA
GAAACAGAAAATTTTTAAGAAGCAGCCCACTTGTGTGGATAGAT
TGCTATTGCTTTGATTGCTTCAGACAATGGTTTGGGTGTGACTT
AACCCAAGAAGCTCTTCATTGCTGGGAGAAAGTTCTTGGAGACA
CCCCCTACAGGGATCTAAAGCTTTAAGTGCCAACCTATGGAACA
GATGAATGGGAATCCTGGTGGAATACATTTAATGAGAAGTGGGA
TGAAGACCTGTTTTGCCATGAAGAAATGTTTGCCAGTGATGATG
AAAACACAGGATCCCAACACTCTACCCCACCTAAAAAGAAAAAA
AAGGTAGAAGACCCTAAAGACTTTCCTGTAGATCTGCATGCATT
CCTCAGTCAAGCTGTGTTTAGTAATAGAACTGTTGCTTCTTTTG
CTGTGTATACCACTAAAGAAAAAGCTCAAATTTTATATAAGAAA
CTTATGGAAAAATATTCTGTAACTTTTATAAGTAGACATGGTTT
TGGGGGTCATAATATTTTGTTTTTCTTAACACCACATAGACATA
GAGTGTCAGCAATTAATAACTACTGTCAAAAACTATGTACCTTT
AGTTTTTTAATTTGTAAAGGTGTGAATAAGGAATACTTGTTTTA
TAGTGCCCTGTGTAGACAGCCATATGCAGTAGTGGAAGAAAGTA
TTCAGGGGGGCCTTAAGGAGCATGACTTTAACCCAGAAGAACCA
GAAGAAACTAAGCAGGTTTCATGGAAATTAGTTACACAGTATGC
CTTGGAAACCAAGTGTGAGGATGTTTTTTTGCTTATGGGCATGT
ACTTAGACTTTCAGGAAAACCCACAGCAATGCAAAAAATGTGAA
AAAAAGGATCAGCCAAATCACTTTAACCATCATGAAAAACACTA
TTATAATGCCCAAATTTTTGCAGATAGCAAAAATCAAAAAAGCA
TTTGCCAGCAGGCTGTTGATACTGTAGCAGCCAAACAAAGGGTT
GACAGCATCCACATGACCAGAGAAGAAATGTTAGTTGAAAGGTT
TAATTTCTTGCTTGATAAAATGGACTTAATTTTTGGGGCACATG
GCAATGCTGTTTTAGAGCAATATATGGCTGGGGTGGCCTGGATT
CATTGCTTGCTGCCTCAAATGGACACTGTTATTTATGACTTTCT
AAAATGCATTGTATTAAACATTCCAAAAAAAAGGTACTGGCTAT
TCAAGGGGCCAATAGACAGTGGCAAAACTACTTTAGCTGCAGCT
TTACTTGATCTCTGTGGGGGAAAGTCATTAAATGTTAATATGCC
ATTAGAAAGATTAAACTTTGAATTAGGAGTGGGTATAGATCAGT
TTATGGTTGTATTTGAGGATGTAAAAGGCACTGGTGCAGAGTCA
AGGGATTTACCTTCAGGGCATGGCATAAGCAACCTTGATTGCTT
AAGAGATTACTTAGATGGAAGTGTAAAAGTTAATTTAGAGAGAA
AACACCAAAACAAAAGAACACAGGTGTTTCCACCTGGAATTGTA
ACCATGAATGAATATTCAGTGCCTAGAACTTTACAGGCCAGATT
TGTAAGGCAGATAGATTTTAGACCAAAGGCCTACCTGAGAAAAT
CACTAAGCTGCTCTGAGTATTTGCTAGAAAAAAGGATTTTGCAA
AGTGGTATGACTTTGCTTTTGCTTTTAATCTGGTTTAGGCCAGT
TGCTGACTTTGCAGCTGCCATTCATGAGAGGATTGTGCAGTGGA
AAGAAAGGCTGGATTTAGAAATAAGCATGTATACATTTTCTACT
ATGAAAGCTAATGTTGGTATGGGGAGACCCATTCTTGACTTTCC
TAGAGAGGAAGATTCTGAAGCAGAAGACTCTGGACATGGATCAA
GCACTGAATCACAATCACAATGCTTTTCCCAGGTCTCAGAAGCC
TCTGGTGCAGACACACAGGAAAACTGCACTTTTCACATCTGTAA
AGGCTTTCAATGTTTCAAAAAACCAAAGACCCCTCCCCCAAAAT
AACTGCAACTGTGCGGCCGC
[0172] LA23 1-700
TABLE-US-00003 (SEQ ID NO: 933)
CTCGAGCAGCTAACAGCCAGTAAACAAAGCACAAGGGGAAGTGG
AAAGCAGCCAAGGGAACATGTTTTGCGAGCCAGAGCTGTTTTGG
CTTGTCACCAGCTGGCCATGGTTCTTCGCCAGCTGTCACGTAAG
GCTTCTGTGAAAGTTAGTAAAACCTGGAGTGGAACTAAAAAAAG
AGCTCAAAGGATTTTAATTTTTTTGTTAGAATTTTTGCTGGACT
TTTGCACAGGTGAAGACAGTGTAGACGGGAAAAAAAGACAGAGA
CACAGTGGTTTGACTGAGCAGACATACAGTGCTTTGCCTGAACC
AAAAGCTACATAGGTAAGTAATGTTTTTTTTTGTGTTTTCAGGT
TCATGGGTGCCGCACTTGCACTTTTGGGGGACCTAGTTGCTACT
GTTTCTGAGGCTGCTGCTGCCACAGGATTTTCAGTAGCTGAAAT
TGCTGCTGGAGAGGCTGCTGCTACTATAGAAGTTGAAATTGCAT
CCCTTGCTACTGTAGAGGGGATTACAAGTACCTCTGAGGCTATA
GCTGCTATAGGCCTTACTCCTGAAACATATGCTGTAATAACTGG
AGCTCCGGGGGCTGTAGCTGGGTTTGCTGCATTGGTTCAAACTG
TAACTGGTGGTAGTGCTATTGCTCAGTTGGGATATAGATTTTTT
GCTGACTGGGATCATAAAGTTTCAACAGTTGGGCTTTTTCGCGG CCGC
[0173] LA23 701-1438
TABLE-US-00004 (SEQ ID NO: 934)
CTCGAGAGCAGCCAGCTATGGCTTTACAATTATTTAATCCAGAA
GACTACTATGATATTTTATTTCCTGGAGTGAATGCCTTTGTTAA
CAATATTCACTATTTAGATCCTAGACATTGGGGCCCGTCCTTGT
TCTCCACAATCTCCCAGGCTTTTTGGAATCTTGTTAGAGATGAT
TTGCCAGCCTTAACCTCTCAGGAAATTCAGAGAAGAACCCAAAA
ACTATTTGTTGAAAGTTTAGCAAGGTTTTTGGAAGAAACTACTT
GGGCAATAGTTAATTCACCAGCTAACTTATATAATTATATTTCA
GACTATTATTCTAGATTGTCTCCAGTTAGGCCCTCTATGGTAAG
GCAAGTTGCCCAAAGGGAGGGAACCTATATTTCTTTTGGCCACT
CATACACCCAAAGTATAGATGATGCAGACAGCATTCAAGAAGTT
ACCCAAAGGCTAGATTTAAAAACCCCAAATGTGCAATCTGGTGA
ATTTATAGAAAGAAGTATTGCACCAGGAGGTGCAAATCAAAGAT
CTGCTCCTCAATGGATGTTGCCTTTACTTTTAGGGTTGTACGGG
ACTGTAACACCTGCTCTTGAAGCATATGAAGATGGCCCCAACAA
AAAGAAAAGGAGAAAGGAAGGACCCCGTGCAAGTTCCAAAACTT
CTTATAAGAGGAGGAGTAGAAGTTCTAGAAGTTAAAACTGGGGT
TGACTCAATTACAGAGGTAGAATGCTGCGGCCGC
[0174] Screen of JCV siRNAs in Transfected Cells
[0175] Cos-7 cells (DSMZ, Braunschweig, Germany, # ACC-60) were
seeded at 1.5.times.10.sup.4 cells/well on white 96-well plates
with clear bottoms (Greiner Bio-One GmbH, Frickenhausen, Germany)
in 75 .mu.l of growth medium. Directly after seeding the cells, 50
ng of the corresponding reporter-plasmid per well was transfected
with Lipofectamine.TM. 2000 (Invitrogen GmbH, Karlsruhe, Germany),
with the plasmid diluted in Opti-MEM to a final volume of 12.5
.mu.l per well, prepared as a mastermix for the whole plate.
[0176] 4 h after plasmid transfection, growth medium was removed
from cells and replaced by 100 .mu.l/well of fresh medium. siRNA
transfections were performed using Lipofectamine.TM. 2000
(Invitrogen GmbH, Karlsruhe, Germany) as described by the
manufacturer. Cells were incubated for 24 h at 37.degree. C. and 5%
CO.sub.2 in a humidified incubator (Heraeus GmbH, Hanau, Germany).
For the primary screen, all siRNAs were screened at a final
concentration of 30 nM. Selected sequences were rescreened at a
siRNA concentration of 300 pM. Each siRNA was tested in
quadruplicate for each concentration.
[0177] Cells were lysed by removing growth medium and application
of 150 .mu.l of a 1:1 mixture consisting of medium and substrate
from the Dual-Glo Luciferase Assay System (Promega, Mannheim,
Germany). The luciferase assay was performed according to the
manufacturer's protocol for Dual-Glo Luciferase assay and
luminescence was measured in a Victor-Light 1420 Luminescence
Counter (Perkin Elmer, Rodgau-Jugesheim, Germany). Values obtained
with Renilla luciferase were normalized to the respective values
obtained with Firefly luciferase in order to correct for
transfection efficacy. Renilla/Firefly luciferase activities
obtained after transfection with siRNAs directed against a JCV gene
were normalized to Renilla/Firefly luciferase activities obtained
after transfection of an unrelated control siRNA set to 100%.
Tables 1a and b provides the results where the siRNAs, the
sequences of which are given in Tables 1a and b, were tested at a
single dose of 30 nM. The percentage inhibition.+-.standard
deviation, compared to the unrelated control siRNA, is indicated in
the column `Remaining luciferase activity (% of control)`. A number
of JCV siRNAs at 30 nM were effective at reducing levels of the
targeted mRNA by more than 70% in Cos-7 cells (i.e. remaining
luciferase activity was less than 30%).
[0178] Selected JCV siRNAs from the single dose screen were further
characterized by dose response curves. Transfections of JCV siRNAs
for generation of dose response curves were performed with the
following siRNA concentrations according to the above protocol:
[0179] from 33 nM in 3-fold dilutions down to 0.005 nM (for
fragment L1) [0180] from 24 nM in 4-fold dilutions down to 0.001 nM
(for fragment E and fragments LA23 1-700 and LA23 701-1438).
[0181] IC50 values were determined by parameterized curve fitting
using the program XLfit (IDBS, Guildford, Great Britain). Table 2
provides the results from two independent experiments for 32
selected JCV siRNAs. The mean IC50 from these two independent
experiments is shown. Several JCV siRNAs (AD-12622, AD-12677,
AD-12709, AD-12710, AD-12722, AD-12724, AD-12728, AD-12763,
AD-12767, AD-12768, AD-12769, AD-12771, AD-12774, AD-12775,
AD-12777, AD-12781, AD-12784, AD-12795, AD-12813, AD-12821,
AD-12823, AD-12824, AD-12825, AD-12827, AD-12829, AD-12842) were
particularly potent in this experimental paradigm, and exhibited
IC50 values between 70 pM and 1 nM.
TABLE-US-00005 TABLE 2 IC50s Mean IC50 Duplex name [nM] AD-12599
2.37 AD-12622 0.57 AD-12666 3.7 AD-12677 0.49 AD-12709 0.19
AD-12710 0.47 AD-12712 2.33 AD-12722 0.12 AD-12724 0.26 AD-12728
0.8 AD-12761 1.2 AD-12763 0.95 AD-12767 0.09 AD-12768 0.19 AD-12769
0.35 AD-12771 0.35 AD-12774 0.13 AD-12775 0.18 AD-12777 0.17
AD-12778 12.65 AD-12781 0.18 AD-12784 0.44 AD-12795 0.65 AD-12813
0.2 AD-12818 1.88 AD-12821 0.07 AD-12823 0.46 AD-12824 0.25
AD-12825 0.52 AD-12827 0.15 AD-12829 0.14 AD-12842 0.44
[0182] Screen of JCV siRNAs Against Live JC Virus in SVG-A
Cells
[0183] Cells and Virus
[0184] SVG-A cells (human fetal glial cells transformed by SV40 T
antigen) obtained from Walter Atwood at Brown University were
cultured in Eagle's Minimum Essential Media (ATCC, Manassas, Va.)
supplemented to contain 10% fetal bovine serum (FBS) (Omega
Scientific, Tarzana, Calif.), Penicillin 100 U/ml, Streptomycin 100
ug/ml (Invitrogen, Carlsbad Calif.) at 37.degree. C. in an
atmosphere with 5% CO.sub.2 in a humidified incubator (Heraeus
HERAcell, Thermo Electron Corporation, Ashville, N.C.). The
Mad-1-SVE.DELTA. strain of JCV obtained from Walter Atwood at Brown
University was used in all experiments; viral stocks were prepared
using SVG-A cells according to standard published methods (Liu and
Atwood, Propagation and assay of the JC Virus, Methods Mol Biol.
2001; 165:9-17).
[0185] Prophylaxis Assay
[0186] SVG-A cells were seeded on glass coverslips in 6-well dishes
24 hours prior to transfection in the media described above minus
antibiotics. Cells were transfected with the indicated
concentration of siRNA (10 nM, 50 nM, or 100 nM) using
Lipofectamine.TM. 2000 according to the manufacturer's instructions
(Invitrogen, Carlsbad, Calif.). Twenty-four hours post-transfection
cells were washed with media containing 2% FBS and then infected
with a 1:25 dilution of JCV virus stock (Mad-1-SVE.DELTA. strain)
diluted in 2% FBS media. Cells were rocked every 15 minutes by hand
several times to get equal virus binding across the entire
coverslip for one hour and then additional 10% FBS media was added
and the infection was allowed to proceed for 72 hours. Seventy two
hours post-infection, cells were fixed in acetone and stained for
late viral protein (VP1) by standard immunofluorescence methods
using hybridoma supernatant PAB597 recognizing JCV VP1 (obtained
from Walter Atwood at Brown University) with goat anti-mouse Alexa
Fluor 488 secondary antibody (Invitrogen, Carlsbad, Calif.).
Infected cells were scored by counting VP1-immunoreactive cells
using a fluorescence microscope (Zeiss, Imager.Z1, Thornwood, N.J.)
and data were expressed as the percentage of infected cells counted
for the control coverslips transfected with Luciferase siRNA. Table
3 shows the results of the prophylaxis assays at different siRNA
concentrations (10 nM, 50 nM or 100 nM). The VP1 siRNAs were the
most potent as a group, followed by the T antigen siRNAs, with the
VP2/3 siRNAs being the least potent. The VP1 siRNAs most effective
in reducing virus were consistently AD-12622, AD-12728, AD-12795,
and AD-12842. The most potent T antigen siRNA was AD-12813.
TABLE-US-00006 TABLE 3 Prophylaxis Assay Remaining Virus Duplex
Targeted JCV (% of Luciferase Control) Number Transcript 50 nM 10
nM 100 nM AD-12599 VP1 79.9 ND ND AD-12709 VP1 46.0 ND ND AD-12710
VP1 25.9 ND ND AD-12784 VP1 30.9 ND ND AD-12712 VP1 29.7 ND ND
AD-12724 VP1 30.5 38.9 25.8 AD-12622 VP1 22.9 28.2 9.1 AD-12728 VP1
21.1 22.2 ND AD-12795 VP1 13.6 16.9 8.5 AD-12842 VP1 16.0 23.4 12.7
AD-12761 VP1 26.4 52.3 ND AD-12818 VP1 24.0 50.2 28.0 AD-12666 VP1
54.1 ND ND AD-12763 VP1 39.5 ND ND AD-12722 T Antigen 43.6 82.1 ND
AD-12813 T Antigen 21.5 48.8 19.4 AD-12767 T Antigen 37.6 52.2 30.9
AD-12821 T Antigen 33.0 51.2 30.8 AD-12774 T Antigen 74.0 89.2 ND
AD-12827 T Antigen 77.0 92.0 ND AD-12775 T Antigen 81.6 95.4 ND
AD-12777 T Antigen 73.3 93.9 ND AD-12829 T Antigen 78.6 93.6 ND
AD-12781 T Antigen 38.8 62.6 34.4 AD-12768 VP2/3 73.9 92.4 ND
AD-12771 VP2/3 51.6 83.6 ND AD-12824 VP2/3 42.1 79.0 43.7 AD-12769
VP2/3 35.2 78.0 39.7 AD-12823 VP2/3 38.1 78.1 42.0 AD-12677 VP2/3
99.1 102.1 ND AD-12825 VP2/3 100.8 99.1 ND ND indicates no
data.
[0187] Post-Infection Treatment Assay
[0188] SVG-A cells were seeded on glass coverslips in 6-well dishes
24 hours prior to infection in 10% FBS media. Cells were washed
with media containing 2% FBS and then infected with a 1:25 dilution
of JCV virus stock diluted in 2% FBS media. Cells were rocked by
hand approximately 8-10 times to get equal virus binding across the
entire coverslip every 15 minutes for one hour and then additional
10% FBS media was added. Twenty-four and forty-eight hours
postinfection, cells were washed with 10% FBS media containing no
antibiotics and then transfected with 50 nM of the indicated siRNA
using Lipofectamine.TM. 2000 according to the manufacturer's
instructions (Invitrogen, Carlsbad, Calif.). Seventy-two hours
postinfection, cells were fixed in acetone and stained for late
viral protein (VP1) by standard immunofluorescence methods using
hybridoma supernatant PAB597 recognizing JCV VP1 (obtained from
Walter Atwood at Brown University) with goat anti-mouse Alexa Fluor
488 secondary antibody (Molecular Probes, Eugene, Oreg.). Infected
cells were scored by counting VP1-immunoreactive cells using a
fluorescence microscope (Zeiss, Imager.Z1, Thornwood, N.J.) and
data were expressed as the percentage of infected cells counted for
control coverslips transfected with Luciferase siRNA. Table 4 shows
the results of the post-infection treatment experiments. All of the
siRNAs tested in the treatment assay showed significant antiviral
activity against JCV, such that the remaining virus was
significantly less than that in the luciferase siRNA control.
TABLE-US-00007 TABLE 4 Treatment Assay Targeted JCV Remaining Virus
(% of Duplex Number Transcript Luciferase Control) AD-12724 VP1
38.9 AD-12622 VP1 28.2 AD-12795 VP1 16.9 AD-12842 VP1 23.4 AD-12818
VP1 ND AD-12813 T Antigen 48 AD-12767 T Antigen 56.9 AD-12821 T
Antigen 75.8 AD-12781 T Antigen 75.8 AD-12824 VP2/3 60.4 AD-12769
VP2/3 70.7 AD-12823 VP2/3 72.4 ND indicates no data.
[0189] Prophylaxis Administration of JCV siRNAs Inhibits the
Production of Active Progeny JC Virus
[0190] SVG-A cells were seeded in 6-well dishes 24 hours prior to
transfection in the media described above minus antibiotics. Cells
were transfected with 10 nM of the indicated siRNA using
Lipofectamine.TM. 2000 according to the manufacturer's instructions
(Invitrogen, Carlsbad, Calif.). Twenty-four hours post-transfection
cells were washed with media containing 2% FBS and then infected
with a 1:25 dilution of JCV virus stock (Mad-1-SVE.DELTA. strain)
diluted in 2% FBS media. Cells were rocked every 15 minutes by hand
several times to get equal virus binding across the entire
coverslip for one hour and then additional 10% FBS media was added
and the infection was allowed to proceed for 6 days. Six days
post-infection, progeny virus was collected either by removal of
overlay media from infected cells or by scraping cells and
performing virus preparations. The virus preparations consisted of
scraping cells into the supernatant media, vortexing,
freeze-thawing the re-suspended cells 2 times with vortexing in
between, then spinning down the cell debris and taking the
supernatant. Fresh SVG-A cells seeded on glass coverslips were
infected secondarily with virus collected by either method using
the same procedure done with the initial infection to determine the
amount of infectious virus produced by cells transfected with the
various siRNAs. At 72 hours post-infection of coverslips, cells
were fixed in acetone and stained for late viral protein (VP1) by
standard immunofluorescence methods using hybridoma supernatant
PAB597 recognizing JCV VP1 (obtained from Walter Atwood at Brown
University) with goat anti-mouse Alexa Fluor 488 secondary antibody
(Invitrogen, Carlsbad, Calif.). Infected cells were scored by
counting VP1-immunoreactive cells using a fluorescence microscope
(Zeiss, Imager.Z1, Thornwood, N.J.) and data were expressed as the
percentage of infected cells counted for the control coverslips
transfected with Luciferase siRNA. Table 5 shows the results for
selected siRNAs, demonstrating the ability of prophylaxis siRNA
treatment to inhibit active progeny virus production by either
method of virus collection. Transfection with siRNAs targeting VP1
(AD-12622 and AD-12842) had the greatest effect on inhibiting the
production of active progeny virus regardless of whether virus was
collected from media or from infected cell preparations. The T
antigen siRNA AD-12813 had the next strongest inhibitory effect,
whereas the VP2/3 siRNAs AD-12824 and AD-12769 still showed some
albeit a lesser ability to inhibit active progeny JCV
production.
TABLE-US-00008 TABLE 5 Prophylaxis administration of JCV siRNAs
inhibits the production of active progeny JC virus capable of
secondary infection Remaining Virus (% of Luciferase Control)
Duplex Targeted Virus Name Transcript Media Preparation AD-12622
VP1 30.8 24.9 AD-12842 VP1 33.3 26.9 AD-12813 T Antigen 57.8 38.7
AD-12824 VP2/3 83.6 57.6 AD-12769 VP2/3 79.1 52.2
[0191] Stability in Cerebrospinal Fluid (CSF) of Selected siRNAs
Targeting JCV
[0192] Eleven selected JCV siRNAs were tested for stability at 5 uM
over 48 h at 37.degree. C. in human CSF, as well as in PBS for
comparison. 30 .mu.l of human cerebrospinal fluid (CSF) was mixed
with 3 .mu.l of 50 .mu.M duplex (siRNA) solution (150 pmole/well)
in a 96-well plate, sealed to avoid evaporation and incubated for
the indicated time at 37.degree. C. Incubation of the siRNA in 30
ul PBS for 48 h served as a control for non-specific degradation.
Reactions were stopped by the addition of 4 ul proteinase K (20
mg/ml) and 25 ul of proteinase K buffer, and an incubation for 20'
at 42.degree. C. Samples were then spin filtered through a 0.2
.mu.m 96 well filter plate at 3000 rpm for 20'. Incubation wells
were washed with 50 ul Millipore water twice and the combined
washing solutions were spin filtered also.
[0193] Samples were analyzed by ion exchange HPLC under denaturing
conditions. Samples were transferred to single autosampler vials.
IEX-HPLC analysis was performed under the following conditions:
Dionex DNAPac PA200 (4.times.250 mm analytical column), temperature
of 45.degree. C. (denaturing conditions by pH=11), flow rate of 1
ml/min, injection volume of 50 ul, and detection wavelength of 260
nm with 1 nm bandwidth (reference wavelength 600 nm). In addition,
the gradient conditions were as follows with HPLC Eluent A: 20 mM
Na.sub.3PO.sub.4 in 10% ACN; pH=11 and HPLC Eluent B: 1 M NaBr in
HPLC Eluent A:
TABLE-US-00009 Time % A % B 0.00 min 75 25 1.00 min 75 25 19.0 min
38 62 19.5 min 0 100 21.5 min 0 100 22.0 min 75 25 24.0 min 75
25
[0194] Under the above denaturing IEX-HPLC conditions, the duplexes
eluted as two separated single strands. All chromatograms were
integrated automatically by the Dionex Chromeleon 6.60 HPLC
software, and were adjusted manually as necessary. The area under
the peak for each strand was calculated and the %-values for each
intact full length product (FLP) for each time points were
calculated by the following equation:
%-FLP.sub.(s/as;t=x)=(PeakArea.sub.(s/as);t=x/PeakArea.sub.(s/as);t=0min-
)*100%
All values were normalized to FLP at t=0 min. Table 6 provides the
results after 48 hours of incubation in human CSF at 37.degree. C.
At least 75% of both antisense and sense strands of ten JCV siRNAs
(AD-12622, AD-12724, AD-12767, AD-12769, AD-12795, AD-12813,
AD-12818, AD-12823, AD-12824, AD-12842) were recovered,
demonstrating that these siRNAs are highly stable in human CSF at
37.degree. C. For AD-12821, 59% of the antisense and 97% of the
sense strand was recovered after 48 h of incubation in human CSF at
37.degree. C., showing that this siRNA has a half-life of greater
than 48 h in human CSF at 37.degree. C.
