U.S. patent application number 15/794643 was filed with the patent office on 2018-02-15 for compositions for inhibiting checkpoint gene expression and uses thereof.
The applicant listed for this patent is IDERA PHARMACEUTICALS, INC.. Invention is credited to Sudhir AGRAWAL, Wayne JIANG, Xianzhi Mao, Jessica Seitzer, Daqing Wang, Fu-Gang Zhu.
Application Number | 20180044669 15/794643 |
Document ID | / |
Family ID | 56789843 |
Filed Date | 2018-02-15 |
United States Patent
Application |
20180044669 |
Kind Code |
A1 |
AGRAWAL; Sudhir ; et
al. |
February 15, 2018 |
COMPOSITIONS FOR INHIBITING CHECKPOINT GENE EXPRESSION AND USES
THEREOF
Abstract
The present invention is directed to compounds, compositions,
and methods useful for modulating PD1, PDL1, IDO1, LAG3, TIM3,
CTLA4, IDO2, CEACAM1, OX40, and/or OX40L mRNA or protein expression
using gene silencing compounds comprising two or more single
stranded antisense oligonucleotides that are linked through their
5'-ends to allow the presence of two or more accessible
3'-ends.
Inventors: |
AGRAWAL; Sudhir;
(Shrewsbury, MA) ; JIANG; Wayne; (Waltham, MA)
; Wang; Daqing; (Bedford, MA) ; Seitzer;
Jessica; (Windham, NH) ; Zhu; Fu-Gang;
(Bedford, MA) ; Mao; Xianzhi; (Ambler,
PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
IDERA PHARMACEUTICALS, INC. |
Cambridge |
MA |
US |
|
|
Family ID: |
56789843 |
Appl. No.: |
15/794643 |
Filed: |
October 26, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15053309 |
Feb 25, 2016 |
9828601 |
|
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15794643 |
|
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62126368 |
Feb 27, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/7105 20130101;
C12N 2310/51 20130101; A61K 45/06 20130101; C12N 2310/11 20130101;
C12N 2310/314 20130101; C12N 15/11 20130101; C12N 15/1138
20130101 |
International
Class: |
C12N 15/11 20060101
C12N015/11; A61K 31/7105 20060101 A61K031/7105; C12N 15/113
20060101 C12N015/113; A61K 45/06 20060101 A61K045/06 |
Claims
1. A 3.sup.rd generation antisense (3GA) compound comprising two
oligonucleotides linked at their 5' ends, each oligonucleotide,
independently, consists of 12 to 30 nucleotides having a nucleobase
sequence comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 387, SEQ ID
NO: 388, SEQ ID NO: 389, SEQ ID NO: 390, SEQ ID NO: 391, SEQ ID NO:
392, SEQ ID NO: 393, SEQ ID NO: 394, SEQ ID NO: 395, SEQ ID NO:
396, SEQ ID NO: 397, SEQ ID NO: 398, SEQ ID NO: 399, SEQ ID NO:
400, SEQ ID NO: 401, SEQ ID NO: 402, SEQ ID NO: 403, SEQ ID NO:
404, SEQ ID NO: 405, or SEQ ID NO: 406.
2. The 3GA compound according to claim 1, wherein each
oligonucleotide, independently, consisting of 12 to 30 nucleotides
having a nucleobase sequence comprising a portion of at least 12
contiguous nucleobases complementary to an equal length portion of
SEQ ID NO: 388, SEQ ID NO: 390, SEQ ID NO: 392, SEQ ID NO: 394, SEQ
ID NO: 396, SEQ ID NO: 398, SEQ ID NO: 400, SEQ ID NO: 402, SEQ ID
NO: 404, or SEQ ID NO: 406.
3. The 3GA compound according to claim 1, wherein the nucleobase
sequence of each oligonucleotide is, independently, at least 90%
complementary over its entire length to a nucleobase sequence of
SEQ ID NO: 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397,
398, 399, 400, 401, 402, 403, 404, 405, or 406.