TABLE-US-00010 TABLE 6 Stability in human CSF % full length
material after Duplex 48 hours name antisense sense AD-12622 93 105
AD-12724 90 106 AD-12767 85 104 AD-12769 100 104 AD-12795 86 109
AD-12813 94 98 AD-12818 75 99 AD-12821 59 97 AD-12823 98 98
AD-12824 84 98 AD-12842 87 102
[0195] dsRNA Expression Vectors
[0196] In another aspect of the invention, JC virus specific dsRNA
molecules that modulate JC virus genome expression activity are
expressed from transcription units inserted into DNA or RNA vectors
(see, e.g., Couture, A, et al., TIG. (1996), 12:5-10; Skillern, A.,
et al., International PCT Publication No. WO 00/22113, Conrad,
International PCT Publication No. WO 00/22114, and Conrad, U.S.
Pat. No. 6,054,299). These transgenes can be introduced as a linear
construct, a circular plasmid, or a viral vector, which can be
incorporated and inherited as a transgene integrated into the host
genome. The transgene can also be constructed to permit it to be
inherited as an extrachromosomal plasmid (Gassmann, et al., Proc.
Natl. Acad. Sci. USA (1995) 92:1292).
[0197] The individual strands of a dsRNA can be transcribed by
promoters on two separate expression vectors and co-transfected
into a target cell. Alternatively each individual strand of the
dsRNA can be transcribed by promoters both of which are located on
the same expression plasmid. In a preferred embodiment, a dsRNA is
expressed as an inverted repeat joined by a linker polynucleotide
sequence such that the dsRNA has a stem and loop structure.
[0198] The recombinant dsRNA expression vectors are generally DNA
plasmids or viral vectors. dsRNA expressing viral vectors can be
constructed based on, but not limited to, adeno-associated virus
(for a review, see Muzyczka, et al., Curr. Topics Micro. Immunol.
(1992) 158:97-129)); adenovirus (see, for example, Berkner, et al.,
BioTechniques (1998) 6:616), Rosenfeld et al. (1991, Science
252:431-434), and Rosenfeld et al. (1992), Cell 68:143-155)); or
alphavirus as well as others known in the art. Retroviruses have
been used to introduce a variety of genes into many different cell
types, including epithelial cells, in vitro and/or in vivo (see,
e.g., Eglitis, et al., Science (1985) 230:1395-1398; Danos and
Mulligan, Proc. Natl. Acad. Sci. USA (1998) 85:6460-6464; Wilson et
al., 1988, Proc. NatI. Acad. Sci. USA 85:3014-3018; Armentano et
al., 1990, Proc. NatI. Acad. Sci. USA 87:61416145; Huber et al.,
1991, Proc. NatI. Acad. Sci. USA 88:8039-8043; Ferry et al., 1991,
Proc. NatI. Acad. Sci. USA 88:8377-8381; Chowdhury et al., 1991,
Science 254:1802-1805; van Beusechem. et al., 1992, Proc. Nad.
Acad. Sci. USA 89:7640-19; Kay et al., 1992, Human Gene Therapy
3:641-647; Dai et al., 1992, Proc. Natl. Acad. Sci. USA
89:10892-10895; Hwu et al., 1993, J. Immunol. 150:4104-4115; U.S.
Pat. No. 4,868,116; U.S. Pat. No. 4,980,286; PCT Application WO
89/07136; PCT Application WO 89/02468; PCT Application WO 89/05345;
and PCT Application WO 92/07573). Recombinant retroviral vectors
capable of transducing and expressing genes inserted into the
genome of a cell can be produced by transfecting the recombinant
retroviral genome into suitable packaging cell lines such as PA317
and Psi-CRIP (Comette et al., 1991, Human Gene Therapy 2:5-10; Cone
et al., 1984, Proc. Natl. Acad. Sci. USA 81:6349). Recombinant
adenoviral vectors can be used to infect a wide variety of cells
and tissues in susceptible hosts (e.g., rat, hamster, dog, and
chimpanzee) (Hsu et al., 1992, J. Infectious Disease, 166:769), and
also have the advantage of not requiring mitotically active cells
for infection.
[0199] The promoter driving dsRNA expression in either a DNA
plasmid or viral vector of the invention may be a eukaryotic RNA
polymerase I (e.g. ribosomal RNA promoter), RNA polymerase II (e.g.
CMV early promoter or actin promoter or U1 snRNA promoter) or
generally RNA polymerase III promoter (e.g. U6 snRNA or 7SK RNA
promoter) or a prokaryotic promoter, for example the T7 promoter,
provided the expression plasmid also encodes T7 RNA polymerase
required for transcription from a T7 promoter. The promoter can
also direct transgene expression to the pancreas (see, e.g. the
insulin regulatory sequence for pancreas (Bucchini et al., 1986,
Proc. Natl. Acad. Sci. USA 83:2511-2515)).
[0200] In addition, expression of the transgene can be precisely
regulated, for example, by using an inducible regulatory sequence
and expression systems such as a regulatory sequence that is
sensitive to certain physiological regulators, e.g., circulating
glucose levels, or hormones (Docherty et al., 1994, FASEB J.
8:20-24). Such inducible expression systems, suitable for the
control of transgene expression in cells or in mammals include
regulation by ecdysone, by estrogen, progesterone, tetracycline,
chemical inducers of dimerization, and isopropyl-beta-D
1-thiogalactopyranoside (EPTG). A person skilled in the art would
be able to choose the appropriate regulatory/promoter sequence
based on the intended use of the dsRNA transgene.
[0201] Generally, recombinant vectors capable of expressing dsRNA
molecules are delivered as described below, and persist in target
cells. Alternatively, viral vectors can be used that provide for
transient expression of dsRNA molecules. Such vectors can be
repeatedly administered as necessary. Once expressed, the dsRNAs
bind to target RNA and modulate its function or expression.
Delivery of dsRNA expressing vectors can be systemic, such as by
intravenous or intramuscular administration, by administration to
target cells ex-planted from the patient followed by reintroduction
into the patient, or by any other means that allows for
introduction into a desired target cell.
[0202] dsRNA expression DNA plasmids are typically transfected into
target cells as a complex with cationic lipid carriers (e.g.
Oligofectamine) or non-cationic lipid-based carriers (e.g.
Transit-TKO.TM.). Multiple lipid transfections for dsRNA-mediated
knockdowns targeting different regions of a single JC virus genome
or multiple JC virus genomes over a period of a week or more are
also contemplated by the invention. Successful introduction of the
vectors of the invention into host cells can be monitored using
various known methods. For example, transient transfection. can be
signaled with a reporter, such as a fluorescent marker, such as
Green Fluorescent Protein (GFP). Stable transfection. of ex vivo
cells can be ensured using markers that provide the transfected
cell with resistance to specific environmental factors (e.g.,
antibiotics and drugs), such as hygromycin B resistance.
[0203] The JC virus specific dsRNA molecules can also be inserted
into vectors and used as gene therapy vectors for human patients.
Gene therapy vectors can be delivered to a subject by, for example,
intravenous injection, local administration (see U.S. Pat. No.
5,328,470) or by stereotactic injection (see e.g., Chen et al.
(1994) Proc. Natl. Acad. Sci. USA 91:3054-3057). The pharmaceutical
preparation of the gene therapy vector can include the gene therapy
vector in an acceptable diluent, or can comprise a slow release
matrix in which the gene delivery vehicle is imbedded.
Alternatively, where the complete gene delivery vector can be
produced intact from recombinant cells, e.g., retroviral vectors,
the pharmaceutical preparation can include one or more cells which
produce the gene delivery system.
[0204] Tables 1a-1 and 1a-2
TABLE-US-00011 TABLE 1a JCV Gene Walk; siRNAs targeting >95% of
all stransins (>= out of 388); Human specific pan-JCV: 208
siRNAs; allsiRNAs double overhang design; dTdT, no modifications.
1a-1: sequences; 1a-2: assay results Table 1a-1 position SEQ SEQ
duplex in ID sense strand ID antisense strand name consensus NO:
sequence (5'-3') NO: sequence (5'-3') AD-14742 1533-1551 515
CUUAUAAGAGGAGGAGUAGTT 516 CUACUCCUCCUCUUAUAAGTT AD-14743 1703-1721
517 CAUGCUUCCUUGUUACAGUTT 518 ACUGUAACAAGGAAGCAUGTT AD-14744
1439-1457 519 UACGGGACUGUAACACCUGTT 520 CAGGUGUUACAGUCCCGUATT
AD-14745 1705-1723 521 UGCUUCCUUGUUACAGUGUTT 522
ACACUGUAACAAGGAAGCATT AD-14746 2064-2082 523 CCUGUUGAAUGUUGGGUUCTT
524 GAACCCAACAUUCAACAGGTT AD-14747 2067-2085 525
GUUGAAUGUUGGGUUCCUGTT 526 CAGGAACCCAACAUUCAACTT AD-14748 2071-2089
527 AAUGUUGGGUUCCUGAUCCTT 528 GGAUCAGGAACCCAACAUUTT AD-14749
2121-2139 529 ACACUAACAGGAGGAGAAATT 530 UUUCUCCUCCUGUUAGUGUTT
AD-14750 1535-1553 531 UAUAAGAGGAGGAGUAGAATT 532
UUCUACUCCUCCUCUUAUATT AD-14751 1536-1554 533 AUAAGAGGAGGAGUAGAAGTT
534 CUUCUACUCCUCCUCUUAUTT AD-14752 1445-1463 535
ACUGUAACACCUGCUCUUGTT 536 CAAGAGCAGGUGUUACAGUTT AD-14753 1700-1718
537 GGACAUGCUUCCUUGUUACTT 538 GUAACAAGGAAGCAUGUCCTT AD-14754
1702-1720 539 ACAUGCUUCCUUGUUACAGTT 540 CUGUAACAAGGAAGCAUGUTT
AD-14755 1704-1722 541 AUGCUUCCUUGUUACAGUGTT 542
CACUGUAACAAGGAAGCAUTT AD-14756 2065-2083 543 CUGUUGAAUGUUGGGUUCCTT
544 GGAACCCAACAUUCAACAGTT AD-14757 2070-2088 545
GAAUGUUGGGUUCCUGAUCTT 546 GAUCAGGAACCCAACAUUCTT AD-14758 1441-1459
547 CGGGACUGUAACACCUGCUTT 548 AGCAGGUGUUACAGUCCCGTT AD-14759
1443-1461 549 GGACUGUAACACCUGCUCUTT 550 AGAGCAGGUGUUACAGUCCTT
AD-14760 1444-1462 551 GACUGUAACACCUGCUCUUTT 552
AAGAGCAGGUGUUACAGUCTT AD-14761 1609-1627 553 CUCCAGAAAUGGGUGACCCTT
554 GGGUCACCCAUUUCUGGAGTT AD-14762 1537-1555 555
UAAGAGGAGGAGUAGAAGUTT 556 ACUUCUACUCCUCCUCUUATT AD-14763 629-647
557 GAGGCUGCUGCUACUAUAGTT 558 CUAUAGUAGCAGCAGCCUCTT AD-14764
656-674 559 AUUGCAUCCCUUGCUACUGTT 560 CAGUAGCAAGGGAUGCAAUTT
AD-14765 658-676 561 UGCAUCCCUUGCUACUGUATT 562
UACAGUAGCAAGGGAUGCATT AD-14766 517-535 563 UUGUGUUUUCAGGUUCAUGTT
564 CAUGAACCUGAAAACACAATT AD-14767 559-577 565
GGACCUAGUUGCUACUGUUTT 566 AACAGUAGCAACUAGGUCCTT AD-14768 591-609
567 CUGCCACAGGAUUUUCAGUTT 568 ACUGAAAAUCCUGUGGCAGTT AD-14769
638-656 569 GCUACUAUAGAAGUUGAAATT 570 UUUCAACUUCUAUAGUAGCTT
AD-14770 655-673 571 AAUUGCAUCCCUUGCUACUTT 572
AGUAGCAAGGGAUGCAAUUTT AD-14771 561-579 573 ACCUAGUUGCUACUGUUUCTT
574 GAAACAGUAGCAACUAGGUTT AD-14772 639-657 575
CUACUAUAGAAGUUGAAAUTT 576 AUUUCAACUUCUAUAGUAGTT AD-14773 715-733
577 AGGCCUUACUCCUGAAACATT 578 UGUUUCAGGAGUAAGGCCUTT AD-14774
716-734 579 GGCCUUACUCCUGAAACAUTT 580 AUGUUUCAGGAGUAAGGCCTT
AD-14775 326-344 581 GUAAAACCUGGAGUGGAACTT 582
GUUCCACUCCAGGUUUUACTT AD-14776 518-536 583 UGUGUUUUCAGGUUCAUGGTT
584 CCAUGAACCUGAAAACACATT AD-14777 520-538 585
UGUUUUCAGGUUCAUGGGUTT 586 ACCCAUGAACCUGAAAACATT AD-14778 661-679
587 AUCCCUUGCUACUGUAGAGTT 588 CUCUACAGUAGCAAGGGAUTT AD-14779
560-578 589 GACCUAGUUGCUACUGUUUTT 590 AAACAGUAGCAACUAGGUCTT
AD-14780 681-699 591 GGAUUACAAGUACCUCUGATT 592
UCAGAGGUACUUGUAAUCCTT AD-14781 714-732 593 UAGGCCUUACUCCUGAAACTT
594 GUUUCAGGAGUAAGGCCUATT AD-14782 377-395 595
UGUUAGAAUUUUUGCUGGATT 596 UCCAGCAAAAAUUCUAACATT AD-14783 589-607
597 UGCUGCCACAGGAUUUUCATT 598 UGAAAAUCCUGUGGCAGCATT AD-14784
594-612 599 CCACAGGAUUUUCAGUAGCTT 600 GCUACUGAAAAUCCUGUGGTT
AD-14785 648-666 601 AAGUUGAAAUUGCAUCCCUTT 602
AGGGAUGCAAUUUCAACUUTT AD-14786 649-667 603 AGUUGAAAUUGCAUCCCUUTT
604 AAGGGAUGCAAUUUCAACUTT AD-14787 587-605 605
GCUGCUGCCACAGGAUUUUTT 606 AAAAUCCUGUGGCAGCAGCTT AD-14788 325-343
607 AGUAAAACCUGGAGUGGAATT 608 UUCCACUCCAGGUUUUACUTT AD-14789
515-533 609 UUUUGUGUUUUCAGGUUCATT 610 UGAACCUGAAAACACAAAATT
AD-14790 516-534 611 UUUGUGUUUUCAGGUUCAUTT 612
AUGAACCUGAAAACACAAATT AD-14791 519-537 613 GUGUUUUCAGGUUCAUGGGTT
614 CCCAUGAACCUGAAAACACTT AD-14792 521-539 615
GUUUUCAGGUUCAUGGGUGTT 616 CACCCAUGAACCUGAAAACTT AD-14793 522-540
617 UUUUCAGGUUCAUGGGUGCTT 618 GCACCCAUGAACCUGAAAATT AD-14794
523-541 619 UUUCAGGUUCAUGGGUGCCTT 620 GGCACCCAUGAACCUGAAATT
AD-14795 616-634 621 AAUUGCUGCUGGAGAGGCUTT 622
AGCCUCUCCAGCAGCAAUUTT AD-14796 657-675 623 UUGCAUCCCUUGCUACUGUTT
624 ACAGUAGCAAGGGAUGCAATT AD-14797 761-779 625
GCUGUAGCUGGGUUUGCUGTT 626 CAGCAAACCCAGCUACAGCTT AD-14798 645-663
627 UAGAAGUUGAAAUUGCAUCTT 628 GAUGCAAUUUCAACUUCUATT AD-14799
647-665 629 GAAGUUGAAAUUGCAUCCCTT 630 GGGAUGCAAUUUCAACUUCTT
AD-14800 660-678 631 CAUCCCUUGCUACUGUAGATT 632
UCUACAGUAGCAAGGGAUGTT AD-14801 324-342 633 UAGUAAAACCUGGAGUGGATT
634 UCCACUCCAGGUUUUACUATT AD-14802 372-390 635
UUUUUUGUUAGAAUUUUUGTT 636 CAAAAAUUCUAACAAAAAATT AD-14803 640-658
637 UACUAUAGAAGUUGAAAUUTT 638 AAUUUCAACUUCUAUAGUATT AD-14804
562-580 639 CCUAGUUGCUACUGUUUCUTT 640 AGAAACAGUAGCAACUAGGTT
AD-14805 563-581 641 CUAGUUGCUACUGUUUCUGTT 642
CAGAAACAGUAGCAACUAGTT AD-14806 566-584 643 GUUGCUACUGUUUCUGAGGTT
644 CCUCAGAAACAGUAGCAACTT AD-14807 625-643 645
UGGAGAGGCUGCUGCUACUTT 646 AGUAGCAGCAGCCUCUCCATT AD-14808 627-645
647 GAGAGGCUGCUGCUACUAUTT 648 AUAGUAGCAGCAGCCUCUCTT AD-14809
628-646 649 AGAGGCUGCUGCUACUAUATT 650 UAUAGUAGCAGCAGCCUCUTT
AD-14810 632-650 651 GCUGCUGCUACUAUAGAAGTT 652
CUUCUAUAGUAGCAGCAGCTT AD-14811 513-531 653 UUUUUUGUGUUUUCAGGUUTT
654 AACCUGAAAACACAAAAAATT AD-14812 641-659 655
ACUAUAGAAGUUGAAAUUGTT 656 CAAUUUCAACUUCUAUAGUTT AD-14813 323-341
657 UUAGUAAAACCUGGAGUGGTT 658 CCACUCCAGGUUUUACUAATT AD-14814
717-735 659 GCCUUACUCCUGAAACAUATT 660 UAUGUUUCAGGAGUAAGGCTT
AD-14815 646-664 661 AGAAGUUGAAAUUGCAUCCTT 662
GGAUGCAAUUUCAACUUCUTT AD-14816 592-610 663 UGCCACAGGAUUUUCAGUATT
664 UACUGAAAAUCCUGUGGCATT AD-14817 590-608 665
GCUGCCACAGGAUUUUCAGTT 666 CUGAAAAUCCUGUGGCAGCTT AD-14818 526-544
667 CAGGUUCAUGGGUGCCGCATT 668 UGCGGCACCCAUGAACCUGTT AD-14819
615-633 669 AAAUUGCUGCUGGAGAGGCTT 670 GCCUCUCCAGCAGCAAUUUTT
AD-14820 617-635 671 AUUGCUGCUGGAGAGGCUGTT 672
CAGCCUCUCCAGCAGCAAUTT AD-14821 652-670 673 UGAAAUUGCAUCCCUUGCUTT
674 AGCAAGGGAUGCAAUUUCATT AD-14822 374-392 675
UUUUGUUAGAAUUUUUGCUTT 676 AGCAAAAAUUCUAACAAAATT AD-14823 375-393
677 UUUGUUAGAAUUUUUGCUGTT 678 CAGCAAAAAUUCUAACAAATT AD-14824
631-649 679 GGCUGCUGCUACUAUAGAATT 680 UUCUAUAGUAGCAGCAGCCTT
AD-14825 376-394 681 UUGUUAGAAUUUUUGCUGGTT 682
CCAGCAAAAAUUCUAACAATT AD-14826 512-530 683 UUUUUUUGUGUUUUCAGGUTT
684 ACCUGAAAACACAAAAAAATT AD-14827 1127-1145 685
GAAACUACUUGGGCAAUAGTT 686 CUAUUGCCCAAGUAGUUUCTT AD-14828 1410-1428
687 AAUGGAUGUUGCCUUUACUTT 688 AGUAAAGGCAACAUCCAUUTT AD-14829
1406-1424 689 CCUCAAUGGAUGUUGCCUUTT 690 AAGGCAACAUCCAUUGAGGTT
AD-14830 1418-1436 691 UUGCCUUUACUUUUAGGGUTT 692
ACCCUAAAAGUAAAGGCAATT AD-14831 1126-1144 693 AGAAACUACUUGGGCAAUATT
694 UAUUGCCCAAGUAGUUUCUTT AD-14832 1125-1143 695
AAGAAACUACUUGGGCAAUTT 696 AUUGCCCAAGUAGUUUCUUTT AD-14833 1419-1437
697 UGCCUUUACUUUUAGGGUUTT 698 AACCCUAAAAGUAAAGGCATT AD-14834
1420-1438 699 GCCUUUACUUUUAGGGUUGTT 700 CAACCCUAAAAGUAAAGGCTT
AD-14835 1422-1440 701 CUUUACUUUUAGGGUUGUATT 702
UACAACCCUAAAAGUAAAGTT AD-14836 1423-1441 703 UUUACUUUUAGGGUUGUACTT
704 GUACAACCCUAAAAGUAAATT AD-14837 1425-1443 705
UACUUUUAGGGUUGUACGGTT 706 CCGUACAACCCUAAAAGUATT AD-14838 1123-1141
707 GGAAGAAACUACUUGGGCATT 708 UGCCCAAGUAGUUUCUUCCTT AD-14839
1409-1427 709 CAAUGGAUGUUGCCUUUACTT 710 GUAAAGGCAACAUCCAUUGTT
AD-14840 1413-1431 711 GGAUGUUGCCUUUACUUUUTT 712
AAAAGUAAAGGCAACAUCCTT AD-14841 1416-1434 713 UGUUGCCUUUACUUUUAGGTT
714 CCUAAAAGUAAAGGCAACATT AD-14842 1414-1432 715
GAUGUUGCCUUUACUUUUATT 716 UAAAAGUAAAGGCAACAUCTT AD-14843 911-929
717 CCAGAAGACUACUAUGAUATT 718 UAUCAUAGUAGUCUUCUGGTT AD-14844
910-928 719 UCCAGAAGACUACUAUGAUTT 720 AUCAUAGUAGUCUUCUGGATT
AD-14845 1120-1138 721 UUUGGAAGAAACUACUUGGTT 722
CCAAGUAGUUUCUUCCAAATT AD-14846 1404-1422 723 CUCCUCAAUGGAUGUUGCCTT
724 GGCAACAUCCAUUGAGGAGTT AD-14847 1337-1355 725