4. The 3GA compound according to claim 3, wherein the nucleobase
sequence of each oligonucleotide is, independently, at least 90%
complementary over its entire length to a nucleobase sequence of
SEQ ID NO: 388, 390, 392, 394, 396, 398, 400, 402, 404, or 406.
5. The 3GA compound according to claim 1, wherein each
oligonucleotide, independently, comprises a portion of at least 12
contiguous nucleobases of SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,
28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,
45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,
62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78,
79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95,
96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109,
110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122,
123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135,
136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148,
149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161,
162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174,
175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187,
188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200,
201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213,
214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226,
227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239,
240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252,
253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265,
266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278,
279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291,
292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304,
305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317,
318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330,
331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343,
344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356,
357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369,
370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382,
383, 384, 385, or 386, or combinations thereof.
6. The 3GA compound according to claim 5, wherein each
oligonucleotide, independently, comprises a portion of least 12
contiguous nucleobases of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,
27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,
44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60,
61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77,
78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94,
95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108,
109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121,
122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134,
135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147,
148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160,
161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173,
174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186,
187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199,
200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212,
213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225,
226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238,
239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251,
252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264,
265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277,
278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290,
291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303,
304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316,
317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329,
330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342,
343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355,
356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368,
369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381,
382, 383, 384, 385, or 386, and is at least 80% complimentary to
its target site with SEQ ID NO: 387, SEQ ID NO: 388, SEQ ID NO:
389, SEQ ID NO: 390, SEQ ID NO: 391, SEQ ID NO: 392, SEQ ID NO:
393, SEQ ID NO: 394, SEQ ID NO: 395, SEQ ID NO: 396, SEQ ID NO:
397, SEQ ID NO: 398, SEQ ID NO: 399, SEQ ID NO: 400, SEQ ID NO:
401, SEQ ID NO: 402, SEQ ID NO: 403, SEQ ID NO: 404, SEQ ID NO:
405, or SEQ ID NO: 406.
7. The 3GA compound according to claim 6, wherein each
oligonucleotide, independently, comprises a portion of at least 12
contiguous nucleobases of SEQ ID NOs: 9, 10, 11, 12, 13, 14, 15,
16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,
33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 55,
56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,
73, 74, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95,
96, 97, 98, 99, 100, 125, 126, 127, 128, 129, 130, 131, 132, 133,
134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146,
147, 148, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179,
180, 181, 182, 183, 184, 185, 186, 187, 188, 209, 210, 211, 212,
213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225,
226, 227, 228, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258,
259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 288,
289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301,
302, 303, 304, 305, 306, 307, 328, 329, 330, 331, 332, 333, 334,
335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 366,
367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379,
380, 381, 382, 383, 384, 385, or 386, and is at least 80%
complimentary to its target site within SEQ ID NO: 388, SEQ ID NO:
390, SEQ ID NO: 392, SEQ ID NO: 394, SEQ ID NO: 396, SEQ ID NO:
398, SEQ ID NO: 400, SEQ ID NO: 402, SEQ ID NO: 404, or SEQ ID NO:
406.
8. A composition comprising a 3GA compound according to claim 1 and
a pharmaceutically acceptable carrier.
9. The composition according to claim 8, further one or more
vaccines, antigens, antibodies, cytotoxic agents, chemotherapeutic
agents, kinase inhibitors, allergens, antibiotics, agonist,
antagonist, antisense oligonucleotides, ribozymes, RNAi molecules,
siRNA molecules, miRNA molecules, aptamers, proteins, gene therapy
vectors, DNA vaccines, adjuvants, co-stimulatory molecules or
combinations thereof.
10. A method for inhibiting PD1, PDL1, IDO1, LAG3, TIM3, CTLA4,
IDO2, CEACAM1, OX40, and/or OX40L mRNA or protein expression, the
method comprising contacting a cell with at least one 3GA compound
according to claim 1.
11. The method according to claim 10, wherein the cell is contacted
with two or more 3GA compounds targeting different regions of the
same checkpoint.
12. The method according to claim 10, wherein the cell is contacted
with two or more 3GA compounds targeting different checkpoints.
13. A method for inhibiting immune system tolerance to tumors
comprising administering to an animal at least one 3GA compound
according to claim 1 or composition according to claim 8 to reduce
PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, and/or
OX40L mRNA or protein expression.
14. A method for the treatment of a disease, disorder, or condition
associated with PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1,
OX40, or OX40L in an individual in need thereof, the method
comprising administering at least one 3GA compound according to
claim 1.
15. The method according to claim 1, wherein the disease, disorder,
or condition is a hyperproliferative disease or an autoimmune
disease.
16. The method according to claim 2, wherein the hyperproliferative
disease is cancer, carcinomas, sarcomas, lymphomas, leukemias and
associated malignancies and metastases.
17. The method according to claim 3, wherein the 3GA compound is
administered intratumorally.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. provisional
patent application Ser. No. 62/126,368, filed on Feb. 27, 2015, the
contents of which are incorporated herein by reference in its
entirety.
BACKGROUND OF THE INVENTION
Field of the Invention
[0002] The present invention relates to compounds, compositions,
and methods of use for the inhibition of checkpoint gene expression
or for diagnosing, treating and/or preventing diseases and/or
conditions that respond to the inhibition of checkpoint gene
expression.
Summary of the Related Art
[0003] The immune system is a hosts defense against foreign
antigens; however, in order to function properly a variety of
checks and balances are required to protect against self-antigens
(i.e., autoimmunity) and, at the same time, provide an appropriate
response against foreign. Immune-activating and immune-suppressive
receptors and ligands provide these regulatory checks and balances
(see Pardoll et al., The blockade of immune checkpoints in cancer
immunotherapy, Nat. Rev. Canc. 12, 252 (2012)).
[0004] Immune checkpoints refer to a group of endogenous
immune-suppressive ligands and receptors that are crucial for the
maintenance of self-tolerance and the protection of tissues from
damage when the immune system is responding to an infection. (see
Y. L. Wu, et al., Immunotherapies: The Blockade of Inhibitory
Signals, Int. J. Biol. Sci. 8, 1420 (2012)) In response to the
induction of an immune response expression of checkpoints
increases. These checkpoints act as regulatory feedback to maintain
immune homeostasis.
[0005] In patients with cancer, tumor mutations give rise to
tumor-specific antigens that can be recognized by the immune
system, particularly T-cells, leading to elimination of cancer
cells. However, to defend themselves, tumor cells can co-opt immune
checkpoint pathways to suppress the immune response in the tumor
microenvironment and evade the host immune system by inhibiting T
cells that might otherwise attack the tumor cells. (see J. F.
Grosso & M. N. Jure-Kunkel; CTLA-4 blockade in tumor models: an
overview of preclinical and translational research, Cancer Immun.
13, 5 (2013); M. E. Turnis, et al.; Combinatorial immunotherapy:
PD-1 may not be LAG-ing behind any more, OncoImmunology 1, 1172
(2012)).
[0006] Many previous cancer immunotherapies have likely been
limited by these suppressive mechanisms. Thus there is a need to
over these immunosuppressive mechanisms in order to enhance
antitumor immunotherapy applications.
BRIEF SUMMARY OF THE INVENTION
[0007] The present invention is directed to compounds,
compositions, and methods useful for modulating PD1, PDL1, IDO1,
LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, and/or OX40L mRNA or
protein expression using gene silencing compounds comprising two or
more single stranded antisense oligonucleotides that are linked
through their 5'-ends to allow the presence of two or more
accessible 3'-ends. The gene silencing compounds according to the
invention effectively inhibit or decrease PD1, PDL1, IDO1, LAG3,
TIM3, CTLA4, IDO2, CEACAM1, OX40, and/or OX40L mRNA or protein
expression.