CCAAAUGUGCAAUCUGGUGTT 726 CACCAGAUUGCACAUUUGGTT AD-14848 1338-1356
727 CAAAUGUGCAAUCUGGUGATT 728 UCACCAGAUUGCACAUUUGTT AD-14849
1397-1415 729 AGAUCUGCUCCUCAAUGGATT 730 UCCAUUGAGGAGCAGAUCUTT
AD-14850 1407-1425 731 CUCAAUGGAUGUUGCCUUUTT 732
AAAGGCAACAUCCAUUGAGTT AD-14851 4157-4175 733 GCUCAAAUUUUAUAUAAGATT
734 UCUUAUAUAAAAUUUGAGCTT AD-14852 4795-4813 735
AGCCUGAUUUUGGUACAUGTT 736 CAUGUACCAAAAUCAGGCUTT AD-14853 4156-4174
737 CUCAAAUUUUAUAUAAGAATT 738 UUCUUAUAUAAAAUUUGAGTT AD-14854
5002-5020 739 ACAAAGUGCUGAAUAGGGATT 740 UCCCUAUUCAGCACUUUGUTT
AD-14855 4792-4810 741 CUGAUUUUGGUACAUGGAATT 742
UUCCAUGUACCAAAAUCAGTT AD-14856 4790-4808 743 GAUUUUGGUACAUGGAAUATT
744 UAUUCCAUGUACCAAAAUCTT AD-14857 4801-4819 745
CUCAUCAGCCUGAUUUUGGTT 746 CCAAAAUCAGGCUGAUGAGTT AD-14858 4622-4640
747 AGCCCACUUGUGUGGAUAGTT 748 CUAUCCACACAAGUGGGCUTT AD-14859
4997-5015 749 GUGCUGAAUAGGGAGGAAUTT 750 AUUCCUCCCUAUUCAGCACTT
AD-14860 5094-5112 751 AGUAAGGGCGUGGAGGCUUTT 752
AAGCCUCCACGCCCUUACUTT AD-14861 4564-4582 753 GUGACUUAACCCAAGAAGCTT
754 GCUUCUUGGGUUAAGUCACTT
AD-14862 5095-5113 755 UAGUAAGGGCGUGGAGGCUTT 756
AGCCUCCACGCCCUUACUATT AD-14863 4800-4818 757 UCAUCAGCCUGAUUUUGGUTT
758 ACCAAAAUCAGGCUGAUGATT AD-14864 4265-4283 759
GUAGAAGACCCUAAAGACUTT 760 AGUCUUUAGGGUCUUCUACTT AD-14865 4267-4285
761 AGGUAGAAGACCCUAAAGATT 762 UCUUUAGGGUCUUCUACCUTT AD-14866
4270-4288 763 AAAAGGUAGAAGACCCUAATT 764 UUAGGGUCUUCUACCUUUUTT
AD-14867 4269-4287 765 AAAGGUAGAAGACCCUAAATT 766
UUUAGGGUCUUCUACCUUUTT AD-14868 2874-2892 767 GAUUGUGCAGUGGAAAGAATT
768 UUCUUUCCACUGCACAAUCTT AD-14869 2875-2893 769
GGAUUGUGCAGUGGAAAGATT 770 UCUUUCCACUGCACAAUCCTT AD-14870 3950-3968
771 UGUAGACAGCCAUAUGCAGTT 772 CUGCAUAUGGCUGUCUACATT AD-14871
3896-3914 773 CAUGACUUUAACCCAGAAGTT 774 CUUCUGGGUUAAAGUCAUGTT
AD-14872 4990-5008 775 AUAGGGAGGAAUCCAUGGATT 776
UCCAUGGAUUCCUCCCUAUTT AD-14873 4994-5012 777 CUGAAUAGGGAGGAAUCCATT
778 UGGAUUCCUCCCUAUUCAGTT AD-14874 5000-5018 779
AAAGUGCUGAAUAGGGAGGTT 780 CCUCCCUAUUCAGCACUUUTT AD-14875 4563-4581
781 UGACUUAACCCAAGAAGCUTT 782 AGCUUCUUGGGUUAAGUCATT AD-14876
3895-3913 783 AUGACUUUAACCCAGAAGATT 784 UCUUCUGGGUUAAAGUCAUTT
AD-14877 4262-4280 785 GAAGACCCUAAAGACUUUCTT 786
GAAAGUCUUUAGGGUCUUCTT AD-14878 4162-4180 787 AAAAAGCUCAAAUUUUAUATT
788 UAUAAAAUUUGAGCUUUUUTT AD-14879 4798-4816 789
AUCAGCCUGAUUUUGGUACTT 790 GUACCAAAAUCAGGCUGAUTT AD-14880 4799-4817
791 CAUCAGCCUGAUUUUGGUATT 792 UACCAAAAUCAGGCUGAUGTT AD-14881
5006-5024 793 AUGGACAAAGUGCUGAAUATT 794 UAUUCAGCACUUUGUCCAUTT
AD-14882 4264-4282 795 UAGAAGACCCUAAAGACUUTT 796
AAGUCUUUAGGGUCUUCUATT AD-14883 4268-4286 797 AAGGUAGAAGACCCUAAAGTT
798 CUUUAGGGUCUUCUACCUUTT AD-14884 4623-4641 799
CAGCCCACUUGUGUGGAUATT 800 UAUCCACACAAGUGGGCUGTT AD-14885 4788-4806
801 UUUUGGUACAUGGAAUAGUTT 802 ACUAUUCCAUGUACCAAAATT AD-14886
4993-5011 803 UGAAUAGGGAGGAAUCCAUTT 804 AUGGAUUCCUCCCUAUUCATT
AD-14887 4995-5013 805 GCUGAAUAGGGAGGAAUCCTT 806
GGAUUCCUCCCUAUUCAGCTT AD-14888 4996-5014 807 UGCUGAAUAGGGAGGAAUCTT
808 GAUUCCUCCCUAUUCAGCATT AD-14889 3952-3970 809
UGUGUAGACAGCCAUAUGCTT 810 GCAUAUGGCUGUCUACACATT AD-14890 4595-4613
811 UGCUUUGAUUGCUUCAGACTT 812 GUCUGAAGCAAUCAAAGCATT AD-14891
4596-4614 813 UUGCUUUGAUUGCUUCAGATT 814 UCUGAAGCAAUCAAAGCAATT
AD-14892 4597-4615 815 AUUGCUUUGAUUGCUUCAGTT 816
CUGAAGCAAUCAAAGCAAUTT AD-14893 4599-4617 817 CUAUUGCUUUGAUUGCUUCTT
818 GAAGCAAUCAAAGCAAUAGTT AD-14894 4726-4744 819
AUUGCAAGGAAUGGCCUAATT 820 UUAGGCCAUUCCUUGCAAUTT AD-14895 4753-4771
821 AUUUUCCUCCUAAUUCUGATT 822 UCAGAAUUAGGAGGAAAAUTT AD-14896
4802-4820 823 GCUCAUCAGCCUGAUUUUGTT 824 CAAAAUCAGGCUGAUGAGCTT
AD-14897 4803-4821 825 UGCUCAUCAGCCUGAUUUUTT 826
AAAAUCAGGCUGAUGAGCATT AD-14898 4806-4824 827 AGUUGCUCAUCAGCCUGAUTT
828 AUCAGGCUGAUGAGCAACUTT AD-14899 5091-5109 829
AAGGGCGUGGAGGCUUUUUTT 830 AAAAAGCCUCCACGCCCUUTT AD-14900 5093-5111
831 GUAAGGGCGUGGAGGCUUUTT 832 AAAGCCUCCACGCCCUUACTT AD-14901
4259-4277 833 GACCCUAAAGACUUUCCUGTT 834 CAGGAAAGUCUUUAGGGUCTT
AD-14902 3901-3919 835 AGGAGCAUGACUUUAACCCTT 836
GGGUUAAAGUCAUGCUCCUTT AD-14903 4757-4775 837 UGUGAUUUUCCUCCUAAUUTT
838 AAUUAGGAGGAAAAUCACATT AD-14904 4758-4776 839
UUGUGAUUUUCCUCCUAAUTT 840 AUUAGGAGGAAAAUCACAATT AD-14905 4562-4580
841 GACUUAACCCAAGAAGCUCTT 842 GAGCUUCUUGGGUUAAGUCTT AD-14906
4585-4603 843 GCUUCAGACAAUGGUUUGGTT 844 CCAAACCAUUGUCUGAAGCTT
AD-14907 4587-4605 845 UUGCUUCAGACAAUGGUUUTT 846
AAACCAUUGUCUGAAGCAATT AD-14908 4588-4606 847 AUUGCUUCAGACAAUGGUUTT
848 AACCAUUGUCUGAAGCAAUTT AD-14909 4591-4609 849
UUGAUUGCUUCAGACAAUGTT 850 CAUUGUCUGAAGCAAUCAATT AD-14910 5003-5021
851 GACAAAGUGCUGAAUAGGGTT 852 CCCUAUUCAGCACUUUGUCTT AD-14911
4165-4183 853 AAGAAAAAGCUCAAAUUUUTT 854 AAAAUUUGAGCUUUUUCUUTT
AD-14912 4166-4184 855 AAAGAAAAAGCUCAAAUUUTT 856
AAAUUUGAGCUUUUUCUUUTT AD-14913 4263-4281 857 AGAAGACCCUAAAGACUUUTT
858 AAAGUCUUUAGGGUCUUCUTT AD-14914 4274-4292 859
AAAAAAAAGGUAGAAGACCTT 860 GGUCUUCUACCUUUUUUUUTT AD-14915 4266-4284
861 GGUAGAAGACCCUAAAGACTT 862 GUCUUUAGGGUCUUCUACCTT AD-14916
4272-4290 863 AAAAAAGGUAGAAGACCCUTT 864 AGGGUCUUCUACCUUUUUUTT
AD-14917 4271-4289 865 AAAAAGGUAGAAGACCCUATT 866
UAGGGUCUUCUACCUUUUUTT AD-14918 4559-4577 867 UUAACCCAAGAAGCUCUUCTT
868 GAAGAGCUUCUUGGGUUAATT AD-14919 4789-4807 869
AUUUUGGUACAUGGAAUAGTT 870 CUAUUCCAUGUACCAAAAUTT AD-14920 4998-5016
871 AGUGCUGAAUAGGGAGGAATT 872 UUCCUCCCUAUUCAGCACUTT AD-14921
5070-5088 873 GAGGCCAGGGAAAUUCCCUTT 874 AGGGAAUUUCCCUGGCCUCTT
AD-14922 4158-4176 875 AGCUCAAAUUUUAUAUAAGTT 876
CUUAUAUAAAAUUUGAGCUTT AD-14923 5065-5083 877 CAGGGAAAUUCCCUUGUUUTT
878 AAACAAGGGAAUUUCCCUGTT AD-14924 2872-2890 879
UUGUGCAGUGGAAAGAAAGTT 880 CUUUCUUUCCACUGCACAATT AD-14925 4782-4800
881 UACAUGGAAUAGUUCAGAGTT 882 CUCUGAACUAUUCCAUGUATT AD-14926
4783-4801 883 GUACAUGGAAUAGUUCAGATT 884 UCUGAACUAUUCCAUGUACTT
AD-14927 5064-5082 885 AGGGAAAUUCCCUUGUUUUTT 886
AAAACAAGGGAAUUUCCCUTT AD-14928 5071-5089 887 GGAGGCCAGGGAAAUUCCCTT
888 GGGAAUUUCCCUGGCCUCCTT AD-14929 3951-3969 889
GUGUAGACAGCCAUAUGCATT 890 UGCAUAUGGCUGUCUACACTT AD-14930 3949-3967
891 GUAGACAGCCAUAUGCAGUTT 892 ACUGCAUAUGGCUGUCUACTT AD-14931
4355-4373 893 GAAGACCUGUUUUGCCAUGTT 894 CAUGGCAAAACAGGUCUUCTT
AD-14932 4363-4381 895 AGUGGGAUGAAGACCUGUUTT 896
AACAGGUCUUCAUCCCACUTT AD-14933 4356-4374 897 UGAAGACCUGUUUUGCCAUTT
898 AUGGCAAAACAGGUCUUCATT AD-14934 4361-4379 899
UGGGAUGAAGACCUGUUUUTT 900 AAAACAGGUCUUCAUCCCATT AD-14935 4560-4578
901 CUUAACCCAAGAAGCUCUUTT 902 AAGAGCUUCUUGGGUUAAGTT AD-14936
2873-2891 903 AUUGUGCAGUGGAAAGAAATT 904 UUUCUUUCCACUGCACAAUTT
AD-14937 4730-4748 905 CUUUAUUGCAAGGAAUGGCTT 906
GCCAUUCCUUGCAAUAAAGTT AD-14938 3899-3917 907 GAGCAUGACUUUAACCCAGTT
908 CUGGGUUAAAGUCAUGCUCTT AD-14939 4756-4774 909
GUGAUUUUCCUCCUAAUUCTT 910 GAAUUAGGAGGAAAAUCACTT AD-14940 4590-4608
911 UGAUUGCUUCAGACAAUGGTT 912 CCAUUGUCUGAAGCAAUCATT AD-14941
4159-4177 913 AAGCUCAAAUUUUAUAUAATT 914 UUAUAUAAAAUUUGAGCUUTT
AD-14942 2743-2761 915 CUGGACAUGGAUCAAGCACTT 916
GUGCUUGAUCCAUGUCCAGTT AD-14943 4155-4173 917 UCAAAUUUUAUAUAAGAAATT
918 UUUCUUAUAUAAAAUUUGATT AD-14944 2871-2889 919
UGUGCAGUGGAAAGAAAGGTT 920 CCUUUCUUUCCACUGCACATT AD-14945 4786-4804
921 UUGGUACAUGGAAUAGUUCTT 922 GAACUAUUCCAUGUACCAATT AD-14946
4364-4382 923 AAGUGGGAUGAAGACCUGUTT 924 ACAGGUCUUCAUCCCACUUTT
AD-14947 4359-4377 925 GGAUGAAGACCUGUUUUGCTT 926
GCAAAACAGGUCUUCAUCCTT AD-14948 2744-2762 927 UCUGGACAUGGAUCAAGCATT
928 UGCUUGAUCCAUGUCCAGATT AD-14949 4787-4805 929
UUUGGUACAUGGAAUAGUUTT 930 AACUAUUCCAUGUACCAAATT
TABLE-US-00012 TABLE 1a-2 Residual luciferase activity SD of
Relative siRNA SD of (relative to residual Residual activity
(normalized relative Relative duplex control siRNA luciferase
luciferase to positive control siRNA siRNA name treated cells)
activity activity +/- SD luc-siRNA) activity activity +/- SD
AD-14742 40.85 4.38 41 .+-. 4% 82.24 8.83 82 .+-. 9% AD-14743 20.92
4.10 21 .+-. 4% 109.97 21.56 110 .+-. 22% AD-14744 62.20 4.47 62
.+-. 4% 52.56 3.78 53 .+-. 4% AD-14745 43.97 2.60 44 .+-. 3% 77.91
4.60 78 .+-. 5% AD-14746 24.52 1.96 25 .+-. 2% 104.96 8.38 105 .+-.
8% AD-14747 32.67 4.51 33 .+-. 5% 93.62 12.94 94 .+-. 13% AD-14748
93.99 3.23 94 .+-. 3% 8.36 0.29 8 .+-. 0% AD-14749 55.16 2.81 55
.+-. 3% 62.35 3.18 62 .+-. 3% AD-14750 30.86 3.11 31 .+-. 3% 96.14
9.70 96 .+-. 10% AD-14751 54.44 4.03 54 .+-. 4% 63.35 4.69 63 .+-.
5% AD-14752 53.88 7.58 54 .+-. 8% 64.13 9.02 64 .+-. 9% AD-14753
35.24 7.45 35 .+-. 7% 90.05 19.03 90 .+-. 19% AD-14754 70.39 2.80
70 .+-. 3% 41.17 1.64 41 .+-. 2% AD-14755 41.80 1.60 42 .+-. 2%
80.93 3.10 81 .+-. 3% AD-14756 56.69 3.05 57 .+-. 3% 60.22 3.24 60
.+-. 3% AD-14757 39.16 2.16 39 .+-. 2% 84.60 4.67 85 .+-. 5%
AD-14758 39.79 2.95 40 .+-. 3% 83.72 6.22 84 .+-. 6% AD-14759 30.62
1.01 31 .+-. 1% 96.48 3.20 96 .+-. 3% AD-14760 28.14 2.74 28 .+-.
3% 99.93 9.72 100 .+-. 10% AD-14761 67.42 2.83 67 .+-. 3% 45.30
1.90 45 .+-. 2% AD-14762 36.10 1.30 36 .+-. 1% 88.85 3.21 89 .+-.
3% AD-14763 49.39 6.77 49 .+-. 7% 78.14 10.71 78 .+-. 11% AD-14764
74.04 5.32 74 .+-. 5% 40.09 2.88 40 .+-. 3% AD-14765 50.84 10.47 51
.+-. 10% 75.91 15.63 76 .+-. 16% AD-14766 72.59 3.55 73 .+-. 4%
42.32 2.07 42 .+-. 2% AD-14767 34.82 7.41 35 .+-. 7% 100.63 21.40
101 .+-. 21% AD-14768 48.68 6.31 49 .+-. 6% 79.24 10.27 79 .+-. 10%
AD-14769 39.07 5.53 39 .+-. 6% 94.08 13.31 94 .+-. 13% AD-14770
45.59 5.89 46 .+-. 6% 84.01 10.85 84 .+-. 11% AD-14771 45.57 4.10
46 .+-. 4% 84.04 7.56 84 .+-. 8% AD-14772 33.12 3.64 33 .+-. 4%
103.26 11.36 103 .+-. 11% AD-14773 37.38 5.72 37 .+-. 6% 96.69
14.78 97 .+-. 15% AD-14774 42.38 4.41 42 .+-. 4% 88.96 9.26 89 .+-.
9% AD-14775 46.59 3.00 47 .+-. 3% 82.47 5.31 82 .+-. 5% AD-14776
71.28 8.67 71 .+-. 9% 44.35 5.40 44 .+-. 5% AD-14777 64.55 6.21 65
.+-. 6% 54.74 5.26 55 .+-. 5% AD-14778 60.45 8.91 60 .+-. 9% 61.07
9.00 61 .+-. 9% AD-14779 32.46 0.82 32 .+-. 1% 104.27 2.63 104 .+-.
3% AD-14780 22.96 2.86 23 .+-. 3% 118.94 14.81 119 .+-. 15%
AD-14781 56.99 9.43 57 .+-. 9% 66.41 10.99 66 .+-. 11% AD-14782
29.90 8.74 30 .+-. 9% 108.24 31.65 108 .+-. 32% AD-14783 42.63 6.57
43 .+-. 7% 88.58 13.66 89 .+-. 14% AD-14784 67.06 1.35 67 .+-. 1%
50.86 1.03 51 .+-. 1% AD-14785 48.90 3.32 49 .+-. 3% 78.89 5.35 79
.+-. 5% AD-14786 27.74 2.06 28 .+-. 2% 111.57 8.29 112 .+-. 8%
AD-14787 38.77 6.24 39 .+-. 6% 94.53 15.22 95 .+-. 15% AD-14788
32.84 8.60 33 .+-. 9% 103.70 27.17 104 .+-. 27% AD-14789 46.96 1.70
47 .+-. 2% 81.89 2.96 82 .+-. 3% AD-14790 43.61 4.90 44 .+-. 5%
87.06 9.79 87 .+-. 10% AD-14791 35.55 4.34 36 .+-. 4% 99.51 12.15
100 .+-. 12% AD-14792 38.22 3.51 38 .+-. 4% 95.38 8.75 95 .+-. 9%
AD-14793 90.85 5.92 91 .+-. 6% 14.13 0.92 14 .+-. 1% AD-14794 83.37
3.27 83 .+-. 3% 25.68 1.01 26 .+-. 1% AD-14795 55.06 3.61 55 .+-.
4% 69.38 4.55 69 .+-. 5% AD-14796 30.98 5.78 31 .+-. 6% 106.56
19.89 107 .+-. 20% AD-14797 28.95 3.15 29 .+-. 3% 109.70 11.95 110
.+-. 12% AD-14798 67.39 3.70 67 .+-. 4% 50.35 2.76 50 .+-. 3%
AD-14799 66.83 4.72 67 .+-. 5% 51.21 3.61 51 .+-. 4% AD-14800 33.26
5.72 33 .+-. 6% 103.04 17.71 103 .+-. 18% AD-14801 39.15 4.57 39
.+-. 5% 93.96 10.97 94 .+-. 11% AD-14802 91.20 5.35 91 .+-. 5%
13.58 0.80 14 .+-. 1% AD-14803 34.15 7.94 34 .+-. 8% 101.67 23.64
102 .+-. 24% AD-14804 30.08 6.54 30 .+-. 7% 107.96 23.48 108 .+-.
23% AD-14805 32.44 4.27 32 .+-. 4% 104.31 13.73 104 .+-. 14%
AD-14806 35.62 3.11 36 .+-. 3% 99.41 8.67 99 .+-. 9% AD-14807 28.27
7.28 28 .+-. 7% 110.76 28.52 111 .+-. 29% AD-14808 30.29 3.96 30
.+-. 4% 107.63 14.08 108 .+-. 14% AD-14809 31.59 4.46 32 .+-. 4%
105.63 14.91 106 .+-. 15% AD-14810 30.11 5.71 30 .+-. 6% 107.91
20.46 108 .+-. 20% AD-14811 55.27 6.82 55 .+-. 7% 69.06 8.52 69
.+-. 9% AD-14812 45.27 5.99 45 .+-. 6% 84.51 11.19 85 .+-. 11%
AD-14813 77.97 7.01 78 .+-. 7% 34.01 3.06 34 .+-. 3% AD-14814 29.54
3.56 30 .+-. 4% 108.78 13.09 109 .+-. 13% AD-14815 65.04 3.18 65
.+-. 3% 53.97 2.64 54 .+-. 3% AD-14816 64.03 4.63 64 .+-. 5% 55.53
4.02 56 .+-. 4% AD-14817 37.83 2.89 38 .+-. 3% 95.99 7.33 96 .+-.
7% AD-14818 28.88 5.60 29 .+-. 6% 109.82 21.30 110 .+-. 21%
AD-14819 92.90 4.87 93 .+-. 5% 10.97 0.58 11 .+-. 1% AD-14820 75.41
3.69 75 .+-. 4% 37.97 1.86 38 .+-. 2% AD-14821 73.08 6.22 73 .+-.
6% 41.57 3.54 42 .+-. 4% AD-14822 86.39 9.34 86 .+-. 9% 21.02 2.27
21 .+-. 2% AD-14823 96.50 10.46 97 .+-. 10% 5.40 0.59 5 .+-. 1%
AD-14824 32.62 3.41 33 .+-. 3% 104.03 10.89 104 .+-. 11% AD-14825
102.71 7.66 103 .+-. 8% -4.18 0.31 -4 .+-. 0% AD-14826 92.45 5.66
92 .+-. 6% 11.66 0.71 12 .+-. 1% AD-14827 63.46 16.38 63 .+-. 16%
46.00 11.88 46 .+-. 12% AD-14828 45.99 15.21 46 .+-. 15% 67.99
22.49 68 .+-. 22% AD-14829 40.54 16.03 41 .+-. 16% 74.86 29.60 75
.+-. 30% AD-14830 117.10 3.66 117 .+-. 4% -21.52 0.67 -22 .+-. 1%
AD-14831 54.78 21.12 55 .+-. 21% 56.93 21.95 57 .+-. 22% AD-14832
67.07 10.81 67 .+-. 11% 41.46 6.68 41 .+-. 7% AD-14833 71.52 11.90
72 .+-. 12% 35.85 5.97 36 .+-. 6% AD-14834 58.05 16.37 58 .+-. 16%
52.81 14.89 53 .+-. 15% AD-14835 93.36 5.43 93 .+-. 5% 8.36 0.49 8
.+-. 0% AD-14836 108.84 4.85 109 .+-. 5% -11.13 0.50 -11 .+-. 0%
AD-14837 106.68 10.06 107 .+-. 10% -8.41 0.79 -8 .+-. 1% AD-14838
37.06 6.68 37 .+-. 7% 79.23 14.28 79 .+-. 14% AD-14839 36.03 7.54
36 .+-. 8% 80.53 16.84 81 .+-. 17% AD-14840 38.51 5.90 39 .+-. 6%
77.40 11.86 77 .+-. 12% AD-14841 110.86 8.91 111 .+-. 9% -13.67
1.10 -14 .+-. 1% AD-14842 34.83 5.51 35 .+-. 6% 82.04 12.98 82 .+-.
13% AD-14843 23.75 6.04 24 .+-. 6% 95.99 24.41 96 .+-. 24% AD-14844
27.47 5.29 27 .+-. 5% 91.30 17.57 91 .+-. 18% AD-14845 93.12 4.70
93 .+-. 5% 8.67 0.44 9 .+-. 0% AD-14846 81.72 8.26 82 .+-. 8% 23.01
2.33 23 .+-. 2% AD-14847 77.89 5.29 78 .+-. 5% 27.83 1.89 28 .+-.
2% AD-14848 44.40 4.95 44 .+-. 5% 69.99 7.81 70 .+-. 8% AD-14849
46.41 5.08 46 .+-. 5% 67.46 7.38 67 .+-. 7% AD-14850 35.52 6.70 36
.+-. 7% 81.17 15.31 81 .+-. 15% AD-14851 36.07 1.13 36 .+-. 1%
102.63 3.22 103 .+-. 3% AD-14852 67.98 6.75 68 .+-. 7% 51.41 5.11
51 .+-. 5% AD-14853 69.44 3.07 69 .+-. 3% 49.05 2.17 49 .+-. 2%
AD-14854 29.12 6.88 29 .+-. 7% 113.79 26.89 114 .+-. 27% AD-14855
36.04 7.07 36 .+-. 7% 102.68 20.14 103 .+-. 20% AD-14856 33.61 7.93
34 .+-. 8% 106.57 25.15 107 .+-. 25% AD-14857 50.76 8.76 51 .+-. 9%
79.04 13.64 79 .+-. 14% AD-14858 53.60 7.26 54 .+-. 7% 74.49 10.09
74 .+-. 10% AD-14859 39.07 9.34 39 .+-. 9% 97.82 23.38 98 .+-. 23%
AD-14860 62.78 6.85 63 .+-. 7% 59.75 6.52 60 .+-. 7% AD-14861 87.47
1.86 87 .+-. 2% 20.12 0.43 20 .+-. 0% AD-14862 79.95 4.02 80 .+-.
4% 32.19 1.62 32 .+-. 2% AD-14863 30.46 4.49 30 .+-. 4% 111.64
16.46 112 .+-. 16% AD-14864 33.18 5.07 33 .+-. 5% 107.26 16.38 107
.+-. 16% AD-14865 26.25 3.98 26 .+-. 4% 118.39 17.96 118 .+-. 18%
AD-14866 36.73 1.24 37 .+-. 1% 101.57 3.44 102 .+-. 3% AD-14867
33.16 3.13 33 .+-. 3% 107.30 10.12 107 .+-. 10% AD-14868 29.91 4.56
30 .+-. 5% 112.52 17.16 113 .+-. 17% AD-14869 28.24 3.66 28 .+-. 4%
115.20 14.91 115 .+-. 15% AD-14870 50.37 3.04 50 .+-. 3% 79.67 4.81
80 .+-. 5% AD-14871 39.37 5.11 39 .+-. 5% 97.32 12.63 97 .+-. 13%
AD-14872 34.71 4.12 35 .+-. 4% 104.82 12.43 105 .+-. 12% AD-14873
32.14 1.79 32 .+-. 2% 108.93 6.07 109 .+-. 6% AD-14874 101.77 4.87
102 .+-. 5% -2.85 0.14 -3 .+-. 0% AD-14875 80.81 4.39 81 .+-. 4%
30.80 1.67 31 .+-. 2% AD-14876 30.74 1.88 31 .+-. 2% 111.18 6.81
111 .+-. 7% AD-14877 57.38 2.84 57 .+-. 3% 68.42 3.39 68 .+-. 3%
AD-14878 70.23 3.35 70 .+-. 3% 47.79 2.28 48 .+-. 2% AD-14879 79.03
7.72 79 .+-. 8% 33.66 3.29 34 .+-. 3% AD-14880 21.65 2.46 22 .+-.