[0008] Provided herein are methods, compounds, and compositions for
modulating expression of PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2,
CEACAM1, OX40, and/or OX40L mRNA and protein. In certain
embodiments, compounds useful for modulating expression of PD1,
PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, and/or OX40L
mRNA and protein are gene silencing compounds.
[0009] In certain embodiments, modulation can occur in a cell or
tissue. In certain embodiments the cell is a tumor cell. In certain
embodiments, the tissue is a tumor. In certain embodiments, the
cell or tissue is in an animal. In certain embodiments, the animal
is a human. In certain embodiments, PD1, PDL1, IDO1, LAG3, TIM3,
CTLA4, IDO2, CEACAM1, OX40, and/or OX40L mRNA levels are reduced.
In certain embodiments, PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2,
CEACAM1, OX40, and/or OX40L protein levels are reduced. Such
reduction can occur in a time-dependent manner or in a
dose-dependent manner.
[0010] Also provided are methods, compounds, and compositions
useful for preventing, treating, and ameliorating diseases,
disorders, and conditions. In certain embodiments, such diseases,
disorders, and conditions are hyperproliferative diseases,
disorders, and conditions. In certain embodiments such
hyperproliferative diseases, disorders, and conditions include
cancer as well as associated malignancies and metastases.
[0011] In certain embodiments, methods of treatment include
administering a PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1,
OX40, and/or OX40L gene silencing compound or composition to an
individual in need thereof. In certain embodiments, the gene
silencing compound or composition is administered
intratumorally.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0012] The invention relates to the therapeutic and prophylactic
use of gene silencing compounds, also referred to as 3.sup.rd
generation antisense (3GA) compounds, to down-regulate checkpoint
mRNA or protein expression. Such molecules are useful, for example,
in providing compositions for modulation of checkpoint gene
expression or for treating and/or preventing diseases and/or
conditions that are capable of responding to modulation of
checkpoint gene expression in patients, subjects, animals or
organisms.
[0013] The objects of the present invention, the various features
thereof, as well as the invention itself may be more fully
understood from the following description, when read together with
the accompanying drawings in which the following terms have the
ascribed meaning. Unless specific definitions are provided, the
nomenclature utilized in connection with, and the procedures and
techniques of, analytical chemistry, synthetic organic chemistry,
and medicinal and pharmaceutical chemistry described herein are
those well-known and commonly used in the art. Standard techniques
may be used for chemical synthesis, and chemical analysis. Where
permitted, all patents, applications, published applications and
other publications, GENBANK Accession Numbers and associated
sequence information obtainable through databases such as National
Center for Biotechnology Information (NCBI) and other data referred
to throughout in the disclosure herein are incorporated by
reference for the portions of the document discussed herein, as
well as in their entirety.
[0014] The term "2'-O-substituted" means substitution of the 2'
position of the pentose moiety with an -O-lower alkyl group
containing 1-6 saturated or unsaturated carbon atoms (for example,
but not limited to, 2'-O-methyl), or with an -O-aryl or allyl group
having 2-6 carbon atoms, wherein such alkyl, aryl or allyl group
may be unsubstituted or may be substituted, (for example, with
2'-O-methoxyethyl, ethoxy, methoxy, halo, hydroxyl,
trifluoromethyl, cyano, nitro, acyl, acyloxy, alkoxy, carboxyl,
carbalkoxyl, or amino groups); or with a hydroxyl, an amino or a
halo group, but not with a 2'-H group. In some embodiments the
oligonucleotides of the invention include four or five 2'-O-alky
nucleotides at their 5' terminus, and/or four or five 2'-O-alky
nucleotides at their 3' terminus.
[0015] The term "3", when used directionally, generally refers to a
region or position in a polynucleotide or oligonucleotide 3'
(toward the 3'end of the nucleotide) from another region or
position in the same polynucleotide or oligonucleotide.
[0016] The term "3' end" generally refers to the 3' terminal
nucleotide of the component oligonucleotides. "Two or more
oligonucleotides linked at their 3' ends" generally refers to a
linkage between the 3' terminal nucleotides of the oligonucleotides
which may be directly via 5', 3' or 2' hydroxyl groups, or
indirectly, via a non-nucleotide linker. Such linkages may also be
via a nucleoside, utilizing both 2' and 3' hydroxyl positions of
the nucleoside. Such linkages may also utilize a functionalized
sugar or nucleobase of a 3'terminal nucleotide.
[0017] The term "5'", when used directionally, generally refers to
a region or position in a polynucleotide or oligonucleotide 5'
(toward the 5'end of the nucleotide) from another region or
position in the same polynucleotide or oligonucleotide.
[0018] The term "5' end" generally refers to the 5' terminal
nucleotide of the component oligonucleotides. "Two or more
single-stranded antisense oligonucleotides linked at their 5' ends"
generally refers to a linkage between the 5' terminal nucleotides
of the oligonucleotides which may be directly via 5', 3' or 2'
hydroxyl groups, or indirectly, via a non-nucleotide linker. Such
linkages may also be via a nucleoside, utilizing both 2' and 3'
hydroxyl positions of the nucleoside. Such linkages may also
utilize a functionalized sugar or nucleobase of a 5'terminal
nucleotide.
[0019] The term "about" generally means that the exact number is
not critical. Thus, oligonucleotides having one or two fewer
nucleoside residues, or from one to several additional nucleoside
residues are contemplated as equivalents of each of the embodiments
described above.
[0020] The term "accessible" generally means when related to a
compound according to the invention, that the relevant portion of
the molecule is able to be recognized by the cellular components
necessary to elicit an intended response to the compound.
[0021] The term "agonist" generally refers to a substance that
binds to a receptor of a cell and induces a response. An agonist
can be a naturally occurring substance such as bacterial DNA or a
synthetic composition. A synthetic agonist often mimics the action
of a naturally occurring substance such as a ligand.
[0022] The term "antigen" generally refers to a substance that is
recognized and selectively bound by an antibody or by a T cell
antigen receptor. Antigens may include but are not limited to
peptides, proteins, lipids, carbohydrates, nucleosides,
nucleotides, nucleic acids, and combinations thereof. Antigens may
be natural or synthetic and generally induce an immune response
that is specific for that antigen.
[0023] "Antisense activity" means any detectable or measurable
activity attributable to the hybridization of a gene silencing
compound to its target nucleic acid. In certain embodiments,
antisense activity is a decrease in the amount or expression of a
target nucleic acid or protein encoded by such target nucleic
acid.
[0024] As used herein, "Gene silencing oligonucleotide (GSO)",
"Gene silencing compound", or "3.sup.rd generation antisense (3GA)"
compound are used interchangeably to refer to an oligomeric
compound comprising two or more single stranded antisense
oligonucleotides that are linked through their 5'-ends to allow the
presence of two or more accessible 3'-ends. Gene silencing
compounds are capable of undergoing hybridization to a target
nucleic acid through hydrogen bonding.
[0025] "Antisense inhibition" means reduction of target nucleic
acid levels or target protein levels in the presence of a gene
silencing compound complementary to a target nucleic acid as
compared to target nucleic acid levels or target protein levels in
the absence of the gene silencing compound.
[0026] "Antisense oligonucleotide" means a single-stranded
oligonucleotide having a nucleobase sequence that permits
hybridization to a corresponding region or segment of a target
nucleic acid.
[0027] The term "biologic instability" generally refers to a
molecule's ability to be degraded and subsequently inactivated in
vivo. For oligonucleotides, such degradation results from
exonuclease activity and/or endonuclease activity, wherein
exonuclease activity refers to cleaving nucleotides from the 3' or
5' end of an oligonucleotide, and endonuclease activity refers to
cleaving phosphodiester bonds at positions other than at the ends
of the oligonucleotide.