2% 125.78 14.28 126 .+-. 14% AD-14881 27.66 1.71 28 .+-. 2% 116.13
7.17 116 .+-. 7% AD-14882 34.01 2.94 34 .+-. 3% 105.93 9.16 106
.+-. 9% AD-14883 40.62 3.22 41 .+-. 3% 95.33 7.56 95 .+-. 8%
AD-14884 35.73 5.94 36 .+-. 6% 103.18 17.14 103 .+-. 17% AD-14885
47.40 7.65 47 .+-. 8% 84.45 13.63 84 .+-. 14% AD-14886 37.23 3.94
37 .+-. 4% 100.76 10.67 101 .+-. 11% AD-14887 42.94 7.26 43 .+-. 7%
91.61 15.50 92 .+-. 15% AD-14888 32.58 4.06 33 .+-. 4% 108.24 13.50
108 .+-. 14% AD-14889 83.09 2.98 83 .+-. 3% 27.15 0.97 27 .+-. 1%
AD-14890 59.49 2.94 59 .+-. 3% 65.04 3.22 65 .+-. 3% AD-14891 21.93
5.52 22 .+-. 6% 125.32 31.52 125 .+-. 32% AD-14892 72.69 2.19 73
.+-. 2% 43.84 1.32 44 .+-. 1% AD-14893 24.43 7.07 24 .+-. 7% 121.32
35.11 121 .+-. 35% AD-14894 33.84 5.08 34 .+-. 5% 106.20 15.95 106
.+-. 16% AD-14895 21.68 4.46 22 .+-. 4% 125.73 25.84 126 .+-. 26%
AD-14896 26.99 5.01 27 .+-. 5% 117.20 21.73 117 .+-. 22% AD-14897
29.04 2.72 29 .+-. 3% 113.92 10.67 114 .+-. 11% AD-14898 32.64 4.87
33 .+-. 5% 108.14 16.13 108 .+-. 16% AD-14899 61.71 4.59 62 .+-. 5%
61.47 4.57 61 .+-. 5% AD-14900 31.01 2.84 31 .+-. 3% 110.75 10.14
111 .+-. 10% AD-14901 31.47 1.57 31 .+-. 2% 110.01 5.49 110 .+-. 5%
AD-14902 76.99 0.55 77 .+-. 1% 36.95 0.26 37 .+-. 0% AD-14903 20.55
3.55 21 .+-. 4% 127.55 22.05 128 .+-. 22% AD-14904 22.65 6.87 23
.+-. 7% 124.18 37.68 124 .+-. 38% AD-14905 56.98 4.94 57 .+-. 5%
69.07 5.99 69 .+-. 6% AD-14906 34.20 3.66 34 .+-. 4% 105.63 11.29
106 .+-. 11% AD-14907 28.59 8.12 29 .+-. 8% 114.64 32.56 115 .+-.
33% AD-14908 34.08 3.36 34 .+-. 3% 105.82 10.44 106 .+-. 10%
AD-14909 76.57 2.33 77 .+-. 2% 37.61 1.15 38 .+-. 1% AD-14910 46.50
4.14 46 .+-. 4% 85.89 7.64 86 .+-. 8% AD-14911 29.62 2.02 30 .+-.
2% 112.99 7.69 113 .+-. 8% AD-14912 22.27 0.48 22 .+-. 0% 124.78
2.69 125 .+-. 3% AD-14913 59.80 2.85 60 .+-. 3% 64.53 3.08 65 .+-.
3% AD-14914 93.21 5.10 93 .+-. 5% 10.90 0.60 11 .+-. 1% AD-14915
25.99 4.45 26 .+-. 4% 118.82 20.34 119 .+-. 20% AD-14916 48.20 1.46
48 .+-. 1% 83.16 2.51 83 .+-. 3% AD-14917 41.03 3.07 41 .+-. 3%
94.67 7.08 95 .+-. 7% AD-14918 110.62 6.34 111 .+-. 6% -17.04 0.98
-17 .+-. 1% AD-14919 73.66 3.68 74 .+-. 4% 42.29 2.11 42 .+-. 2%
AD-14920 19.80 1.72 20 .+-. 2% 128.75 11.20 129 .+-. 11% AD-14921
33.13 1.14 33 .+-. 1% 107.34 3.71 107 .+-. 4% AD-14922 52.94 6.99
53 .+-. 7% 63.41 8.37 63 .+-. 8% AD-14923 33.77 8.92 34 .+-. 9%
89.23 23.56 89 .+-. 24% AD-14924 64.47 10.96 64 .+-. 11% 47.86 8.13
48 .+-. 8% AD-14925 97.16 7.57 97 .+-. 8% 3.83 0.30 4 .+-. 0%
AD-14926 27.29 8.79 27 .+-. 9% 97.96 31.56 98 .+-. 32% AD-14927
27.02 10.01 27 .+-. 10% 98.33 36.42 98 .+-. 36% AD-14928 76.75 4.78
77 .+-. 5% 31.32 1.95 31 .+-. 2% AD-14929 32.92 9.44 33 .+-. 9%
90.38 25.93 90 .+-. 26% AD-14930 31.00 9.40 31 .+-. 9% 92.97 28.21
93 .+-. 28% AD-14931 31.36 8.73 31 .+-. 9% 92.48 25.74 92 .+-. 26%
AD-14932 32.42 9.01 32 .+-. 9% 91.05 25.29 91 .+-. 25% AD-14933
39.94 6.96 40 .+-. 7% 80.92 14.10 81 .+-. 14% AD-14934 42.94 7.66
43 .+-. 8% 76.88 13.71 77 .+-. 14% AD-14935 47.74 8.48 48 .+-. 8%
70.41 12.51 70 .+-. 13% AD-14936 35.21 4.02 35 .+-. 4% 87.29 9.97
87 .+-. 10% AD-14937 89.25 3.53 89 .+-. 4% 14.48 0.57 14 .+-. 1%
AD-14938 29.38 6.46 29 .+-. 6% 95.15 20.91 95 .+-. 21% AD-14939
26.45 8.33 26 .+-. 8% 99.09 31.21 99 .+-. 31% AD-14940 77.50 6.51
78 .+-. 7% 30.31 2.55 30 .+-. 3% AD-14941 36.40 10.76 36 .+-. 11%
85.68 25.32 86 .+-. 25% AD-14942 65.11 5.84 65 .+-. 6% 47.01 4.22
47 .+-. 4% AD-14943 89.96 4.69 90 .+-. 5% 13.52 0.71 14 .+-. 1%
AD-14944 48.98 5.85 49 .+-. 6% 68.74 8.21 69 .+-. 8% AD-14945 43.45
3.29 43 .+-. 3% 76.18 5.77 76 .+-. 6% AD-14946 41.25 1.26 41 .+-.
1% 79.15 2.43 79 .+-. 2% AD-14947 42.10 7.34 42 .+-. 7% 78.01 13.60
78 .+-. 14% AD-14948 42.39 5.75 42 .+-. 6% 77.62 10.54 78 .+-. 11%
AD-14949 27.68 5.79 28 .+-. 6% 97.44 20.39 97 .+-. 20%
[0205] Tables 1b-1 and 1b-2
TABLE-US-00013 TABLE 1b siRNAs targeting JCV transcripts for
primary screen; 1b-1: sequences; 1b-2: assay results. C* column
describes chemistries as follows: Description of chemistries: a
exo/endo-light + 2'-O-methyl in position 2 of antisense b
exo/endo-light: sense strand: dTsdT + 2'OMe@all Py; antisense
strand: dTsdT + 2'OMe@ Py in uA, cA c exo/endo-light + 2'-O-methyl
in position 2 of sense d exo/endo-light + 2'-O-methyl in position 2
of sense and antisense Table 1b-1 SEQ SEQ duplex position in ID
sense strand ID antisense strand name C* consensus NO: sequence
(5'-3') NO: sequence (5'-3') AD-12598 a 1426-1444 1
AcuuuuAGGGuuGuAcGGGTsT 2 CcCGuAcAACCCuAAAAGUTsT AD-12708 b
1426-1444 3 AcuuuuAGGGuuGuAcGGGTsT 4 CCCGuAcAACCCuAAAAGUTsT
AD-12599 a 1427-1445 5 cuuuuAGGGuuGuAcGGGATsT 6
UcCCGuAcAACCCuAAAAGTsT AD-12709 b 1427-1445 7
cuuuuAGGGuuGuAcGGGATsT 8 UCCCGuAcAACCCuAAAAGTsT AD-12600 a
2026-2044 9 cAGAGcAcAAGGcGuAccuTsT 10 AgGuACGCCUUGUGCUCUGTsT
AD-12710 b 2026-2044 11 cAGAGcAcAAGGcGuAccuTsT 12
AGGuACGCCUUGUGCUCUGTsT AD-12784 c 2026-2044 13
caGAGcAcAAGGcGuAccuTsT 14 AGGuACGCCUUGUGCUCUGTsT AD-12832 d
2026-2044 15 caGAGcAcAAGGcGuAccuTsT 16 AgGuACGCCUUGUGCUCUGTsT
AD-12601 a 1431-1449 17 uAGGGuuGuAcGGGAcuGuTsT 18
AcAGUCCCGuAcAACCCuATsT AD-12785 c 1431-1449 19
uaGGGuuGuAcGGGAcuGuTsT 20 AcAGUCCCGuAcAACCCuATsT AD-12602 a
1432-1450 21 AGGGuuGuAcGGGAcuGuATsT 22 uacAGUCCCGuAcAACCCUTsT
AD-12711 b 1432-1450 23 AGGGuuGuAcGGGAcuGuATsT 24
uAcAGUCCCGuAcAACCCUTsT AD-12786 c 1432-1450 25
AgGGuuGuAcGGGAcuGuATsT 26 uAcAGUCCCGuAcAACCCUTsT AD-12833 d
1432-1450 27 AgGGuuGuAcGGGAcuGuATsT 28 uacAGUCCCGuAcAACCCUTsT
AD-12603 a 1436-1454 29 uuGuAcGGGAcuGuAAcAcTsT 30
GuGUuAcAGUCCCGuAcAATsT AD-12712 b 1436-1454 31
uuGuAcGGGAcuGuAAcAcTsT 32 GUGUuAcAGUCCCGuAcAATsT AD-12604 a
4794-4812 33 GccuGAuuuuGGuAcAuGGTsT 34 CcAUGuACcAAAAUcAGGCTsT
AD-12605 a 5099-5117 35 GAAGuAGuAAGGGcGuGGATsT 36
UccACGCCCUuACuACUUCTsT AD-12713 b 5099-5117 37
GAAGuAGuAAGGGcGuGGATsT 38 UCcACGCCCUuACuACUUCTsT AD-12787 c
5099-5117 39 GaAGuAGuAAGGGcGuGGATsT 40 UCcACGCCCUuACuACUUCTsT
AD-12834 d 5099-5117 41 GaAGuAGuAAGGGcGuGGATsT 42
UccACGCCCUuACuACUUCTsT AD-12606 a 713-731 43 AuAGGccuuAcuccuGAAATsT
44 UuUcAGGAGuAAGGCCuAUTsT AD-12714 b 713-731 45
AuAGGccuuAcuccuGAAATsT 46 UUUcAGGAGuAAGGCCuAUTsT AD-12607 a
3946-3964 47 GAcAGccAuAuGcAGuAGuTsT 48 AcuACUGcAuAUGGCUGUCTsT
AD-12715 b 3946-3964 49 GAcAGccAuAuGcAGuAGuTsT 50
ACuACUGcAuAUGGCUGUCTsT AD-12788 c 3946-3964 51
GacAGccAuAuGcAGuAGuTsT 52 ACuACUGcAuAUGGCUGUCTsT AD-12835 d
3946-3964 53 GacAGccAuAuGcAGuAGuTsT 54 AcuACUGcAuAUGGCUGUCTsT
AD-12608 a 1128-1146 55 AAAcuAcuuGGGcAAuAGuTsT 56
AcuAUUGCCcAAGuAGUUUTsT AD-12716 b 1128-1146 57
AAAcuAcuuGGGcAAuAGuTsT 58 ACuAUUGCCcAAGuAGUUUTsT AD-12789 c
1128-1146 59 AaAcuAcuuGGGcAAuAGuTsT 60 ACuAUUGCCcAAGuAGUUUTsT
AD-12836 d 1128-1146 61 AaAcuAcuuGGGcAAuAGuTsT 62
AcuAUUGCCcAAGuAGUUUTsT AD-12609 a 525-543 63 ucAGGuucAuGGGuGccGcTsT
64 GcGGcACCcAUGAACCUGATsT AD-12717 b 525-543 65
ucAGGuucAuGGGuGccGcTsT 66 GCGGcACCcAUGAACCUGATsT AD-12610 a
5096-5114 67 GuAGuAAGGGcGuGGAGGcTsT 68 GcCUCcACGCCCUuACuACTsT
AD-12718 b 5096-5114 69 GuAGuAAGGGcGuGGAGGcTsT 70
GCCUCcACGCCCUuACuACTsT AD-12611 a 4727-4745 71
uAuuGcAAGGAAuGGccuATsT 72 uaGGCcAUUCCUUGcAAuATsT AD-12719 b
4727-4745 73 uAuuGcAAGGAAuGGccuATsT 74 uAGGCcAUUCCUUGcAAuATsT
AD-12790 c 4727-4745 75 uauuGcAAGGAAuGGccuATsT 76
uAGGCcAUUCCUUGcAAuATsT AD-12837 d 4727-4745 77
uauuGcAAGGAAuGGccuATsT 78 uaGGCcAUUCCUUGcAAuATsT AD-12612 a
5097-5115 79 AGuAGuAAGGGcGuGGAGGTsT 80 CcUCcACGCCCUuACuACUTsT
AD-12720 b 5097-5115 81 AGuAGuAAGGGcGuGGAGGTsT 82
CCUCcACGCCCUuACuACUTsT AD-12791 c 5097-5115 83
AguAGuAAGGGcGuGGAGGTsT 84 CCUCcACGCCCUuACuACUTsT AD-12838 d
5097-5115 85 AguAGuAAGGGcGuGGAGGTsT 86 CcUCcACGCCCUuACuACUTsT
AD-12613 a 4601-4619 87 uGcuAuuGcuuuGAuuGcuTsT 88
AgcAAUcAAAGcAAuAGcATsT AD-12721 b 4601-4619 89
uGcuAuuGcuuuGAuuGcuTsT 90 AGcAAUcAAAGcAAuAGcATsT AD-12792 c
4601-4619 91 ugcuAuuGcuuuGAuuGcuTsT 92 AGcAAUcAAAGcAAuAGcATsT
AD-12839 d 4601-4619 93 ugcuAuuGcuuuGAuuGcuTsT 94
AgcAAUcAAAGcAAuAGcATsT AD-12614 a 4600-4618 95
GcuAuuGcuuuGAuuGcuuTsT 96 AaGcAAUcAAAGcAAuAGCTsT AD-12722 b
4600-4618 97 GcuAuuGcuuuGAuuGcuuTsT 98 AAGcAAUcAAAGcAAuAGCTsT
AD-12615 a 1421-1439 99 ccuuuAcuuuuAGGGuuGuTsT 100
AcAACCCuAAAAGuAAAGGTsT AD-12616 a 1424-1442 101
uuAcuuuuAGGGuuGuAcGTsT 102 CguAcAACCCuAAAAGuAATsT AD-12723 b
1424-1442 103 uuAcuuuuAGGGuuGuAcGTsT 104 CGuAcAACCCuAAAAGuAATsT
AD-12617 a 1403-1421 105 GcuccucAAuGGAuGuuGcTsT 106
GcAAcAUCcAUUGAGGAGCTsT AD-12618 a 1534-1552 107
uuAuAAGAGGAGGAGuAGATsT 108 UcuACUCCUCCUCUuAuAATsT AD-12724 b
1534-1552 109 uuAuAAGAGGAGGAGuAGATsT 110 UCuACUCCUCCUCUuAuAATsT
AD-12619 a 5098-5116 111 AAGuAGuAAGGGcGuGGAGTsT 112
CuCcACGCCCUuACuACUUTsT AD-12725 b 5098-5116 113
AAGuAGuAAGGGcGuGGAGTsT 114 CUCcACGCCCUuACuACUUTsT AD-12793 c
5098-5116 115 AaGuAGuAAGGGcGuGGAGTsT 116 CUCcACGCCCUuACuACUUTsT
AD-12840 d 5098-5116 117 AaGuAGuAAGGGcGuGGAGTsT 118
CuCcACGCCCUuACuACUUTsT AD-12620 a 1430-1448 119
uuAGGGuuGuAcGGGAcuGTsT 120 caGUCCCGuAcAACCCuAATsT AD-12726 b
1430-1448 121 uuAGGGuuGuAcGGGAcuGTsT 122 cAGUCCCGuAcAACCCuAATsT
AD-12621 a 1701-1719 123 GAcAuGcuuccuuGuuAcATsT 124
UguAAcAAGGAAGcAUGUCTsT AD-12727 b 1701-1719 125
GAcAuGcuuccuuGuuAcATsT 126 UGuAAcAAGGAAGcAUGUCTsT AD-12794 c
1701-1719 127 GacAuGcuuccuuGuuAcATsT 128 UGuAAcAAGGAAGcAUGUCTsT
AD-12841 d 1701-1719 129 GacAuGcuuccuuGuuAcATsT 130
UguAAcAAGGAAGcAUGUCTsT AD-12622 a 2066-2084 131
uGuuGAAuGuuGGGuuccuTsT 132 AgGAACCcAAcAUUcAAcATsT AD-12728 b
2066-2084 133 uGuuGAAuGuuGGGuuccuTsT 134 AGGAACCcAAcAUUcAAcATsT
AD-12795 c 2066-2084 135 uguuGAAuGuuGGGuuccuTsT 136
AGGAACCcAAcAUUcAAcATsT AD-12842 d 2066-2084 137
uguuGAAuGuuGGGuuccuTsT 138 AgGAACCcAAcAUUcAAcATsT AD-12623 a
4561-4579 139 AcuuAAcccAAGAAGcucuTsT 140 AgAGCUUCUUGGGUuAAGUTsT
AD-12729 b 4561-4579 141 AcuuAAcccAAGAAGcucuTsT 142
AGAGCUUCUUGGGUuAAGUTsT AD-12624 a 4797-4815 143
ucAGccuGAuuuuGGuAcATsT 144 UguACcAAAAUcAGGCUGATsT AD-12730 b
4797-4815 145 ucAGccuGAuuuuGGuAcATsT 146 UGuACcAAAAUcAGGCUGATsT
AD-12625 a 1428-1446 147 uuuuAGGGuuGuAcGGGAcTsT 148
GuCCCGuAcAACCCuAAAATsT AD-12731 b 1428-1446 149
uuuuAGGGuuGuAcGGGAcTsT 150 GUCCCGuAcAACCCuAAAATsT AD-12626 a
1429-1447 151 uuuAGGGuuGuAcGGGAcuTsT 152 AgUCCCGuAcAACCCuAAATsT
AD-12732 b 1429-1447 153 uuuAGGGuuGuAcGGGAcuTsT 154
AGUCCCGuAcAACCCuAAATsT
AD-12627 a 662-680 155 ucccuuGcuAcuGuAGAGGTsT 156
CcUCuAcAGuAGcAAGGGATsT AD-12733 b 662-680 157
ucccuuGcuAcuGuAGAGGTsT 158 CCUCuAcAGuAGcAAGGGATsT AD-12628 a
663-681 159 cccuuGcuAcuGuAGAGGGTsT 160 CcCUCuAcAGuAGcAAGGGTsT
AD-12734 b 663-681 161 cccuuGcuAcuGuAGAGGGTsT 162
CCCUCuAcAGuAGcAAGGGTsT AD-12629 a 1402-1420 163
uGcuccucAAuGGAuGuuGTsT 164 caAcAUCcAUUGAGGAGcATsT AD-12735 b
1402-1420 165 uGcuccucAAuGGAuGuuGTsT 166 cAAcAUCcAUUGAGGAGcATsT
AD-12796 c 1402-1420 167 ugcuccucAAuGGAuGuuGTsT 168
cAAcAUCcAUUGAGGAGcATsT AD-12843 d 1402-1420 169
ugcuccucAAuGGAuGuuGTsT 170 caAcAUCcAUUGAGGAGcATsT AD-12630 a
1398-1416 171 GAucuGcuccucAAuGGAuTsT 172 AuCcAUUGAGGAGcAGAUCTsT
AD-12736 b 1398-1416 173 GAucuGcuccucAAuGGAuTsT 174
AUCcAUUGAGGAGcAGAUCTsT AD-12797 c 1398-1416 175
GaucuGcuccucAAuGGAuTsT 176 AUCcAUUGAGGAGcAGAUCTsT AD-12844 d
1398-1416 177 GaucuGcuccucAAuGGAuTsT 178 AuCcAUUGAGGAGcAGAUCTsT
AD-12631 a 1399-1417 179 AucuGcuccucAAuGGAuGTsT 180
caUCcAUUGAGGAGcAGAUTsT AD-12737 b 1399-1417 181
AucuGcuccucAAuGGAuGTsT 182 cAUCcAUUGAGGAGcAGAUTsT AD-12632 a
1400-1418 183 ucuGcuccucAAuGGAuGuTsT 184 AcAUCcAUUGAGGAGcAGATsT
AD-12633 a 1401-1419 185 cuGcuccucAAuGGAuGuuTsT 186
AacAUCcAUUGAGGAGcAGTsT AD-12738 b 1401-1419 187
cuGcuccucAAuGGAuGuuTsT 188 AAcAUCcAUUGAGGAGcAGTsT AD-12634 a
1435-1453 189 GuuGuAcGGGAcuGuAAcATsT 190 UgUuAcAGUCCCGuAcAACTsT
AD-12739 b 1435-1453 191 GuuGuAcGGGAcuGuAAcATsT 192
UGUuAcAGUCCCGuAcAACTsT AD-12635 a 1437-1455 193
uGuAcGGGAcuGuAAcAccTsT 194 GgUGUuAcAGUCCCGuAcATsT AD-12740 b
1437-1455 195 uGuAcGGGAcuGuAAcAccTsT 196 GGUGUuAcAGUCCCGuAcATsT
AD-12798 c 1437-1455 197 uguAcGGGAcuGuAAcAccTsT 198
GGUGUuAcAGUCCCGuAcATsT AD-12845 d 1437-1455 199
uguAcGGGAcuGuAAcAccTsT 200 GgUGUuAcAGUCCCGuAcATsT AD-12636 a
1438-1456 201 GuAcGGGAcuGuAAcAccuTsT 202 AgGUGUuAcAGUCCCGuACTsT
AD-12741 b 1438-1456 203 GuAcGGGAcuGuAAcAccuTsT 204
AGGUGUuAcAGUCCCGuACTsT AD-12637 a 4796-4814 205
cAGccuGAuuuuGGuAcAuTsT 206 AuGuACcAAAAUcAGGCUGTsT AD-12742 b
4796-4814 207 cAGccuGAuuuuGGuAcAuTsT 208 AUGuACcAAAAUcAGGCUGTsT
AD-12799 c 4796-4814 209 caGccuGAuuuuGGuAcAuTsT 210
AUGuACcAAAAUcAGGCUGTsT AD-12846 d 4796-4814 211
caGccuGAuuuuGGuAcAuTsT 212 AuGuACcAAAAUcAGGCUGTsT AD-12638 a
4992-5010 213 GAAuAGGGAGGAAuccAuGTsT 214 caUGGAUUCCUCCCuAUUCTsT
AD-12743 b 4992-5010 215 GAAuAGGGAGGAAuccAuGTsT 216
cAUGGAUUCCUCCCuAUUCTsT AD-12800 c 4992-5010 217
GaAuAGGGAGGAAuccAuGTsT 218 cAUGGAUUCCUCCCuAUUCTsT AD-12847 d
4992-5010 219 GaAuAGGGAGGAAuccAuGTsT 220 caUGGAUUCCUCCCuAUUCTsT
AD-12639 a 4999-5017 221 AAGuGcuGAAuAGGGAGGATsT 222
UcCUCCCuAUUcAGcACUUTsT AD-12744 b 4999-5017 223
AAGuGcuGAAuAGGGAGGATsT 224 UCCUCCCuAUUcAGcACUUTsT AD-12801 c
4999-5017 225 AaGuGcuGAAuAGGGAGGATsT 226 UCCUCCCuAUUcAGcACUUTsT
AD-12848 d 4999-5017 227 AaGuGcuGAAuAGGGAGGATsT 228
UcCUCCCuAUUcAGcACUUTsT AD-12640 a 630-648 229
AGGcuGcuGcuAcuAuAGATsT 230 UcuAuAGuAGcAGcAGCCUTsT AD-12745 b
630-648 231 AGGcuGcuGcuAcuAuAGATsT 232 UCuAuAGuAGcAGcAGCCUTsT
AD-12802 c 630-648 233 AgGcuGcuGcuAcuAuAGATsT 234
UCuAuAGuAGcAGcAGCCUTsT AD-12849 d 630-648 235
AgGcuGcuGcuAcuAuAGATsT 236 UcuAuAGuAGcAGcAGCCUTsT AD-12641 a
3947-3965 237 AGAcAGccAuAuGcAGuAGTsT 238 CuACUGcAuAUGGCUGUCUTsT
AD-12803 c 3947-3965 239 AgAcAGccAuAuGcAGuAGTsT 240
CuACUGcAuAUGGCUGUCUTsT AD-12642 a 524-542 241
uucAGGuucAuGGGuGccGTsT 242 CgGcACCcAUGAACCUGAATsT AD-12746 b
524-542 243 uucAGGuucAuGGGuGccGTsT 244 CGGcACCcAUGAACCUGAATsT
AD-12643 a 3948-3966 245 uAGAcAGccAuAuGcAGuATsT 246
uaCUGcAuAUGGCUGUCuATsT AD-12747 b 3948-3966 247
uAGAcAGccAuAuGcAGuATsT 248 uACUGcAuAUGGCUGUCuATsT AD-12804 c
3948-3966 249 uaGAcAGccAuAuGcAGuATsT 250 uACUGcAuAUGGCUGUCuATsT
AD-12850 d 3948-3966 251 uaGAcAGccAuAuGcAGuATsT 252
uaCUGcAuAUGGCUGUCuATsT AD-12644 a 3900-3918 253
GGAGcAuGAcuuuAAcccATsT 254 UgGGUuAAAGUcAUGCUCCTsT AD-12748 b
3900-3918 255 GGAGcAuGAcuuuAAcccATsT 256 UGGGUuAAAGUcAUGCUCCTsT
AD-12805 c 3900-3918 257 GgAGcAuGAcuuuAAcccATsT 258
UGGGUuAAAGUcAUGCUCCTsT AD-12851 d 3900-3918 259
GgAGcAuGAcuuuAAcccATsT 260 UgGGUuAAAGUcAUGCUCCTsT AD-12645 a
1417-1435 261 GuuGccuuuAcuuuuAGGGTsT 262 CcCuAAAAGuAAAGGcAACTsT
AD-12749 b 1417-1435 263 GuuGccuuuAcuuuuAGGGTsT 264
CCCuAAAAGuAAAGGcAACTsT AD-12646 a 4565-4583 265
uGuGAcuuAAcccAAGAAGTsT 266 CuUCUUGGGUuAAGUcAcATsT AD-12750 b
4565-4583 267 uGuGAcuuAAcccAAGAAGTsT 268 CUUCUUGGGUuAAGUcAcATsT
AD-12806 c 4565-4583 269 uguGAcuuAAcccAAGAAGTsT 270
CUUCUUGGGUuAAGUcAcATsT AD-12852 d 4565-4583 271
uguGAcuuAAcccAAGAAGTsT 272 CuUCUUGGGUuAAGUcAcATsT AD-12647 a
4598-4616 273 uAuuGcuuuGAuuGcuucATsT 274 UgAAGcAAUcAAAGcAAuATsT
AD-12751 b 4598-4616 275 uAuuGcuuuGAuuGcuucATsT 276
UGAAGcAAUcAAAGcAAuATsT AD-12807 c 4598-4616 277
uauuGcuuuGAuuGcuucATsT 278 UGAAGcAAUcAAAGcAAuATsT AD-12853 d
4598-4616 279 uauuGcuuuGAuuGcuucATsT 280 UgAAGcAAUcAAAGcAAuATsT
AD-12648 a 2060-2078 281 AuAuccuGuuGAAuGuuGGTsT 282
CcAAcAUUcAAcAGGAuAUTsT AD-12649 a 4729-4747 283
uuuAuuGcAAGGAAuGGccTsT 284 GgCcAUUCCUUGcAAuAAATsT AD-12752 b
4729-4747 285 uuuAuuGcAAGGAAuGGccTsT 286 GGCcAUUCCUUGcAAuAAATsT
AD-12650 a 1122-1140 287 uGGAAGAAAcuAcuuGGGcTsT 288
GcCcAAGuAGUUUCUUCcATsT AD-12753 b 1122-1140 289
uGGAAGAAAcuAcuuGGGcTsT 290 GCCcAAGuAGUUUCUUCcATsT AD-12808 c
1122-1140 291 ugGAAGAAAcuAcuuGGGcTsT 292 GCCcAAGuAGUUUCUUCcATsT
AD-12854 d 1122-1140 293 ugGAAGAAAcuAcuuGGGcTsT 294
GcCcAAGuAGUUUCUUCcATsT AD-12651 a 4261-4279 295
AAGAcccuAAAGAcuuuccTsT 296 GgAAAGUCUUuAGGGUCUUTsT AD-12754 b
4261-4279 297 AAGAcccuAAAGAcuuuccTsT 298 GGAAAGUCUUuAGGGUCUUTsT
AD-12809 c 4261-4279 299 AaGAcccuAAAGAcuuuccTsT 300
GGAAAGUCUUuAGGGUCUUTsT AD-12855 d 4261-4279 301
AaGAcccuAAAGAcuuuccTsT 302 GgAAAGUCUUuAGGGUCUUTsT AD-12652 a
1412-1430 303 uGGAuGuuGccuuuAcuuuTsT 304 AaAGuAAAGGcAAcAUCcATsT
AD-12755 b 1412-1430 305 uGGAuGuuGccuuuAcuuuTsT 306
AAAGuAAAGGcAAcAUCcATsT AD-12810 c 1412-1430 307
ugGAuGuuGccuuuAcuuuTsT 308 AAAGuAAAGGcAAcAUCcATsT AD-12856 d
1412-1430 309 ugGAuGuuGccuuuAcuuuTsT 310 AaAGuAAAGGcAAcAUCcATsT
AD-12653 a 4592-4610 311 uuuGAuuGcuucAGAcAAuTsT 312
AuUGUCUGAAGcAAUcAAATsT AD-12756 b 4592-4610 313
uuuGAuuGcuucAGAcAAuTsT 314 AUUGUCUGAAGcAAUcAAATsT AD-12654 a
4991-5009 315 AAuAGGGAGGAAuccAuGGTsT 316 CcAUGGAUUCCUCCCuAUUTsT
AD-12811 c 4991-5009 317 AauAGGGAGGAAuccAuGGTsT 318
CcAUGGAUUCCUCCCuAUUTsT AD-12655 a 5004-5022 319
GGAcAAAGuGcuGAAuAGGTsT 320 CcuAUUcAGcACUUUGUCCTsT AD-12757 b
5004-5022 321 GGAcAAAGuGcuGAAuAGGTsT 322 CCuAUUcAGcACUUUGUCCTsT
AD-12812 c 5004-5022 323 GgAcAAAGuGcuGAAuAGGTsT 324
CCuAUUcAGcACUUUGUCCTsT AD-12857 d 5004-5022 325
GgAcAAAGuGcuGAAuAGGTsT 326 CcuAUUcAGcACUUUGUCCTsT AD-12656 a
5005-5023 327 uGGAcAAAGuGcuGAAuAGTsT 328 CuAUUcAGcACUUUGUCcATsT
AD-12813 c 5005-5023 329 ugGAcAAAGuGcuGAAuAGTsT 330
CuAUUcAGcACUUUGUCcATsT AD-12657 a 654-672 331
AAAuuGcAucccuuGcuAcTsT 332 GuAGcAAGGGAUGcAAUUUTsT AD-12814 c
654-672 333 AaAuuGcAucccuuGcuAcTsT 334 GuAGcAAGGGAUGcAAUUUTsT
AD-12658 a 659-677 335 GcAucccuuGcuAcuGuAGTsT 336
CuAcAGuAGcAAGGGAUGCTsT AD-12659 a 4273-4291 337
AAAAAAAGGuAGAAGAcccTsT 338 GgGUCUUCuACCUUUUUUUTsT AD-12758 b
4273-4291 339 AAAAAAAGGuAGAAGAcccTsT 340 GGGUCUUCuACCUUUUUUUTsT
AD-12815 c 4273-4291 341 AaAAAAAGGuAGAAGAcccTsT 342
GGGUCUUCuACCUUUUUUUTsT AD-12858 d 4273-4291 343
AaAAAAAGGuAGAAGAcccTsT 344 GgGUCUUCuACCUUUUUUUTsT AD-12660 a
2025-2043 345 AcAGAGcAcAAGGcGuAccTsT 346 GguACGCCUUGUGCUCUGUTsT
AD-12759 b 2025-2043 347 AcAGAGcAcAAGGcGuAccTsT 348
GGuACGCCUUGUGCUCUGUTsT AD-12661 a 4791-4809 349
uGAuuuuGGuAcAuGGAAuTsT 350 AuUCcAUGuACcAAAAUcATsT AD-12760 b
4791-4809 351 uGAuuuuGGuAcAuGGAAuTsT 352 AUUCcAUGuACcAAAAUcATsT
AD-12816 c 4791-4809 353 ugAuuuuGGuAcAuGGAAuTsT 354
AUUCcAUGuACcAAAAUcATsT AD-12859 d 4791-4809 355
ugAuuuuGGuAcAuGGAAuTsT 356 AuUCcAUGuACcAAAAUcATsT AD-12662 a
1433-1451 357 GGGuuGuAcGGGAcuGuAATsT 358 UuAcAGUCCCGuAcAACCCTsT
AD-12817 c 1433-1451 359 GgGuuGuAcGGGAcuGuAATsT 360
UuAcAGUCCCGuAcAACCCTsT AD-12663 a 1434-1452 361
GGuuGuAcGGGAcuGuAAcTsT 362 GuuAcAGUCCCGuAcAACCTsT AD-12761 b
1434-1452 363 GGuuGuAcGGGAcuGuAAcTsT 364 GUuAcAGUCCCGuAcAACCTsT
AD-12818 c 1434-1452 365 GguuGuAcGGGAcuGuAAcTsT 366
GUuAcAGUCCCGuAcAACCTsT AD-12860 d 1434-1452 367
GguuGuAcGGGAcuGuAAcTsT 368 GuuAcAGUCCCGuAcAACCTsT AD-12664 a
1440-1458 369 AcGGGAcuGuAAcAccuGcTsT 370 GcAGGUGUuAcAGUCCCGUTsT
AD-12665 a 1442-1460 371 GGGAcuGuAAcAccuGcucTsT 372
GaGcAGGUGUuAcAGUCCCTsT AD-12762 b 1442-1460 373
GGGAcuGuAAcAccuGcucTsT 374 GAGcAGGUGUuAcAGUCCCTsT AD-12819 c
1442-1460 375 GgGAcuGuAAcAccuGcucTsT 376 GAGcAGGUGUuAcAGUCCCTsT
AD-12861 d 1442-1460 377 GgGAcuGuAAcAccuGcucTsT 378
GaGcAGGUGUuAcAGUCCCTsT AD-12666 a 1608-1626 379
AcuccAGAAAuGGGuGAccTsT 380 GgUcACCcAUUUCUGGAGUTsT AD-12763 b
1608-1626 381 AcuccAGAAAuGGGuGAccTsT 382 GGUcACCcAUUUCUGGAGUTsT
AD-12667 a 4793-4811 383 ccuGAuuuuGGuAcAuGGATsT 384
UccAUGuACcAAAAUcAGGTsT AD-12764 b 4793-4811 385
ccuGAuuuuGGuAcAuGGATsT 386 UCcAUGuACcAAAAUcAGGTsT AD-12668 a
5001-5019 387 cAAAGuGcuGAAuAGGGAGTsT 388 CuCCCuAUUcAGcACUUUGTsT
AD-12765 b 5001-5019 389 cAAAGuGcuGAAuAGGGAGTsT 390
CUCCCuAUUcAGcACUUUGTsT AD-12820 c 5001-5019 391
caAAGuGcuGAAuAGGGAGTsT 392 CUCCCuAUUcAGcACUUUGTsT AD-12862 d
5001-5019 393 caAAGuGcuGAAuAGGGAGTsT 394 CuCCCuAUUcAGcACUUUGTsT
AD-12669 a 5066-5084 395 ccAGGGAAAuucccuuGuuTsT 396
AacAAGGGAAUUUCCCUGGTsT AD-12766 b 5066-5084 397
ccAGGGAAAuucccuuGuuTsT 398 AAcAAGGGAAUUUCCCUGGTsT AD-12670 a
5069-5087 399 AGGccAGGGAAAuucccuuTsT 400 AaGGGAAUUUCCCUGGCCUTsT
AD-12767 b 5069-5087 401 AGGccAGGGAAAuucccuuTsT 402
AAGGGAAUUUCCCUGGCCUTsT AD-12821 c 5069-5087 403
AgGccAGGGAAAuucccuuTsT 404 AAGGGAAUUUCCCUGGCCUTsT AD-12863 d
5069-5087 405 AgGccAGGGAAAuucccuuTsT 406 AaGGGAAUUUCCCUGGCCUTsT
AD-12671 a 564-582 407 uAGuuGcuAcuGuuucuGATsT 408
UcAGAAAcAGuAGcAACuATsT AD-12822 c 564-582 409
uaGuuGcuAcuGuuucuGATsT 410 UcAGAAAcAGuAGcAACuATsT AD-12672 a
633-651 411 cuGcuGcuAcuAuAGAAGuTsT 412 AcUUCuAuAGuAGcAGcAGTsT
AD-12768 b 633-651 413 cuGcuGcuAcuAuAGAAGuTsT 414
ACUUCuAuAGuAGcAGcAGTsT AD-12673 a 634-652 415
uGcuGcuAcuAuAGAAGuuTsT 416 AaCUUCuAuAGuAGcAGcATsT AD-12769 b
634-652 417 uGcuGcuAcuAuAGAAGuuTsT 418 AACUUCuAuAGuAGcAGcATsT
AD-12823 c 634-652 419 ugcuGcuAcuAuAGAAGuuTsT 420
AACUUCuAuAGuAGcAGcATsT AD-12864 d 634-652 421
ugcuGcuAcuAuAGAAGuuTsT 422 AaCUUCuAuAGuAGcAGcATsT AD-12674 a
635-653 423 GcuGcuAcuAuAGAAGuuGTsT 424 caACUUCuAuAGuAGcAGCTsT
AD-12770 b 635-653 425 GcuGcuAcuAuAGAAGuuGTsT 426
cAACUUCuAuAGuAGcAGCTsT AD-12675 a 636-654 427
cuGcuAcuAuAGAAGuuGATsT 428 UcAACUUCuAuAGuAGcAGTsT AD-12676 a
637-655 429 uGcuAcuAuAGAAGuuGAATsT 430 UucAACUUCuAuAGuAGcATsT
AD-12771 b 637-655 431 uGcuAcuAuAGAAGuuGAATsT 432
UUcAACUUCuAuAGuAGcATsT AD-12824 c 637-655 433
ugcuAcuAuAGAAGuuGAATsT 434 UUcAACUUCuAuAGuAGcATsT AD-12865 d
637-655 435 ugcuAcuAuAGAAGuuGAATsT 436 UucAACUUCuAuAGuAGcATsT
AD-12677 a 912-930 437 cAGAAGAcuAcuAuGAuAuTsT 438
AuAUcAuAGuAGUCUUCUGTsT AD-12825 c 912-930 439
caGAAGAcuAcuAuGAuAuTsT 440 AuAUcAuAGuAGUCUUCUGTsT AD-12678 a
4153-4171 441 AAAuuuuAuAuAAGAAAcuTsT 442 AgUUUCUuAuAuAAAAUUUTsT
AD-12772 b 4153-4171 443 AAAuuuuAuAuAAGAAAcuTsT 444
AGUUUCUuAuAuAAAAUUUTsT AD-12826 c 4153-4171 445
AaAuuuuAuAuAAGAAAcuTsT 446 AGUUUCUuAuAuAAAAUUUTsT AD-12866 d
4153-4171 447 AaAuuuuAuAuAAGAAAcuTsT 448 AgUUUCUuAuAuAAAAUUUTsT
AD-12679 a 4779-4797 449 AuGGAAuAGuucAGAGGuuTsT 450
AaCCUCUGAACuAUUCcAUTsT AD-12773 b 4779-4797 451
AuGGAAuAGuucAGAGGuuTsT 452 AACCUCUGAACuAUUCcAUTsT AD-12680 a
4780-4798 453 cAuGGAAuAGuucAGAGGuTsT 454 AcCUCUGAACuAUUCcAUGTsT
AD-12774 b 4780-4798 455 cAuGGAAuAGuucAGAGGuTsT 456
ACCUCUGAACuAUUCcAUGTsT AD-12827 c 4780-4798 457
cauGGAAuAGuucAGAGGuTsT 458 ACCUCUGAACuAUUCcAUGTsT AD-12867 d
4780-4798 459 cauGGAAuAGuucAGAGGuTsT 460 AcCUCUGAACuAUUCcAUGTsT
AD-12681 a 4781-4799 461 AcAuGGAAuAGuucAGAGGTsT 462
CcUCUGAACuAUUCcAUGUTsT AD-12775 b 4781-4799 463
AcAuGGAAuAGuucAGAGGTsT 464 CCUCUGAACuAUUCcAUGUTsT AD-12682 a
4784-4802 465 GGuAcAuGGAAuAGuucAGTsT 466 CuGAACuAUUCcAUGuACCTsT
AD-12776 b 4784-4802 467 GGuAcAuGGAAuAGuucAGTsT 468
CUGAACuAUUCcAUGuACCTsT AD-12828 c 4784-4802 469
GguAcAuGGAAuAGuucAGTsT 470 CUGAACuAUUCcAUGuACCTsT AD-12868 d
4784-4802 471 GguAcAuGGAAuAGuucAGTsT 472 CuGAACuAUUCcAUGuACCTsT
AD-12683 a 4785-4803 473 uGGuAcAuGGAAuAGuucATsT 474
UgAACuAUUCcAUGuACcATsT AD-12777 b 4785-4803 475
uGGuAcAuGGAAuAGuucATsT 476 UGAACuAUUCcAUGuACcATsT AD-12829 c
4785-4803 477 ugGuAcAuGGAAuAGuucATsT 478 UGAACuAUUCcAUGuACcATsT
AD-12869 d 4785-4803 479 ugGuAcAuGGAAuAGuucATsT 480
UgAACuAUUCcAUGuACcATsT AD-12684 a 719-737 481
cuuAcuccuGAAAcAuAuGTsT 482 cauAUGUUUcAGGAGuAAGTsT AD-12778 b
719-737 483 cuuAcuccuGAAAcAuAuGTsT 484 cAuAUGUUUcAGGAGuAAGTsT
AD-12685 a 909-927 485 AuccAGAAGAcuAcuAuGATsT 486
UcAuAGuAGUCUUCUGGAUTsT AD-12686 a 1119-1137 487
uuuuGGAAGAAAcuAcuuGTsT 488 caAGuAGUUUCUUCcAAAATsT AD-12779 b
1119-1137 489 uuuuGGAAGAAAcuAcuuGTsT 490 cAAGuAGUUUCUUCcAAAATsT
AD-12687 a 1121-1139 491 uuGGAAGAAAcuAcuuGGGTsT 492
CccAAGuAGUUUCUUCcAATsT AD-12780 b 1121-1139 493
uuGGAAGAAAcuAcuuGGGTsT 494 CCcAAGuAGUUUCUUCcAATsT AD-12688 a
4357-4375 495 AuGAAGAccuGuuuuGccATsT 496 UgGcAAAAcAGGUCUUcAUTsT
AD-12781 b 4357-4375 497 AuGAAGAccuGuuuuGccATsT 498
UGGcAAAAcAGGUCUUcAUTsT AD-12689 a 4358-4376 499
GAuGAAGAccuGuuuuGccTsT 500 GgcAAAAcAGGUCUUcAUCTsT AD-12782 b
4358-4376 501 GAuGAAGAccuGuuuuGccTsT 502 GGcAAAAcAGGUCUUcAUCTsT
AD-12830 c 4358-4376 503 GauGAAGAccuGuuuuGccTsT 504
GGcAAAAcAGGUCUUcAUCTsT AD-12870 d 4358-4376 505
GauGAAGAccuGuuuuGccTsT 506 GgcAAAAcAGGUCUUcAUCTsT AD-12690 a
4360-4378 507 GGGAuGAAGAccuGuuuuGTsT 508 caAAAcAGGUCUUcAUCCCTsT
AD-12783 b 4360-4378 509 GGGAuGAAGAccuGuuuuGTsT 510
cAAAAcAGGUCUUcAUCCCTsT
AD-12831 c 4360-4378 511 GgGAuGAAGAccuGuuuuGTsT 512
cAAAAcAGGUCUUcAUCCCTsT AD-12871 d 4360-4378 513
GgGAuGAAGAccuGuuuuGTsT 514 caAAAcAGGUCUUcAUCCCTsT
TABLE-US-00014 TABLE 1b-2 Residual luciferase activity SD of
Relative siRNA SD of (relative to residual Residual activity
(normalized relative Relative duplex control siRNA luciferase
luciferase to positive control siRNA siRNA name treated cells)
activity activity +/- SD luc-siRNA) activity activity +/- SD
AD-12598 91 11 91 .+-. 11% 9 2 9 .+-. 2% AD-12708 32 5 32 .+-. 5%
76 17 76 .+-. 17% AD-12599 25 6 25 .+-. 6% 79 13 79 .+-. 13%
AD-12709 16 4 16 .+-. 4% 97 26 97 .+-. 26% AD-12600 79 9 79 .+-. 9%
21 3 21 .+-. 3% AD-12710 25 4 25 .+-. 4% 85 24 85 .+-. 24% AD-12784
23 2 23 .+-. 2% 87 14 87 .+-. 14% AD-12832 84 11 84 .+-. 11% 18 4
18 .+-. 4% AD-12601 102 8 102 .+-. 8% -6 1 -6 .+-. 1% AD-12785 95
10 95 .+-. 10% 6 1 6 .+-. 1% AD-12602 107 9 107 .+-. 9% -11 2 -11
.+-. 2% AD-12711 70 4 70 .+-. 4% 34 3 34 .+-. 3% AD-12786 69 8 69
.+-. 8% 35 7 35 .+-. 7% AD-12833 94 8 94 .+-. 8% 7 1 7 .+-. 1%
AD-12603 100 9 100 .+-. 9% -4 1 -4 .+-. 1% AD-12712 27 5 27 .+-. 5%
82 16 82 .+-. 16% AD-12604 15 2 15 .+-. 2% 94 13 94 .+-. 13%
AD-12605 94 5 94 .+-. 5% 7 0 7 .+-. 0% AD-12713 61 10 61 .+-. 10%
41 8 41 .+-. 8% AD-12787 55 6 55 .+-. 6% 47 6 47 .+-. 6% AD-12834
92 16 92 .+-. 16% 8 2 8 .+-. 2% AD-12606 78 3 78 .+-. 3% 25 1 25
.+-. 1% AD-12714 63 6 63 .+-. 6% 42 5 42 .+-. 5% AD-12607 101 9 101
.+-. 9% -1 0 -1 .+-. 0% AD-12715 101 5 101 .+-. 5% -1 0 -1 .+-. 0%
AD-12788 85 18 85 .+-. 18% 15 4 15 .+-. 4% AD-12835 95 9 95 .+-. 9%
6 1 6 .+-. 1% AD-12608 103 13 103 .+-. 13% -3 0 -3 .+-. 0% AD-12716
81 9 81 .+-. 9% 22 3 22 .+-. 3% AD-12789 61 4 61 .+-. 4% 44 4 44
.+-. 4% AD-12836 103 11 103 .+-. 11% -3 0 -3 .+-. 0% AD-12609 108
19 108 .+-. 19% -9 2 -9 .+-. 2% AD-12717 94 17 94 .+-. 17% 7 1 7
.+-. 1% AD-12610 88 9 88 .+-. 9% 14 2 14 .+-. 2% AD-12718 39 4 39
.+-. 4% 64 8 64 .+-. 8% AD-12611 38 6 38 .+-. 6% 69 12 69 .+-. 12%
AD-12719 26 4 26 .+-. 4% 78 13 78 .+-. 13% AD-12790 17 3 17 .+-. 3%
87 18 87 .+-. 18% AD-12837 22 4 22 .+-. 4% 81 16 81 .+-. 16%
AD-12612 100 6 100 .+-. 6% 0 0 0 .+-. 0% AD-12720 73 6 73 .+-. 6%
28 3 28 .+-. 3% AD-12791 46 9 46 .+-. 9% 57 12 57 .+-. 12% AD-12838
97 15 97 .+-. 15% 3 1 3 .+-. 1% AD-12613 26 4 26 .+-. 4% 82 15 82
.+-. 15% AD-12721 10 1 10 .+-. 1% 94 12 94 .+-. 12% AD-12792 10 3
10 .+-. 3% 94 40 94 .+-. 40% AD-12839 22 3 22 .+-. 3% 81 12 81 .+-.
12% AD-12614 15 5 15 .+-. 5% 94 38 94 .+-. 38% AD-12722 6 1 6 .+-.
1% 98 26 98 .+-. 26% AD-12615 93 4 93 .+-. 4% 8 0 8 .+-. 0%
AD-12616 95 4 95 .+-. 4% 5 0 5 .+-. 0% AD-12723 73 7 73 .+-. 7% 30
3 30 .+-. 3% AD-12617 88 10 88 .+-. 10% 13 2 13 .+-. 2% AD-12618 42
7 42 .+-. 7% 60 7 60 .+-. 7% AD-12724 21 5 21 .+-. 5% 89 32 89 .+-.
32% AD-12619 95 7 95 .+-. 7% 6 1 6 .+-. 1% AD-12725 71 2 71 .+-. 2%
30 1 30 .+-. 1% AD-12793 54 7 54 .+-. 7% 48 7 48 .+-. 7% AD-12840
94 9 94 .+-. 9% 7 1 7 .+-. 1% AD-12620 106 7 106 .+-. 7% -8 1 -8
.+-. 1% AD-12726 100 7 100 .+-. 7% 0 0 0 .+-. 0% AD-12621 107 9 107
.+-. 9% -7 1 -7 .+-. 1% AD-12727 47 4 47 .+-. 4% 60 8 60 .+-. 8%
AD-12794 40 8 40 .+-. 8% 67 20 67 .+-. 20% AD-12841 78 13 78 .+-.
13% 25 8 25 .+-. 8% AD-12622 16 4 16 .+-. 4% 92 29 92 .+-. 29%
AD-12728 25 6 25 .+-. 6% 84 29 84 .+-. 29% AD-12795 23 3 23 .+-. 3%
86 20 86 .+-. 20% AD-12842 19 4 19 .+-. 4% 91 20 91 .+-. 20%
AD-12623 103 9 103 .+-. 9% -3 0 -3 .+-. 0% AD-12729 84 8 84 .+-. 8%
17 2 17 .+-. 2% AD-12624 31 4 31 .+-. 4% 77 12 77 .+-. 12% AD-12730
18 1 18 .+-. 1% 85 3 85 .+-. 3% AD-12625 94 10 94 .+-. 10% 5 1 5
.+-. 1% AD-12731 57 4 57 .+-. 4% 48 4 48 .+-. 4% AD-12626 99 7 99
.+-. 7% 0 0 0 .+-. 0% AD-12732 82 5 82 .+-. 5% 20 1 20 .+-. 1%
AD-12627 80 6 80 .+-. 6% 22 2 22 .+-. 2% AD-12733 65 6 65 .+-. 6%
39 4 39 .+-. 4% AD-12628 81 6 81 .+-. 6% 21 2 21 .+-. 2% AD-12734
82 7 82 .+-. 7% 21 2 21 .+-. 2% AD-12629 113 11 113 .+-. 11% -14 2
-14 .+-. 2% AD-12735 90 9 90 .+-. 9% 11 1 11 .+-. 1% AD-12796 92 8
92 .+-. 8% 9 1 9 .+-. 1% AD-12843 117 7 117 .+-. 7% -19 1 -19 .+-.
1% AD-12630 124 3 124 .+-. 3% -27 1 -27 .+-. 1% AD-12736 85 4 85
.+-. 4% 16 1 16 .+-. 1% AD-12797 52 1 52 .+-. 1% 53 1 53 .+-. 1%
AD-12844 96 4 96 .+-. 4% 5 0 5 .+-. 0% AD-12631 110 11 110 .+-. 11%
-12 1 -12 .+-. 1% AD-12737 115 13 115 .+-. 13% -17 2 -17 .+-. 2%
AD-12632 106 2 106 .+-. 2% -7 0 -7 .+-. 0% AD-12633 107 12 107 .+-.
12% -8 1 -8 .+-. 1% AD-12738 88 5 88 .+-. 5% 14 1 14 .+-. 1%
AD-12634 79 5 79 .+-. 5% 24 1 24 .+-. 1% AD-12739 69 8 69 .+-. 8%
35 6 35 .+-. 6% AD-12635 75 8 75 .+-. 8% 25 6 25 .+-. 6% AD-12740
65 8 65 .+-. 8% 40 8 40 .+-. 8% AD-12798 56 4 56 .+-. 4% 50 6 50
.+-. 6% AD-12845 74 6 74 .+-. 6% 30 3 30 .+-. 3% AD-12636 89 8 89
.+-. 8% 9 1 9 .+-. 1% AD-12741 31 4 31 .+-. 4% 78 14 78 .+-. 14%
AD-12637 16 2 16 .+-. 2% 93 14 93 .+-. 14% AD-12742 18 3 18 .+-. 3%
85 14 85 .+-. 14% AD-12799 18 4 18 .+-. 4% 86 22 86 .+-. 22%
AD-12846 15 2 15 .+-. 2% 89 14 89 .+-. 14% AD-12638 95 6 95 .+-. 6%
5 0 5 .+-. 0% AD-12743 23 4 23 .+-. 4% 81 15 81 .+-. 15% AD-12800
14 1 14 .+-. 1% 90 10 90 .+-. 10% AD-12847 90 12 90 .+-. 12% 10 2
10 .+-. 2% AD-12639 113 11 113 .+-. 11% -15 2 -15 .+-. 2% AD-12744
42 4 42 .+-. 4% 60 7 60 .+-. 7% AD-12801 34 3 34 .+-. 3% 68 8 68
.+-. 8% AD-12848 114 3 114 .+-. 3% -14 0 -14 .+-. 0% AD-12640 96 11
96 .+-. 11% 4 1 4 .+-. 1% AD-12745 52 7 52 .+-. 7% 53 8 53 .+-. 8%
AD-12802 74 9 74 .+-. 9% 29 4 29 .+-. 4% AD-12849 111 5 111 .+-. 5%
-12 1 -12 .+-. 1% AD-12641 103 8 103 .+-. 8% -3 0 -3 .+-. 0%
AD-12803 94 13 94 .+-. 13% 6 1 6 .+-. 1% AD-12642 105 3 105 .+-. 3%
-6 0 -6 .+-. 0% AD-12746 100 9 100 .+-. 9% 0 0 0 .+-. 0% AD-12643
33 4 33 .+-. 4% 74 10 74 .+-. 10% AD-12747 21 3 21 .+-. 3% 83 13 83
.+-. 13% AD-12804 25 4 25 .+-. 4% 78 14 78 .+-. 14% AD-12850 28 4
28 .+-. 4% 75 11 75 .+-. 11% AD-12644 82 7 82 .+-. 7% 20 2 20 .+-.
2% AD-12748 25 4 25 .+-. 4% 78 14 78 .+-. 14% AD-12805 23 7 23 .+-.
7% 80 30 80 .+-. 30% AD-12851 61 7 61 .+-. 7% 41 5 41 .+-. 5%
AD-12645 112 6 112 .+-. 6% -14 1 -14 .+-. 1% AD-12749 86 10 86 .+-.
10% 16 2 16 .+-. 2% AD-12646 94 10 94 .+-. 10% 6 1 6 .+-. 1%
AD-12750 93 11 93 .+-. 11% 7 1 7 .+-. 1% AD-12806 77 8 77 .+-. 8%
24 3 24 .+-. 3% AD-12852 96 4 96 .+-. 4% 5 0 5 .+-. 0% AD-12647 27
3 27 .+-. 3% 81 11 81 .+-. 11% AD-12751 29 6 29 .+-. 6% 74 19 74
.+-. 19% AD-12807 31 2 31 .+-. 2% 72 6 72 .+-. 6% AD-12853 26 3 26
.+-. 3% 78 11 78 .+-. 11% AD-12648 81 9 81 .+-. 9% 17 3 17 .+-. 3%
AD-12649 92 9 92 .+-. 9% 8 1 8 .+-. 1% AD-12752 71 9 71 .+-. 9% 30
5 30 .+-. 5% AD-12650 81 2 81 .+-. 2% 21 1 21 .+-. 1% AD-12753 57 1
57 .+-. 1% 48 1 48 .+-. 1% AD-12808 52 4 52 .+-. 4% 54 5 54 .+-. 5%
AD-12854 77 5 77 .+-. 5% 26 2 26 .+-. 2% AD-12651 89 6 89 .+-. 6%
13 1 13 .+-. 1% AD-12754 88 7 88 .+-. 7% 12 1 12 .+-. 1% AD-12809
67 6 67 .+-. 6% 35 4 35 .+-. 4% AD-12855 88 10 88 .+-. 10% 12 2 12
.+-. 2% AD-12652 91 2 91 .+-. 2% 10 0 10 .+-. 0% AD-12755 40 3 40
.+-. 3% 67 6 67 .+-. 6% AD-12810 35 1 35 .+-. 1% 72 3 72 .+-. 3%
AD-12856 75 8 75 .+-. 8% 28 4 28 .+-. 4% AD-12653 79 8 79 .+-. 8%
23 3 23 .+-. 3% AD-12756 17 5 17 .+-. 5% 86 27 86 .+-. 27% AD-12654
97 6 97 .+-. 6% 3 0 3 .+-. 0% AD-12811 74 5 74 .+-. 5% 27 2 27 .+-.
2% AD-12655 46 6 46 .+-. 6% 59 9 59 .+-. 9% AD-12757 14 0 14 .+-.
0% 89 2 89 .+-. 2% AD-12812 12 3 12 .+-. 3% 92 28 92 .+-. 28%
AD-12857 35 7 35 .+-. 7% 70 17 70 .+-. 17% AD-12656 10 3 10 .+-. 3%
99 33 99 .+-. 33% AD-12813 9 1 9 .+-. 1% 95 18 95 .+-. 18% AD-12657
108 1 108 .+-. 1% -9 0 -9 .+-. 0% AD-12814 101 4 101 .+-. 4% -1 0
-1 .+-. 0% AD-12658 98 9 98 .+-. 9% 2 0 2 .+-. 0% AD-12659 83 4 83
.+-. 4% 18 1 18 .+-. 1% AD-12758 80 14 80 .+-. 14% 21 4 21 .+-. 4%
AD-12815 25 3 25 .+-. 3% 79 11 79 .+-. 11% AD-12858 67 4 67 .+-. 4%
35 2 35 .+-. 2% AD-12660 95 11 95 .+-. 11% 8 3 8 .+-. 3% AD-12759
66 7 66 .+-. 7% 39 6 39 .+-. 6% AD-12661 34 2 34 .+-. 2% 73 5 73
.+-. 5% AD-12760 10 3 10 .+-. 3% 94 30 94 .+-. 30% AD-12816 12 4 12
.+-. 4% 92 37 92 .+-. 37% AD-12859 33 1 33 .+-. 1% 72 2 72 .+-. 2%
AD-12662 92 7 92 .+-. 7% 7 1 7 .+-. 1% AD-12817 91 11 91 .+-. 11%
10 2 10 .+-. 2% AD-12663 99 10 99 .+-. 10% 3 1 3 .+-. 1% AD-12761
20 5 20 .+-. 5% 89 22 89 .+-. 22% AD-12818 20 4 20 .+-. 4% 90 20 90
.+-. 20% AD-12860 93 11 93 .+-. 11% 8 1 8 .+-. 1% AD-12664 93 9 93
.+-. 9% 6 2 6 .+-. 2% AD-12665 94 8 94 .+-. 8% 10 1 10 .+-. 1%
AD-12762 58 8 58 .+-. 8% 47 10 47 .+-. 10% AD-12819 49 6 49 .+-. 6%
58 9 58 .+-. 9% AD-12861 93 8 93 .+-. 8% 8 1 8 .+-. 1% AD-12666 30
5 30 .+-. 5% 76 18 76 .+-. 18% AD-12763 25 2 25 .+-. 2% 84 9 84
.+-. 9% AD-12667 65 10 65 .+-. 10% 38 7 38 .+-. 7% AD-12764 34 7 34
.+-. 7% 69 17 69 .+-. 17% AD-12668 34 4 34 .+-. 4% 73 10 73 .+-.
10% AD-12765 13 3 13 .+-. 3% 91 22 91 .+-. 22% AD-12820 11 2 11
.+-. 2% 93 17 93 .+-. 17% AD-12862 19 4 19 .+-. 4% 87 22 87 .+-.
22% AD-12669 22 3 22 .+-. 3% 87 12 87 .+-. 12% AD-12766 11 4 11
.+-. 4% 93 39 93 .+-. 39% AD-12670 45 3 45 .+-. 3% 61 5 61 .+-. 5%
AD-12767 10 3 10 .+-. 3% 94 31 94 .+-. 31% AD-12821 12 1 12 .+-. 1%
92 13 92 .+-. 13% AD-12863 41 4 41 .+-. 4% 64 8 64 .+-. 8% AD-12671
83 9 83 .+-. 9% 19 2 19 .+-. 2% AD-12822 74 7 74 .+-. 7% 29 3 29
.+-. 3% AD-12672 52 7 52 .+-. 7% 54 9 54 .+-. 9% AD-12768 28 3 28
.+-. 3% 81 12 81 .+-. 12% AD-12673 56 5 56 .+-. 5% 49 5 49 .+-. 5%
AD-12769 36 2 36 .+-. 2% 72 5 72 .+-. 5% AD-12823 33 2 33 .+-. 2%
75 5 75 .+-. 5% AD-12864 49 7 49 .+-. 7% 57 10 57 .+-. 10% AD-12674
90 9 90 .+-. 9% 11 1 11 .+-. 1% AD-12770 45 6 45 .+-. 6% 61 9 61
.+-. 9% AD-12675 45 5 45 .+-. 5% 62 8 62 .+-. 8% AD-12676 47 6 47
.+-. 6% 59 9 59 .+-. 9% AD-12771 31 4 31 .+-. 4% 77 11 77 .+-. 11%
AD-12824 31 3 31 .+-. 3% 77 10 77 .+-. 10% AD-12865 43 7 43 .+-. 7%
64 12 64 .+-. 12% AD-12677 23 4 23 .+-. 4% 86 16 86 .+-. 16%
AD-12825 22 4 22 .+-. 4% 87 16 87 .+-. 16% AD-12678 102 8 102 .+-.
8% -2 0 -2 .+-. 0% AD-12772 101 13 101 .+-. 13% -1 0 -1 .+-. 0%
AD-12826 99 1 99 .+-. 1% 1 0 1 .+-. 0% AD-12866 91 7 91 .+-. 7% 10
1 10 .+-. 1% AD-12679 81 8 81 .+-. 8% 21 2 21 .+-. 2% AD-12773 11 2
11 .+-. 2% 93 19 93 .+-. 19% AD-12680 17 3 17 .+-. 3% 92 17 92 .+-.
17% AD-12774 15 2 15 .+-. 2% 89 17 89 .+-. 17% AD-12827 11 2 11
.+-. 2% 93 18 93 .+-. 18% AD-12867 15 3 15 .+-. 3% 91 22 91 .+-.
22% AD-12681 28 3 28 .+-. 3% 79 10 79 .+-. 10% AD-12775 8 1 8 .+-.
1% 95 19 95 .+-. 19% AD-12682 43 6 43 .+-. 6% 63 9 63 .+-. 9%
AD-12776 23 5 23 .+-. 5% 80 19 80 .+-. 19% AD-12828 23 5 23 .+-. 5%
80 20 80 .+-. 20% AD-12868 25 4 25 .+-. 4% 81 16 81 .+-. 16%
AD-12683 17 2 17 .+-. 2% 91 15 91 .+-. 15% AD-12777 11 2 11 .+-. 2%
92 22 92 .+-. 22% AD-12829 12 1 12 .+-. 1% 92 11 92 .+-. 11%
AD-12869 19 3 19 .+-. 3% 87 16 87 .+-. 16%
AD-12684 87 12 87 .+-. 12% 14 2 14 .+-. 2% AD-12778 41 4 41 .+-. 4%
66 8 66 .+-. 8% AD-12685 35 1 35 .+-. 1% 72 1 72 .+-. 1% AD-12686
68 5 68 .+-. 5% 36 3 36 .+-. 3% AD-12779 58 5 58 .+-. 5% 47 5 47
.+-. 5% AD-12687 73 8 73 .+-. 8% 30 4 30 .+-. 4% AD-12780 62 8 62
.+-. 8% 42 7 42 .+-. 7% AD-12688 18 1 18 .+-. 1% 91 4 91 .+-. 4%
AD-12781 11 3 11 .+-. 3% 93 33 93 .+-. 33% AD-12689 96 4 96 .+-. 4%
4 0 4 .+-. 0% AD-12782 45 7 45 .+-. 7% 58 10 58 .+-. 10% AD-12830
15 3 15 .+-. 3% 89 19 89 .+-. 19% AD-12870 51 3 51 .+-. 3% 52 4 52
.+-. 4% AD-12690 93 6 93 .+-. 6% 8 1 8 .+-. 1% AD-12783 36 3 36
.+-. 3% 66 7 66 .+-. 7% AD-12831 27 2 27 .+-. 2% 76 7 76 .+-. 7%
AD-12871 81 18 81 .+-. 18% 21 5 21 .+-. 5%
Sequence CWU 1
1
937121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 1acuuuuaggg uuguacgggt t
21221DNAArtificial SequenceDescription of Combined DNA/RNA Molecule
Synthetic oligonucleotide 2cccguacaac ccuaaaagut t
21321DNAArtificial SequenceDescription of Combined DNA/RNA Molecule
Synthetic oligonucleotide 3acuuuuaggg uuguacgggt t
21421DNAArtificial SequenceDescription of Combined DNA/RNA Molecule
Synthetic oligonucleotide 4cccguacaac ccuaaaagut t
21521DNAArtificial SequenceDescription of Combined DNA/RNA Molecule
Synthetic oligonucleotide 5cuuuuagggu uguacgggat t
21621DNAArtificial SequenceDescription of Combined DNA/RNA Molecule
Synthetic oligonucleotide 6ucccguacaa cccuaaaagt t
21721DNAArtificial SequenceDescription of Combined DNA/RNA Molecule
Synthetic oligonucleotide 7cuuuuagggu uguacgggat t
21821DNAArtificial SequenceDescription of Combined DNA/RNA Molecule
Synthetic oligonucleotide 8ucccguacaa cccuaaaagt t
21921DNAArtificial SequenceDescription of Combined DNA/RNA Molecule
Synthetic oligonucleotide 9cagagcacaa ggcguaccut t
211021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 10agguacgccu ugugcucugt t
211121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 11cagagcacaa ggcguaccut t
211221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 12agguacgccu ugugcucugt t
211321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 13cagagcacaa ggcguaccut t
211421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 14agguacgccu ugugcucugt t
211521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 15cagagcacaa ggcguaccut t
211621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 16agguacgccu ugugcucugt t
211721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 17uaggguugua cgggacugut t
211821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 18acagucccgu acaacccuat t
211921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 19uaggguugua cgggacugut t
212021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 20acagucccgu acaacccuat t
212121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 21aggguuguac gggacuguat t
212221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 22uacagucccg uacaacccut t
212321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 23aggguuguac gggacuguat t
212421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 24uacagucccg uacaacccut t
212521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 25aggguuguac gggacuguat t
212621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 26uacagucccg uacaacccut t
212721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 27aggguuguac gggacuguat t
212821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 28uacagucccg uacaacccut t
212921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 29uuguacggga cuguaacact t
213021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 30guguuacagu cccguacaat t
213121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 31uuguacggga cuguaacact t
213221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 32guguuacagu cccguacaat t
213321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 33gccugauuuu gguacauggt t
213421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 34ccauguacca aaaucaggct t
213521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 35gaaguaguaa gggcguggat t
213621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 36uccacgcccu uacuacuuct t
213721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 37gaaguaguaa gggcguggat t
213821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 38uccacgcccu uacuacuuct t
213921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 39gaaguaguaa gggcguggat t
214021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 40uccacgcccu uacuacuuct t
214121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 41gaaguaguaa gggcguggat t
214221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 42uccacgcccu uacuacuuct t
214321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 43auaggccuua cuccugaaat t
214421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 44uuucaggagu aaggccuaut t
214521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 45auaggccuua cuccugaaat t
214621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 46uuucaggagu aaggccuaut t
214721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 47gacagccaua ugcaguagut t
214821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 48acuacugcau auggcuguct t
214921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 49gacagccaua ugcaguagut t
215021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 50acuacugcau auggcuguct t
215121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 51gacagccaua ugcaguagut t
215221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 52acuacugcau auggcuguct t
215321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 53gacagccaua ugcaguagut t
215421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 54acuacugcau auggcuguct t
215521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 55aaacuacuug ggcaauagut t
215621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 56acuauugccc aaguaguuut t
215721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 57aaacuacuug ggcaauagut t
215821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 58acuauugccc aaguaguuut t
215921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 59aaacuacuug ggcaauagut t
216021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 60acuauugccc aaguaguuut t
216121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 61aaacuacuug ggcaauagut t
216221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 62acuauugccc aaguaguuut t
216321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 63ucagguucau gggugccgct t
216421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 64gcggcaccca ugaaccugat t
216521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 65ucagguucau gggugccgct t
216621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 66gcggcaccca ugaaccugat t
216721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 67guaguaaggg cguggaggct t
216821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 68gccuccacgc ccuuacuact t
216921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 69guaguaaggg cguggaggct t
217021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 70gccuccacgc ccuuacuact t
217121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 71uauugcaagg aauggccuat t
217221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 72uaggccauuc cuugcaauat t
217321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 73uauugcaagg aauggccuat t
217421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 74uaggccauuc cuugcaauat t
217521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 75uauugcaagg aauggccuat t
217621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 76uaggccauuc cuugcaauat t
217721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 77uauugcaagg aauggccuat t
217821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 78uaggccauuc cuugcaauat t
217921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 79aguaguaagg gcguggaggt t
218021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 80ccuccacgcc cuuacuacut t
218121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 81aguaguaagg gcguggaggt t
218221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 82ccuccacgcc cuuacuacut t
218321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 83aguaguaagg gcguggaggt t
218421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 84ccuccacgcc cuuacuacut t
218521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 85aguaguaagg gcguggaggt t
218621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 86ccuccacgcc cuuacuacut t
218721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 87ugcuauugcu uugauugcut t
218821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 88agcaaucaaa gcaauagcat t
218921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 89ugcuauugcu uugauugcut t
219021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 90agcaaucaaa gcaauagcat t
219121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 91ugcuauugcu uugauugcut t
219221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 92agcaaucaaa gcaauagcat t
219321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 93ugcuauugcu uugauugcut t
219421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 94agcaaucaaa gcaauagcat t
219521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 95gcuauugcuu ugauugcuut t
219621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 96aagcaaucaa agcaauagct t
219721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 97gcuauugcuu ugauugcuut t
219821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 98aagcaaucaa agcaauagct t
219921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 99ccuuuacuuu uaggguugut t
2110021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 100acaacccuaa aaguaaaggt t
2110121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic
oligonucleotide 101uuacuuuuag gguuguacgt t 2110221DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 102cguacaaccc uaaaaguaat t 2110321DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 103uuacuuuuag gguuguacgt t 2110421DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 104cguacaaccc uaaaaguaat t 2110521DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 105gcuccucaau ggauguugct t 2110621DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 106gcaacaucca uugaggagct t 2110721DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 107uuauaagagg aggaguagat t 2110821DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 108ucuacuccuc cucuuauaat t 2110921DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 109uuauaagagg aggaguagat t 2111021DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 110ucuacuccuc cucuuauaat t 2111121DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 111aaguaguaag ggcguggagt t 2111221DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 112cuccacgccc uuacuacuut t 2111321DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 113aaguaguaag ggcguggagt t 2111421DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 114cuccacgccc uuacuacuut t 2111521DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 115aaguaguaag ggcguggagt t 2111621DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 116cuccacgccc uuacuacuut t 2111721DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 117aaguaguaag ggcguggagt t 2111821DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 118cuccacgccc uuacuacuut t 2111921DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 119uuaggguugu acgggacugt t 2112021DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 120cagucccgua caacccuaat t 2112121DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 121uuaggguugu acgggacugt t 2112221DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 122cagucccgua caacccuaat t 2112321DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 123gacaugcuuc cuuguuacat t 2112421DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 124uguaacaagg aagcauguct t 2112521DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 125gacaugcuuc cuuguuacat t 2112621DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 126uguaacaagg aagcauguct t 2112721DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 127gacaugcuuc cuuguuacat t 2112821DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 128uguaacaagg aagcauguct t 2112921DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 129gacaugcuuc cuuguuacat t 2113021DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 130uguaacaagg aagcauguct t 2113121DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 131uguugaaugu uggguuccut t 2113221DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 132aggaacccaa cauucaacat t 2113321DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 133uguugaaugu uggguuccut t 2113421DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 134aggaacccaa cauucaacat t 2113521DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 135uguugaaugu uggguuccut t 2113621DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 136aggaacccaa cauucaacat t 2113721DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 137uguugaaugu uggguuccut t 2113821DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 138aggaacccaa cauucaacat t 2113921DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 139acuuaaccca agaagcucut t 2114021DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 140agagcuucuu ggguuaagut t 2114121DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 141acuuaaccca agaagcucut t 2114221DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 142agagcuucuu ggguuaagut t 2114321DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 143ucagccugau uuugguacat t 2114421DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 144uguaccaaaa ucaggcugat t 2114521DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 145ucagccugau uuugguacat t 2114621DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 146uguaccaaaa ucaggcugat t 2114721DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 147uuuuaggguu guacgggact t 2114821DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 148gucccguaca acccuaaaat t 2114921DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 149uuuuaggguu guacgggact t 2115021DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 150gucccguaca acccuaaaat t 2115121DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 151uuuaggguug uacgggacut t 2115221DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 152agucccguac aacccuaaat t 2115321DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 153uuuaggguug uacgggacut t 2115421DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 154agucccguac aacccuaaat t 2115521DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 155ucccuugcua cuguagaggt t 2115621DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 156ccucuacagu agcaagggat t 2115721DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 157ucccuugcua cuguagaggt t 2115821DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 158ccucuacagu agcaagggat t 2115921DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 159cccuugcuac uguagagggt t 2116021DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 160cccucuacag uagcaagggt t 2116121DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 161cccuugcuac uguagagggt t 2116221DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 162cccucuacag uagcaagggt t 2116321DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 163ugcuccucaa uggauguugt t 2116421DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 164caacauccau ugaggagcat t 2116521DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 165ugcuccucaa uggauguugt t 2116621DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 166caacauccau ugaggagcat t 2116721DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 167ugcuccucaa uggauguugt t 2116821DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 168caacauccau ugaggagcat t 2116921DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 169ugcuccucaa uggauguugt t 2117021DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 170caacauccau ugaggagcat t 2117121DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 171gaucugcucc ucaauggaut t 2117221DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 172auccauugag gagcagauct t 2117321DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 173gaucugcucc ucaauggaut t 2117421DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 174auccauugag gagcagauct t 2117521DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 175gaucugcucc ucaauggaut t 2117621DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 176auccauugag gagcagauct t 2117721DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 177gaucugcucc ucaauggaut t 2117821DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 178auccauugag gagcagauct t 2117921DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 179aucugcuccu caauggaugt t 2118021DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 180cauccauuga ggagcagaut t 2118121DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 181aucugcuccu caauggaugt t 2118221DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 182cauccauuga ggagcagaut t 2118321DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 183ucugcuccuc aauggaugut t 2118421DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 184acauccauug aggagcagat t 2118521DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 185cugcuccuca auggauguut t 2118621DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 186aacauccauu gaggagcagt t 2118721DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 187cugcuccuca auggauguut t 2118821DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 188aacauccauu gaggagcagt t 2118921DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 189guuguacggg acuguaacat t 2119021DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 190uguuacaguc ccguacaact t 2119121DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 191guuguacggg acuguaacat t 2119221DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 192uguuacaguc ccguacaact t 2119321DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 193uguacgggac uguaacacct t 2119421DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 194gguguuacag ucccguacat t 2119521DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 195uguacgggac uguaacacct t 2119621DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 196gguguuacag ucccguacat t 2119721DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 197uguacgggac uguaacacct t 2119821DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 198gguguuacag ucccguacat t 2119921DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 199uguacgggac uguaacacct t 2120021DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 200gguguuacag ucccguacat t 2120121DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 201guacgggacu guaacaccut t
2120221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 202agguguuaca gucccguact t
2120321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 203guacgggacu guaacaccut t
2120421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 204agguguuaca gucccguact t
2120521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 205cagccugauu uugguacaut t
2120621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 206auguaccaaa aucaggcugt t
2120721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 207cagccugauu uugguacaut t
2120821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 208auguaccaaa aucaggcugt t
2120921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 209cagccugauu uugguacaut t
2121021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 210auguaccaaa aucaggcugt t
2121121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 211cagccugauu uugguacaut t
2121221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 212auguaccaaa aucaggcugt t
2121321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 213gaauagggag gaauccaugt t
2121421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 214cauggauucc ucccuauuct t
2121521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 215gaauagggag gaauccaugt t
2121621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 216cauggauucc ucccuauuct t
2121721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 217gaauagggag gaauccaugt t
2121821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 218cauggauucc ucccuauuct t
2121921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 219gaauagggag gaauccaugt t
2122021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 220cauggauucc ucccuauuct t
2122121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 221aagugcugaa uagggaggat t
2122221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 222uccucccuau ucagcacuut t
2122321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 223aagugcugaa uagggaggat t
2122421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 224uccucccuau ucagcacuut t
2122521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 225aagugcugaa uagggaggat t
2122621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 226uccucccuau ucagcacuut t
2122721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 227aagugcugaa uagggaggat t
2122821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 228uccucccuau ucagcacuut t
2122921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 229aggcugcugc uacuauagat t
2123021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 230ucuauaguag cagcagccut t
2123121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 231aggcugcugc uacuauagat t
2123221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 232ucuauaguag cagcagccut t
2123321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 233aggcugcugc uacuauagat t
2123421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 234ucuauaguag cagcagccut t
2123521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 235aggcugcugc uacuauagat t
2123621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 236ucuauaguag cagcagccut t
2123721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 237agacagccau augcaguagt t
2123821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 238cuacugcaua uggcugucut t
2123921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 239agacagccau augcaguagt t
2124021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 240cuacugcaua uggcugucut t
2124121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 241uucagguuca ugggugccgt t
2124221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 242cggcacccau gaaccugaat t
2124321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 243uucagguuca ugggugccgt t
2124421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 244cggcacccau gaaccugaat t
2124521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 245uagacagcca uaugcaguat t
2124621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 246uacugcauau ggcugucuat t
2124721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 247uagacagcca uaugcaguat t
2124821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 248uacugcauau ggcugucuat t
2124921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 249uagacagcca uaugcaguat t
2125021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 250uacugcauau ggcugucuat t
2125121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 251uagacagcca uaugcaguat t
2125221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 252uacugcauau ggcugucuat t
2125321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 253ggagcaugac uuuaacccat t
2125421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 254uggguuaaag ucaugcucct t
2125521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 255ggagcaugac uuuaacccat t
2125621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 256uggguuaaag ucaugcucct t
2125721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 257ggagcaugac uuuaacccat t
2125821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 258uggguuaaag ucaugcucct t
2125921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 259ggagcaugac uuuaacccat t
2126021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 260uggguuaaag ucaugcucct t
2126121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 261guugccuuua cuuuuagggt t
2126221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 262cccuaaaagu aaaggcaact t
2126321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 263guugccuuua cuuuuagggt t
2126421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 264cccuaaaagu aaaggcaact t
2126521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 265ugugacuuaa cccaagaagt t
2126621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 266cuucuugggu uaagucacat t
2126721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 267ugugacuuaa cccaagaagt t
2126821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 268cuucuugggu uaagucacat t
2126921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 269ugugacuuaa cccaagaagt t
2127021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 270cuucuugggu uaagucacat t
2127121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 271ugugacuuaa cccaagaagt t
2127221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 272cuucuugggu uaagucacat t
2127321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 273uauugcuuug auugcuucat t
2127421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 274ugaagcaauc aaagcaauat t
2127521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 275uauugcuuug auugcuucat t
2127621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 276ugaagcaauc aaagcaauat t
2127721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 277uauugcuuug auugcuucat t
2127821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 278ugaagcaauc aaagcaauat t
2127921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 279uauugcuuug auugcuucat t
2128021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 280ugaagcaauc aaagcaauat t
2128121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 281auauccuguu gaauguuggt t
2128221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 282ccaacauuca acaggauaut t
2128321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 283uuuauugcaa ggaauggcct t
2128421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 284ggccauuccu ugcaauaaat t
2128521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 285uuuauugcaa ggaauggcct t
2128621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 286ggccauuccu ugcaauaaat t
2128721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 287uggaagaaac uacuugggct t
2128821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 288gcccaaguag uuucuuccat t
2128921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 289uggaagaaac uacuugggct t
2129021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 290gcccaaguag uuucuuccat t
2129121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 291uggaagaaac uacuugggct t
2129221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 292gcccaaguag uuucuuccat t
2129321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 293uggaagaaac uacuugggct t
2129421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 294gcccaaguag uuucuuccat t
2129521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 295aagacccuaa agacuuucct t
2129621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 296ggaaagucuu uagggucuut t
2129721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 297aagacccuaa agacuuucct t
2129821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 298ggaaagucuu uagggucuut t
2129921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 299aagacccuaa agacuuucct t
2130021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 300ggaaagucuu uagggucuut t
2130121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 301aagacccuaa agacuuucct t
2130221DNAArtificial SequenceDescription of Combined
DNA/RNA Molecule Synthetic oligonucleotide 302ggaaagucuu uagggucuut
t 2130321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 303uggauguugc cuuuacuuut t
2130421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 304aaaguaaagg caacauccat t
2130521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 305uggauguugc cuuuacuuut t
2130621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 306aaaguaaagg caacauccat t
2130721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 307uggauguugc cuuuacuuut t
2130821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 308aaaguaaagg caacauccat t
2130921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 309uggauguugc cuuuacuuut t
2131021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 310aaaguaaagg caacauccat t
2131121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 311uuugauugcu ucagacaaut t
2131221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 312auugucugaa gcaaucaaat t
2131321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 313uuugauugcu ucagacaaut t
2131421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 314auugucugaa gcaaucaaat t
2131521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 315aauagggagg aauccauggt t
2131621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 316ccauggauuc cucccuauut t
2131721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 317aauagggagg aauccauggt t
2131821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 318ccauggauuc cucccuauut t
2131921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 319ggacaaagug cugaauaggt t
2132021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 320ccuauucagc acuuugucct t
2132121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 321ggacaaagug cugaauaggt t
2132221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 322ccuauucagc acuuugucct t
2132321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 323ggacaaagug cugaauaggt t
2132421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 324ccuauucagc acuuugucct t
2132521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 325ggacaaagug cugaauaggt t
2132621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 326ccuauucagc acuuugucct t
2132721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 327uggacaaagu gcugaauagt t
2132821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 328cuauucagca cuuuguccat t
2132921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 329uggacaaagu gcugaauagt t
2133021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 330cuauucagca cuuuguccat t
2133121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 331aaauugcauc ccuugcuact t
2133221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 332guagcaaggg augcaauuut t
2133321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 333aaauugcauc ccuugcuact t
2133421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 334guagcaaggg augcaauuut t
2133521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 335gcaucccuug cuacuguagt t
2133621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 336cuacaguagc aagggaugct t
2133721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 337aaaaaaaggu agaagaccct t
2133821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 338gggucuucua ccuuuuuuut t
2133921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 339aaaaaaaggu agaagaccct t
2134021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 340gggucuucua ccuuuuuuut t
2134121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 341aaaaaaaggu agaagaccct t
2134221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 342gggucuucua ccuuuuuuut t
2134321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 343aaaaaaaggu agaagaccct t
2134421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 344gggucuucua ccuuuuuuut t
2134521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 345acagagcaca aggcguacct t
2134621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 346gguacgccuu gugcucugut t
2134721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 347acagagcaca aggcguacct t
2134821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 348gguacgccuu gugcucugut t
2134921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 349ugauuuuggu acauggaaut t
2135021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 350auuccaugua ccaaaaucat t
2135121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 351ugauuuuggu acauggaaut t
2135221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 352auuccaugua ccaaaaucat t
2135321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 353ugauuuuggu acauggaaut t
2135421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 354auuccaugua ccaaaaucat t
2135521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 355ugauuuuggu acauggaaut t
2135621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 356auuccaugua ccaaaaucat t
2135721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 357ggguuguacg ggacuguaat t
2135821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 358uuacaguccc guacaaccct t
2135921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 359ggguuguacg ggacuguaat t
2136021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 360uuacaguccc guacaaccct t
2136121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 361gguuguacgg gacuguaact t
2136221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 362guuacagucc cguacaacct t
2136321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 363gguuguacgg gacuguaact t
2136421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 364guuacagucc cguacaacct t
2136521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 365gguuguacgg gacuguaact t
2136621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 366guuacagucc cguacaacct t
2136721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 367gguuguacgg gacuguaact t
2136821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 368guuacagucc cguacaacct t
2136921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 369acgggacugu aacaccugct t
2137021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 370gcagguguua cagucccgut t
2137121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 371gggacuguaa caccugcuct t
2137221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 372gagcaggugu uacaguccct t
2137321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 373gggacuguaa caccugcuct t
2137421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 374gagcaggugu uacaguccct t
2137521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 375gggacuguaa caccugcuct t
2137621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 376gagcaggugu uacaguccct t
2137721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 377gggacuguaa caccugcuct t
2137821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 378gagcaggugu uacaguccct t
2137921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 379acuccagaaa ugggugacct t
2138021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 380ggucacccau uucuggagut t
2138121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 381acuccagaaa ugggugacct t
2138221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 382ggucacccau uucuggagut t
2138321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 383ccugauuuug guacauggat t
2138421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 384uccauguacc aaaaucaggt t
2138521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 385ccugauuuug guacauggat t
2138621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 386uccauguacc aaaaucaggt t
2138721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 387caaagugcug aauagggagt t
2138821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 388cucccuauuc agcacuuugt t
2138921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 389caaagugcug aauagggagt t
2139021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 390cucccuauuc agcacuuugt t
2139121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 391caaagugcug aauagggagt t
2139221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 392cucccuauuc agcacuuugt t
2139321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 393caaagugcug aauagggagt t
2139421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 394cucccuauuc agcacuuugt t
2139521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 395ccagggaaau ucccuuguut t
2139621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 396aacaagggaa uuucccuggt t
2139721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 397ccagggaaau ucccuuguut t
2139821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 398aacaagggaa uuucccuggt t
2139921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 399aggccaggga aauucccuut t
2140021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 400aagggaauuu cccuggccut t
2140121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 401aggccaggga aauucccuut t
2140221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 402aagggaauuu cccuggccut
t 2140321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 403aggccaggga aauucccuut t
2140421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 404aagggaauuu cccuggccut t
2140521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 405aggccaggga aauucccuut t
2140621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 406aagggaauuu cccuggccut t
2140721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 407uaguugcuac uguuucugat t
2140821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 408ucagaaacag uagcaacuat t
2140921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 409uaguugcuac uguuucugat t
2141021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 410ucagaaacag uagcaacuat t
2141121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 411cugcugcuac uauagaagut t
2141221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 412acuucuauag uagcagcagt t
2141321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 413cugcugcuac uauagaagut t
2141421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 414acuucuauag uagcagcagt t
2141521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 415ugcugcuacu auagaaguut t
2141621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 416aacuucuaua guagcagcat t
2141721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 417ugcugcuacu auagaaguut t
2141821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 418aacuucuaua guagcagcat t
2141921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 419ugcugcuacu auagaaguut t
2142021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 420aacuucuaua guagcagcat t
2142121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 421ugcugcuacu auagaaguut t
2142221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 422aacuucuaua guagcagcat t
2142321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 423gcugcuacua uagaaguugt t
2142421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 424caacuucuau aguagcagct t
2142521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 425gcugcuacua uagaaguugt t
2142621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 426caacuucuau aguagcagct t
2142721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 427cugcuacuau agaaguugat t
2142821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 428ucaacuucua uaguagcagt t
2142921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 429ugcuacuaua gaaguugaat t
2143021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 430uucaacuucu auaguagcat t
2143121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 431ugcuacuaua gaaguugaat t
2143221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 432uucaacuucu auaguagcat t
2143321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 433ugcuacuaua gaaguugaat t
2143421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 434uucaacuucu auaguagcat t
2143521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 435ugcuacuaua gaaguugaat t
2143621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 436uucaacuucu auaguagcat t
2143721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 437cagaagacua cuaugauaut t
2143821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 438auaucauagu agucuucugt t
2143921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 439cagaagacua cuaugauaut t
2144021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 440auaucauagu agucuucugt t
2144121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 441aaauuuuaua uaagaaacut t
2144221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 442aguuucuuau auaaaauuut t
2144321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 443aaauuuuaua uaagaaacut t
2144421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 444aguuucuuau auaaaauuut t
2144521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 445aaauuuuaua uaagaaacut t
2144621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 446aguuucuuau auaaaauuut t
2144721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 447aaauuuuaua uaagaaacut t
2144821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 448aguuucuuau auaaaauuut t
2144921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 449auggaauagu ucagagguut t
2145021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 450aaccucugaa cuauuccaut t
2145121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 451auggaauagu ucagagguut t
2145221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 452aaccucugaa cuauuccaut t
2145321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 453cauggaauag uucagaggut t
2145421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 454accucugaac uauuccaugt t
2145521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 455cauggaauag uucagaggut t
2145621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 456accucugaac uauuccaugt t
2145721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 457cauggaauag uucagaggut t
2145821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 458accucugaac uauuccaugt t
2145921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 459cauggaauag uucagaggut t
2146021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 460accucugaac uauuccaugt t
2146121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 461acauggaaua guucagaggt t
2146221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 462ccucugaacu auuccaugut t
2146321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 463acauggaaua guucagaggt t
2146421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 464ccucugaacu auuccaugut t
2146521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 465gguacaugga auaguucagt t
2146621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 466cugaacuauu ccauguacct t
2146721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 467gguacaugga auaguucagt t
2146821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 468cugaacuauu ccauguacct t
2146921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 469gguacaugga auaguucagt t
2147021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 470cugaacuauu ccauguacct t
2147121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 471gguacaugga auaguucagt t
2147221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 472cugaacuauu ccauguacct t
2147321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 473ugguacaugg aauaguucat t
2147421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 474ugaacuauuc cauguaccat t
2147521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 475ugguacaugg aauaguucat t
2147621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 476ugaacuauuc cauguaccat t
2147721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 477ugguacaugg aauaguucat t
2147821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 478ugaacuauuc cauguaccat t
2147921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 479ugguacaugg aauaguucat t
2148021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 480ugaacuauuc cauguaccat t
2148121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 481cuuacuccug aaacauaugt t
2148221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 482cauauguuuc aggaguaagt t
2148321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 483cuuacuccug aaacauaugt t
2148421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 484cauauguuuc aggaguaagt t
2148521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 485auccagaaga cuacuaugat t
2148621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 486ucauaguagu cuucuggaut t
2148721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 487uuuuggaaga aacuacuugt t
2148821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 488caaguaguuu cuuccaaaat t
2148921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 489uuuuggaaga aacuacuugt t
2149021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 490caaguaguuu cuuccaaaat t
2149121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 491uuggaagaaa cuacuugggt t
2149221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 492cccaaguagu uucuuccaat t
2149321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 493uuggaagaaa cuacuugggt t
2149421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 494cccaaguagu uucuuccaat t
2149521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 495augaagaccu guuuugccat t
2149621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 496uggcaaaaca ggucuucaut t
2149721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 497augaagaccu guuuugccat t
2149821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 498uggcaaaaca ggucuucaut t
2149921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 499gaugaagacc uguuuugcct t
2150021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 500ggcaaaacag gucuucauct t
2150121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 501gaugaagacc uguuuugcct t
2150221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 502ggcaaaacag gucuucauct t
2150321DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 503gaugaagacc uguuuugcct t 2150421DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 504ggcaaaacag gucuucauct t 2150521DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 505gaugaagacc uguuuugcct t 2150621DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 506ggcaaaacag gucuucauct t 2150721DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 507gggaugaaga ccuguuuugt t 2150821DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 508caaaacaggu cuucauccct t 2150921DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 509gggaugaaga ccuguuuugt t 2151021DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 510caaaacaggu cuucauccct t 2151121DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 511gggaugaaga ccuguuuugt t 2151221DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 512caaaacaggu cuucauccct t 2151321DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 513gggaugaaga ccuguuuugt t 2151421DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 514caaaacaggu cuucauccct t 2151521DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 515cuuauaagag gaggaguagt t 2151621DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 516cuacuccucc ucuuauaagt t 2151721DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 517caugcuuccu uguuacagut t 2151821DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 518acuguaacaa ggaagcaugt t 2151921DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 519uacgggacug uaacaccugt t 2152021DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 520cagguguuac agucccguat t 2152121DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 521ugcuuccuug uuacagugut t 2152221DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 522acacuguaac aaggaagcat t 2152321DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 523ccuguugaau guuggguuct t 2152421DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 524gaacccaaca uucaacaggt t 2152521DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 525guugaauguu ggguuccugt t 2152621DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 526caggaaccca acauucaact t 2152721DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 527aauguugggu uccugaucct t 2152821DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 528ggaucaggaa cccaacauut t 2152921DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 529acacuaacag gaggagaaat t 2153021DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 530uuucuccucc uguuagugut t 2153121DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 531uauaagagga ggaguagaat t 2153221DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 532uucuacuccu ccucuuauat t 2153321DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 533auaagaggag gaguagaagt t 2153421DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 534cuucuacucc uccucuuaut t 2153521DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 535acuguaacac cugcucuugt t 2153621DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 536caagagcagg uguuacagut t 2153721DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 537ggacaugcuu ccuuguuact t 2153821DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 538guaacaagga agcaugucct t 2153921DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 539acaugcuucc uuguuacagt t 2154021DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 540cuguaacaag gaagcaugut t 2154121DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 541augcuuccuu guuacagugt t 2154221DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 542cacuguaaca aggaagcaut t 2154321DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 543cuguugaaug uuggguucct t 2154421DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 544ggaacccaac auucaacagt t 2154521DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 545gaauguuggg uuccugauct t 2154621DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 546gaucaggaac ccaacauuct t 2154721DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 547cgggacugua acaccugcut t 2154821DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 548agcagguguu acagucccgt t 2154921DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 549ggacuguaac accugcucut t 2155021DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 550agagcaggug uuacagucct t 2155121DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 551gacuguaaca ccugcucuut t 2155221DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 552aagagcaggu guuacaguct t 2155321DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 553cuccagaaau gggugaccct t 2155421DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 554gggucaccca uuucuggagt t 2155521DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 555uaagaggagg aguagaagut t 2155621DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 556acuucuacuc cuccucuuat t 2155721DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 557gaggcugcug cuacuauagt t 2155821DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 558cuauaguagc agcagccuct t 2155921DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 559auugcauccc uugcuacugt t 2156021DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 560caguagcaag ggaugcaaut t 2156121DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 561ugcaucccuu gcuacuguat t 2156221DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 562uacaguagca agggaugcat t 2156321DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 563uuguguuuuc agguucaugt t 2156421DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 564caugaaccug aaaacacaat t 2156521DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 565ggaccuaguu gcuacuguut t 2156621DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 566aacaguagca acuaggucct t 2156721DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 567cugccacagg auuuucagut t 2156821DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 568acugaaaauc cuguggcagt t 2156921DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 569gcuacuauag aaguugaaat t 2157021DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 570uuucaacuuc uauaguagct t 2157121DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 571aauugcaucc cuugcuacut t 2157221DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 572aguagcaagg gaugcaauut t 2157321DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 573accuaguugc uacuguuuct t 2157421DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 574gaaacaguag caacuaggut t 2157521DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 575cuacuauaga aguugaaaut t 2157621DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 576auuucaacuu cuauaguagt t 2157721DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 577aggccuuacu ccugaaacat t 2157821DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 578uguuucagga guaaggccut t 2157921DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 579ggccuuacuc cugaaacaut t 2158021DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 580auguuucagg aguaaggcct t 2158121DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 581guaaaaccug gaguggaact t 2158221DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 582guuccacucc agguuuuact t 2158321DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 583uguguuuuca gguucauggt t 2158421DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 584ccaugaaccu gaaaacacat t 2158521DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 585uguuuucagg uucaugggut t 2158621DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 586acccaugaac cugaaaacat t 2158721DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 587aucccuugcu acuguagagt t 2158821DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 588cucuacagua gcaagggaut t 2158921DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 589gaccuaguug cuacuguuut t 2159021DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 590aaacaguagc aacuagguct t 2159121DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 591ggauuacaag uaccucugat t 2159221DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 592ucagagguac uuguaaucct t 2159321DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 593uaggccuuac uccugaaact t 2159421DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 594guuucaggag uaaggccuat t 2159521DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 595uguuagaauu uuugcuggat t 2159621DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 596uccagcaaaa auucuaacat t 2159721DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 597ugcugccaca ggauuuucat t 2159821DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 598ugaaaauccu guggcagcat t 2159921DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 599ccacaggauu uucaguagct t 2160021DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 600gcuacugaaa auccuguggt t 2160121DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 601aaguugaaau ugcaucccut t 2160221DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 602agggaugcaa uuucaacuut t 2160321DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 603aguugaaauu gcaucccuut t 2160421DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 604aagggaugca auuucaacut t 2160521DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 605gcugcugcca caggauuuut t 2160621DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 606aaaauccugu ggcagcagct t 2160721DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 607aguaaaaccu ggaguggaat t 2160821DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 608uuccacucca gguuuuacut t 2160921DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 609uuuuguguuu ucagguucat t 2161021DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 610ugaaccugaa aacacaaaat t 2161121DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 611uuuguguuuu cagguucaut t 2161221DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 612augaaccuga aaacacaaat t 2161321DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 613guguuuucag guucaugggt t 2161421DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 614cccaugaacc ugaaaacact t 2161521DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 615guuuucaggu ucaugggugt t 2161621DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 616cacccaugaa ccugaaaact t 2161721DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 617uuuucagguu caugggugct t 2161821DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 618gcacccauga accugaaaat t 2161921DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 619uuucagguuc augggugcct t 2162021DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 620ggcacccaug aaccugaaat t 2162121DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 621aauugcugcu ggagaggcut t 2162221DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 622agccucucca gcagcaauut t 2162321DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 623uugcaucccu ugcuacugut t 2162421DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 624acaguagcaa gggaugcaat t 2162521DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 625gcuguagcug gguuugcugt t 2162621DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 626cagcaaaccc agcuacagct t 2162721DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 627uagaaguuga aauugcauct t 2162821DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 628gaugcaauuu caacuucuat t 2162921DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 629gaaguugaaa uugcauccct t 2163021DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 630gggaugcaau uucaacuuct t 2163121DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 631caucccuugc uacuguagat t 2163221DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 632ucuacaguag caagggaugt t 2163321DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 633uaguaaaacc uggaguggat t 2163421DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 634uccacuccag guuuuacuat t 2163521DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 635uuuuuuguua gaauuuuugt t 2163621DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 636caaaaauucu aacaaaaaat t 2163721DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 637uacuauagaa guugaaauut t 2163821DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 638aauuucaacu ucuauaguat t 2163921DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 639ccuaguugcu acuguuucut t 2164021DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 640agaaacagua gcaacuaggt t 2164121DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 641cuaguugcua cuguuucugt t 2164221DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 642cagaaacagu agcaacuagt t 2164321DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 643guugcuacug uuucugaggt t 2164421DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 644ccucagaaac aguagcaact t 2164521DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 645uggagaggcu gcugcuacut t 2164621DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 646aguagcagca gccucuccat t 2164721DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 647gagaggcugc ugcuacuaut t 2164821DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 648auaguagcag cagccucuct t 2164921DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 649agaggcugcu gcuacuauat t 2165021DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 650uauaguagca gcagccucut t 2165121DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 651gcugcugcua cuauagaagt t 2165221DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 652cuucuauagu agcagcagct t 2165321DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 653uuuuuugugu uuucagguut t 2165421DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 654aaccugaaaa cacaaaaaat t 2165521DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 655acuauagaag uugaaauugt t 2165621DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 656caauuucaac uucuauagut t 2165721DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 657uuaguaaaac cuggaguggt t 2165821DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 658ccacuccagg uuuuacuaat t 2165921DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 659gccuuacucc ugaaacauat t 2166021DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 660uauguuucag gaguaaggct t 2166121DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 661agaaguugaa auugcaucct t 2166221DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 662ggaugcaauu ucaacuucut t 2166321DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 663ugccacagga uuuucaguat t 2166421DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 664uacugaaaau ccuguggcat t 2166521DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 665gcugccacag gauuuucagt t 2166621DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 666cugaaaaucc uguggcagct t 2166721DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 667cagguucaug ggugccgcat t 2166821DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 668ugcggcaccc augaaccugt t 2166921DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 669aaauugcugc uggagaggct t 2167021DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 670gccucuccag cagcaauuut t 2167121DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 671auugcugcug gagaggcugt t 2167221DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 672cagccucucc agcagcaaut t 2167321DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 673ugaaauugca ucccuugcut t 2167421DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 674agcaagggau gcaauuucat t 2167521DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 675uuuuguuaga auuuuugcut t 2167621DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 676agcaaaaauu cuaacaaaat t 2167721DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 677uuuguuagaa uuuuugcugt t 2167821DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 678cagcaaaaau ucuaacaaat t 2167921DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 679ggcugcugcu acuauagaat t 2168021DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 680uucuauagua gcagcagcct t 2168121DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 681uuguuagaau uuuugcuggt t 2168221DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 682ccagcaaaaa uucuaacaat t 2168321DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 683uuuuuuugug uuuucaggut t 2168421DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 684accugaaaac acaaaaaaat t 2168521DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 685gaaacuacuu gggcaauagt t 2168621DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 686cuauugccca aguaguuuct t 2168721DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 687aauggauguu gccuuuacut t 2168821DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 688aguaaaggca acauccauut t 2168921DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 689ccucaaugga uguugccuut t 2169021DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 690aaggcaacau ccauugaggt t 2169121DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 691uugccuuuac uuuuagggut t 2169221DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 692acccuaaaag uaaaggcaat t 2169321DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 693agaaacuacu ugggcaauat t 2169421DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 694uauugcccaa guaguuucut t 2169521DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 695aagaaacuac uugggcaaut t 2169621DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 696auugcccaag uaguuucuut t 2169721DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 697ugccuuuacu uuuaggguut t 2169821DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 698aacccuaaaa guaaaggcat t 2169921DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 699gccuuuacuu uuaggguugt t 2170021DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 700caacccuaaa aguaaaggct t 2170121DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 701cuuuacuuuu aggguuguat t 2170221DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 702uacaacccua aaaguaaagt t 2170321DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 703uuuacuuuua ggguuguact t
2170421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 704guacaacccu aaaaguaaat t
2170521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 705uacuuuuagg guuguacggt t
2170621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 706ccguacaacc cuaaaaguat t
2170721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 707ggaagaaacu acuugggcat t
2170821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 708ugcccaagua guuucuucct t
2170921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 709caauggaugu ugccuuuact t
2171021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 710guaaaggcaa cauccauugt t
2171121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 711ggauguugcc uuuacuuuut t
2171221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 712aaaaguaaag gcaacaucct t
2171321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 713uguugccuuu acuuuuaggt t
2171421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 714ccuaaaagua aaggcaacat t
2171521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 715gauguugccu uuacuuuuat t
2171621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 716uaaaaguaaa ggcaacauct t
2171721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 717ccagaagacu acuaugauat t
2171821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 718uaucauagua gucuucuggt t
2171921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 719uccagaagac uacuaugaut t
2172021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 720aucauaguag ucuucuggat t
2172121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 721uuuggaagaa acuacuuggt t
2172221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 722ccaaguaguu ucuuccaaat t
2172321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 723cuccucaaug gauguugcct t
2172421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 724ggcaacaucc auugaggagt t
2172521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 725ccaaaugugc aaucuggugt t
2172621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 726caccagauug cacauuuggt t
2172721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 727caaaugugca aucuggugat t
2172821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 728ucaccagauu gcacauuugt t
2172921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 729agaucugcuc cucaauggat t
2173021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 730uccauugagg agcagaucut t
2173121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 731cucaauggau guugccuuut t
2173221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 732aaaggcaaca uccauugagt t
2173321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 733gcucaaauuu uauauaagat t
2173421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 734ucuuauauaa aauuugagct t
2173521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 735agccugauuu ugguacaugt t
2173621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 736cauguaccaa aaucaggcut t
2173721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 737cucaaauuuu auauaagaat t
2173821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 738uucuuauaua aaauuugagt t
2173921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 739acaaagugcu gaauagggat t
2174021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 740ucccuauuca gcacuuugut t
2174121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 741cugauuuugg uacauggaat t
2174221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 742uuccauguac caaaaucagt t
2174321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 743gauuuuggua cauggaauat t
2174421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 744uauuccaugu accaaaauct t
2174521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 745cucaucagcc ugauuuuggt t
2174621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 746ccaaaaucag gcugaugagt t
2174721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 747agcccacuug uguggauagt t
2174821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 748cuauccacac aagugggcut t
2174921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 749gugcugaaua gggaggaaut t
2175021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 750auuccucccu auucagcact t
2175121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 751aguaagggcg uggaggcuut t
2175221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 752aagccuccac gcccuuacut t
2175321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 753gugacuuaac ccaagaagct t
2175421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 754gcuucuuggg uuaagucact t
2175521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 755uaguaagggc guggaggcut t
2175621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 756agccuccacg cccuuacuat t
2175721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 757ucaucagccu gauuuuggut t
2175821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 758accaaaauca ggcugaugat t
2175921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 759guagaagacc cuaaagacut t
2176021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 760agucuuuagg gucuucuact t
2176121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 761agguagaaga cccuaaagat t
2176221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 762ucuuuagggu cuucuaccut t
2176321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 763aaaagguaga agacccuaat t
2176421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 764uuagggucuu cuaccuuuut t
2176521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 765aaagguagaa gacccuaaat t
2176621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 766uuuagggucu ucuaccuuut t
2176721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 767gauugugcag uggaaagaat t
2176821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 768uucuuuccac ugcacaauct t
2176921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 769ggauugugca guggaaagat t
2177021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 770ucuuuccacu gcacaaucct t
2177121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 771uguagacagc cauaugcagt t
2177221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 772cugcauaugg cugucuacat t
2177321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 773caugacuuua acccagaagt t
2177421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 774cuucuggguu aaagucaugt t
2177521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 775auagggagga auccauggat t
2177621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 776uccauggauu ccucccuaut t
2177721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 777cugaauaggg aggaauccat t
2177821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 778uggauuccuc ccuauucagt t
2177921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 779aaagugcuga auagggaggt t
2178021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 780ccucccuauu cagcacuuut t
2178121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 781ugacuuaacc caagaagcut t
2178221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 782agcuucuugg guuaagucat t
2178321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 783augacuuuaa cccagaagat t
2178421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 784ucuucugggu uaaagucaut t
2178521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 785gaagacccua aagacuuuct t
2178621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 786gaaagucuuu agggucuuct t
2178721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 787aaaaagcuca aauuuuauat t
2178821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 788uauaaaauuu gagcuuuuut t
2178921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 789aucagccuga uuuugguact t
2179021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 790guaccaaaau caggcugaut t
2179121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 791caucagccug auuuugguat t
2179221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 792uaccaaaauc aggcugaugt t
2179321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 793auggacaaag ugcugaauat t
2179421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 794uauucagcac uuuguccaut t
2179521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 795uagaagaccc uaaagacuut t
2179621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 796aagucuuuag ggucuucuat t
2179721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 797aagguagaag acccuaaagt t
2179821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 798cuuuaggguc uucuaccuut t
2179921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 799cagcccacuu guguggauat t
2180021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 800uauccacaca agugggcugt t
2180121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 801uuuugguaca uggaauagut t
2180221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 802acuauuccau guaccaaaat t
2180321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 803ugaauaggga ggaauccaut t
2180421DNAArtificial SequenceDescription of Combined
DNA/RNA Molecule Synthetic oligonucleotide 804auggauuccu cccuauucat
t 2180521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 805gcugaauagg gaggaaucct t
2180621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 806ggauuccucc cuauucagct t
2180721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 807ugcugaauag ggaggaauct t
2180821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 808gauuccuccc uauucagcat t
2180921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 809uguguagaca gccauaugct t
2181021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 810gcauauggcu gucuacacat t
2181121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 811ugcuuugauu gcuucagact t
2181221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 812gucugaagca aucaaagcat t
2181321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 813uugcuuugau ugcuucagat t
2181421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 814ucugaagcaa ucaaagcaat t
2181521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 815auugcuuuga uugcuucagt t
2181621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 816cugaagcaau caaagcaaut t
2181721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 817cuauugcuuu gauugcuuct t
2181821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 818gaagcaauca aagcaauagt t
2181921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 819auugcaagga auggccuaat t
2182021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 820uuaggccauu ccuugcaaut t
2182121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 821auuuuccucc uaauucugat t
2182221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 822ucagaauuag gaggaaaaut t
2182321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 823gcucaucagc cugauuuugt t
2182421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 824caaaaucagg cugaugagct t
2182521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 825ugcucaucag ccugauuuut t
2182621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 826aaaaucaggc ugaugagcat t
2182721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 827aguugcucau cagccugaut t
2182821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 828aucaggcuga ugagcaacut t
2182921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 829aagggcgugg aggcuuuuut t
2183021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 830aaaaagccuc cacgcccuut t
2183121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 831guaagggcgu ggaggcuuut t
2183221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 832aaagccucca cgcccuuact t
2183321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 833gacccuaaag acuuuccugt t
2183421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 834caggaaaguc uuuaggguct t
2183521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 835aggagcauga cuuuaaccct t
2183621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 836ggguuaaagu caugcuccut t
2183721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 837ugugauuuuc cuccuaauut t
2183821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 838aauuaggagg aaaaucacat t
2183921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 839uugugauuuu ccuccuaaut t
2184021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 840auuaggagga aaaucacaat t
2184121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 841gacuuaaccc aagaagcuct t
2184221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 842gagcuucuug gguuaaguct t
2184321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 843gcuucagaca augguuuggt t
2184421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 844ccaaaccauu gucugaagct t
2184521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 845uugcuucaga caaugguuut t
2184621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 846aaaccauugu cugaagcaat t
2184721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 847auugcuucag acaaugguut t
2184821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 848aaccauuguc ugaagcaaut t
2184921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 849uugauugcuu cagacaaugt t
2185021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 850cauugucuga agcaaucaat t
2185121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 851gacaaagugc ugaauagggt t
2185221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 852cccuauucag cacuuuguct t
2185321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 853aagaaaaagc ucaaauuuut t
2185421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 854aaaauuugag cuuuuucuut t
2185521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 855aaagaaaaag cucaaauuut t
2185621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 856aaauuugagc uuuuucuuut t
2185721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 857agaagacccu aaagacuuut t
2185821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 858aaagucuuua gggucuucut t
2185921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 859aaaaaaaagg uagaagacct t
2186021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 860ggucuucuac cuuuuuuuut t
2186121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 861gguagaagac ccuaaagact t
2186221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 862gucuuuaggg ucuucuacct t
2186321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 863aaaaaaggua gaagacccut t
2186421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 864agggucuucu accuuuuuut t
2186521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 865aaaaagguag aagacccuat t
2186621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 866uagggucuuc uaccuuuuut t
2186721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 867uuaacccaag aagcucuuct t
2186821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 868gaagagcuuc uuggguuaat t
2186921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 869auuuugguac auggaauagt t
2187021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 870cuauuccaug uaccaaaaut t
2187121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 871agugcugaau agggaggaat t
2187221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 872uuccucccua uucagcacut t
2187321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 873gaggccaggg aaauucccut t
2187421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 874agggaauuuc ccuggccuct t
2187521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 875agcucaaauu uuauauaagt t
2187621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 876cuuauauaaa auuugagcut t
2187721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 877cagggaaauu cccuuguuut t
2187821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 878aaacaaggga auuucccugt t
2187921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 879uugugcagug gaaagaaagt t
2188021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 880cuuucuuucc acugcacaat t
2188121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 881uacauggaau aguucagagt t
2188221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 882cucugaacua uuccauguat t
2188321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 883guacauggaa uaguucagat t
2188421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 884ucugaacuau uccauguact t
2188521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 885agggaaauuc ccuuguuuut t
2188621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 886aaaacaaggg aauuucccut t
2188721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 887ggaggccagg gaaauuccct t
2188821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 888gggaauuucc cuggccucct t
2188921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 889guguagacag ccauaugcat t
2189021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 890ugcauauggc ugucuacact t
2189121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 891guagacagcc auaugcagut t
2189221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 892acugcauaug gcugucuact t
2189321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 893gaagaccugu uuugccaugt t
2189421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 894cauggcaaaa caggucuuct t
2189521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 895agugggauga agaccuguut t
2189621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 896aacaggucuu caucccacut t
2189721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 897ugaagaccug uuuugccaut t
2189821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 898auggcaaaac aggucuucat t
2189921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 899ugggaugaag accuguuuut t
2190021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 900aaaacagguc uucaucccat t
2190121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 901cuuaacccaa gaagcucuut t
2190221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 902aagagcuucu uggguuaagt t
2190321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 903auugugcagu ggaaagaaat t
2190421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 904uuucuuucca cugcacaaut
t 2190521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 905cuuuauugca aggaauggct t
2190621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 906gccauuccuu gcaauaaagt t
2190721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 907gagcaugacu uuaacccagt t
2190821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 908cuggguuaaa gucaugcuct t
2190921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 909gugauuuucc uccuaauuct t
2191021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 910gaauuaggag gaaaaucact t
2191121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 911ugauugcuuc agacaauggt t
2191221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 912ccauugucug aagcaaucat t
2191321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 913aagcucaaau uuuauauaat t
2191421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 914uuauauaaaa uuugagcuut t
2191521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 915cuggacaugg aucaagcact t
2191621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 916gugcuugauc cauguccagt t
2191721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 917ucaaauuuua uauaagaaat t
2191821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 918uuucuuauau aaaauuugat t
2191921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 919ugugcagugg aaagaaaggt t
2192021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 920ccuuucuuuc cacugcacat t
2192121DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 921uugguacaug gaauaguuct t
2192221DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 922gaacuauucc auguaccaat t
2192321DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 923aagugggaug aagaccugut t
2192421DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 924acaggucuuc aucccacuut t
2192521DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 925ggaugaagac cuguuuugct t
2192621DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 926gcaaaacagg ucuucaucct t
2192721DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 927ucuggacaug gaucaagcat t
2192821DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 928ugcuugaucc auguccagat t
2192921DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 929uuugguacau ggaauaguut t
2193021DNAArtificial SequenceDescription of Combined DNA/RNA
Molecule Synthetic oligonucleotide 930aacuauucca uguaccaaat t
219311202DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 931ctcgagactt ttagggttgt acgggactgt
aacacctgct cttgaagcat atgaagatgg 60ccccaacaaa aagaaaagga gaaaggaagg
accccgtgca agttccaaaa cttcttataa 120gaggaggagt agaagttcta
gaagttaaaa ctggggttga ctcaattaca gaggtagaat 180gctttttaac
tccagaaatg ggtgacccag atgagcatct taggggtttt agtaagtcaa
240tttctatatc agatacattt gaaagtgact ccccaaataa ggacatgctt
ccttgttaca 300gtgtggccag aattccacta cccaatctaa atgaggatct
aacctgtgga aatatactaa 360tgtgggaggc tgtgacctta aaaactgagg
ttctaggggt gacaactttg atgaatgtgc 420actctaatgg tcaagcaact
catgacaatg gtgcaggaaa gccagtgcag ggcaccagct 480ttcatttttt
ttctgttggc ggggaggctt tagaattaca gggggtggtt tttaattaca
540gaacaaagta cccagatgga acaatttttc caaagaatgc aacagtgcaa
tctcaagtaa 600tgaacacaga gcacaaggcg tacctagata agaacaaagc
atatcctgtt gaatgttggg 660ttcctgatcc caccagaaat gaaaacacaa
gatattttgg gacactaaca ggaggagaaa 720atgttcctcc agttcttcat
ataacaaaca ctgccacaac agtgctgctt gatgaatttg 780gtgttgggcc
actttgcaaa ggtgacaact tgtatttgtc agctgttgat gtttgtggaa
840tgtttactaa cagatctggt tcccagcagt ggagaggact gtccagatat
tttaaggttc 900agctcagaaa aaggagggtt aaaaacccct acccaatttc
tttccttctt actgatttga 960ttaacagaag gacccctaga gttgatgggc
aacctatgta tggtatggat gctcaggtag 1020aggaggttag agtttttgag
gggacagagg aacttccagg ggacccagac atgatgagat 1080atgttgacag
atatggacag ttgcaaacaa agatgctgta atcaaaatcc tttattgtaa
1140tatgcagtac attttaataa agtataacca gctttacttt acagttgcag
tcatgcggcc 1200gc 12029322479DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 932ctcgagccgc
ctccaagctt actcagaagt agtaagggcg tggaggcttt ttaggaggcc 60agggaaattc
ccttgttttt cccttttttg cagtaatttt ttgctgcaaa aagctaaaat
120ggacaaagtg ctgaataggg aggaatccat ggagcttatg gatttattag
gccttgatag 180gtctgcatgg gggaacattc ctgtcatgag aaaagcttat
ctgaaaaaat gcaaagaact 240ccaccctgat aaaggtgggg acgaagacaa
gatgaagaga atgaattttt tatataaaaa 300aatggaacaa ggtgtaaaag
ttgctcatca gcctgatttt ggtacatgga atagttcaga 360ggttggttgt
gattttcctc ctaattctga taccctttat tgcaaggaat ggcctaactg
420tgccactaat ccttcagtgc attgcccctg tttaatgtgc atgctaaaat
taaggcatag 480aaacagaaaa tttttaagaa gcagcccact tgtgtggata
gattgctatt gctttgattg 540cttcagacaa tggtttgggt gtgacttaac
ccaagaagct cttcattgct gggagaaagt 600tcttggagac accccctaca
gggatctaaa gctttaagtg ccaacctatg gaacagatga 660atgggaatcc
tggtggaata catttaatga gaagtgggat gaagacctgt tttgccatga
720agaaatgttt gccagtgatg atgaaaacac aggatcccaa cactctaccc
cacctaaaaa 780gaaaaaaaag gtagaagacc ctaaagactt tcctgtagat
ctgcatgcat tcctcagtca 840agctgtgttt agtaatagaa ctgttgcttc
ttttgctgtg tataccacta aagaaaaagc 900tcaaatttta tataagaaac
ttatggaaaa atattctgta acttttataa gtagacatgg 960ttttgggggt
cataatattt tgtttttctt aacaccacat agacatagag tgtcagcaat
1020taataactac tgtcaaaaac tatgtacctt tagtttttta atttgtaaag
gtgtgaataa 1080ggaatacttg ttttatagtg ccctgtgtag acagccatat
gcagtagtgg aagaaagtat 1140tcaggggggc cttaaggagc atgactttaa
cccagaagaa ccagaagaaa ctaagcaggt 1200ttcatggaaa ttagttacac
agtatgcctt ggaaaccaag tgtgaggatg tttttttgct 1260tatgggcatg
tacttagact ttcaggaaaa cccacagcaa tgcaaaaaat gtgaaaaaaa
1320ggatcagcca aatcacttta accatcatga aaaacactat tataatgccc
aaatttttgc 1380agatagcaaa aatcaaaaaa gcatttgcca gcaggctgtt
gatactgtag cagccaaaca 1440aagggttgac agcatccaca tgaccagaga
agaaatgtta gttgaaaggt ttaatttctt 1500gcttgataaa atggacttaa
tttttggggc acatggcaat gctgttttag agcaatatat 1560ggctggggtg
gcctggattc attgcttgct gcctcaaatg gacactgtta tttatgactt
1620tctaaaatgc attgtattaa acattccaaa aaaaaggtac tggctattca
aggggccaat 1680agacagtggc aaaactactt tagctgcagc tttacttgat
ctctgtgggg gaaagtcatt 1740aaatgttaat atgccattag aaagattaaa
ctttgaatta ggagtgggta tagatcagtt 1800tatggttgta tttgaggatg
taaaaggcac tggtgcagag tcaagggatt taccttcagg 1860gcatggcata
agcaaccttg attgcttaag agattactta gatggaagtg taaaagttaa
1920tttagagaga aaacaccaaa acaaaagaac acaggtgttt ccacctggaa
ttgtaaccat 1980gaatgaatat tcagtgccta gaactttaca ggccagattt
gtaaggcaga tagattttag 2040accaaaggcc tacctgagaa aatcactaag
ctgctctgag tatttgctag aaaaaaggat 2100tttgcaaagt ggtatgactt
tgcttttgct tttaatctgg tttaggccag ttgctgactt 2160tgcagctgcc
attcatgaga ggattgtgca gtggaaagaa aggctggatt tagaaataag
2220catgtataca ttttctacta tgaaagctaa tgttggtatg gggagaccca
ttcttgactt 2280tcctagagag gaagattctg aagcagaaga ctctggacat
ggatcaagca ctgaatcaca 2340atcacaatgc ttttcccagg tctcagaagc
ctctggtgca gacacacagg aaaactgcac 2400ttttcacatc tgtaaaggct
ttcaatgttt caaaaaacca aagacccctc ccccaaaata 2460actgcaactg
tgcggccgc 2479933708DNAArtificial SequenceDescription of Artificial
Sequence Synthetic polynucleotide 933ctcgagcagc taacagccag
taaacaaagc acaaggggaa gtggaaagca gccaagggaa 60catgttttgc gagccagagc
tgttttggct tgtcaccagc tggccatggt tcttcgccag 120ctgtcacgta
aggcttctgt gaaagttagt aaaacctgga gtggaactaa aaaaagagct
180caaaggattt taattttttt gttagaattt ttgctggact tttgcacagg
tgaagacagt 240gtagacggga aaaaaagaca gagacacagt ggtttgactg
agcagacata cagtgctttg 300cctgaaccaa aagctacata ggtaagtaat
gttttttttt gtgttttcag gttcatgggt 360gccgcacttg cacttttggg
ggacctagtt gctactgttt ctgaggctgc tgctgccaca 420ggattttcag
tagctgaaat tgctgctgga gaggctgctg ctactataga agttgaaatt
480gcatcccttg ctactgtaga ggggattaca agtacctctg aggctatagc
tgctataggc 540cttactcctg aaacatatgc tgtaataact ggagctccgg
gggctgtagc tgggtttgct 600gcattggttc aaactgtaac tggtggtagt
gctattgctc agttgggata tagatttttt 660gctgactggg atcataaagt
ttcaacagtt gggctttttc gcggccgc 708934738DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
934ctcgagagca gccagctatg gctttacaat tatttaatcc agaagactac
tatgatattt 60tatttcctgg agtgaatgcc tttgttaaca atattcacta tttagatcct
agacattggg 120gcccgtcctt gttctccaca atctcccagg ctttttggaa
tcttgttaga gatgatttgc 180cagccttaac ctctcaggaa attcagagaa
gaacccaaaa actatttgtt gaaagtttag 240caaggttttt ggaagaaact
acttgggcaa tagttaattc accagctaac ttatataatt 300atatttcaga
ctattattct agattgtctc cagttaggcc ctctatggta aggcaagttg
360cccaaaggga gggaacctat atttcttttg gccactcata cacccaaagt
atagatgatg 420cagacagcat tcaagaagtt acccaaaggc tagatttaaa
aaccccaaat gtgcaatctg 480gtgaatttat agaaagaagt attgcaccag
gaggtgcaaa tcaaagatct gctcctcaat 540ggatgttgcc tttactttta
gggttgtacg ggactgtaac acctgctctt gaagcatatg 600aagatggccc
caacaaaaag aaaaggagaa aggaaggacc ccgtgcaagt tccaaaactt
660cttataagag gaggagtaga agttctagaa gttaaaactg gggttgactc
aattacagag 720gtagaatgct gcggccgc 73893519DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 935uguugaaugu uggguuccu 1993621DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 936uguugaaugu uggguuccut t 2193721DNAArtificial
SequenceDescription of Combined DNA/RNA Molecule Synthetic
oligonucleotide 937aggaacccaa cauucaacat t 21
* * * * *