[0028] The term "cancer" generally refers to, without limitation,
any malignant growth or tumor caused by abnormal or uncontrolled
cell proliferation and/or division. Cancers may occur in humans
and/or mammals and may arise in any and all tissues. Treating a
patient having cancer may include administration of a compound,
pharmaceutical formulation or vaccine according to the invention
such that the abnormal or uncontrolled cell proliferation and/or
division, or metastasis is affected.
[0029] The term "carrier" generally encompasses any excipient,
diluent, filler, salt, buffer, stabilizer, solubilizer, oil, lipid,
lipid containing vesicle, microspheres, liposomal encapsulation, or
other material for use in pharmaceutical formulations. It will be
understood that the characteristics of the carrier, excipient or
diluent will depend on the route of administration for a particular
application. The preparation of pharmaceutically acceptable
formulations containing these materials is described in, for
example, Remington's Pharmaceutical Sciences, 18th Edition, ed. A.
Gennaro, Mack Publishing Co., Easton, Pa., 1990.
[0030] The term "co-administration" or "co-administered" generally
refers to the administration of at least two different substances.
Co-administration refers to simultaneous administration, as well as
temporally spaced order of up to several days apart, of at least
two different substances in any order, either in a single dose or
separate doses.
[0031] The term "in combination with" generally means administering
two or more agents (e.g., a gene silencing compound according to
the invention and another agent) such that there is an overlap of
an effect of each agent on the patient. Such administration may be
done in any order, including simultaneous administration, as well
as temporally spaced order from a few seconds up to several days
apart. In some embodiments, the administration of the agents are
spaced sufficiently close together such that a combinatorial effect
is achieved. Such combination treatment may also include more than
a single administration of the compound according to the invention
and/or independently the other agent. The administration of the
compound according to the invention and the other agent may be by
the same or different routes. In some embodiments, administration
of at least one agent is made while the other agent is still
present at a therapeutic level in the subject.
[0032] The term "complementary" is intended to mean the capacity
for pairing between nucleobases of a first nucleic acid and a
second nucleic acid.
[0033] "Contiguous nucleobases" means nucleobases immediately
adjacent to each other.
[0034] The term "individual" or "subject" or "patient" generally
refers to a mammal, such as a human.
[0035] "CEACAM1 nucleic acid" means any nucleic acid encoding
CEACAM1. For example, in certain embodiments, a CEACAM1 nucleic
acid includes a DNA sequence encoding CEACAM1, an RNA sequence
transcribed from DNA encoding CEACAM1 (including genomic DNA
comprising introns and exons), and an mRNA sequence encoding
CEACAM1. "CEACAM1 mRNA" means an mRNA encoding a CEACAM1
protein.
[0036] "CTLA4 nucleic acid" means any nucleic acid encoding CTLA4.
For example, in certain embodiments, a CTLA4 nucleic acid includes
a DNA sequence encoding CTLA4, an RNA sequence transcribed from DNA
encoding CTLA4 (including genomic DNA comprising introns and
exons), and an mRNA sequence encoding CTLA4. "CTLA4 mRNA" means an
mRNA encoding a CTLA4 protein.
[0037] "Fully complementary" or "100% complementary" means each
nucleobase of a first nucleic acid has a complementary nucleobase
in a second nucleic acid. In certain embodiments, a first nucleic
acid is an antisense compound and a target nucleic acid is a second
nucleic acid.
[0038] "Hybridization" means the annealing of complementary nucleic
acid molecules. In certain embodiments, complementary nucleic acid
molecules include an antisense compound and a target nucleic
acid.
[0039] "IDO1 nucleic acid" means any nucleic acid encoding IDO1.
For example, in certain embodiments, a IDO1 nucleic acid includes a
DNA sequence encoding IDO1, an RNA sequence transcribed from DNA
encoding IDO1 (including genomic DNA comprising introns and exons),
and an mRNA sequence encoding IDO1. "IDO1 mRNA" means an mRNA
encoding an IDO1 protein.
[0040] "IDO2 nucleic acid" means any nucleic acid encoding IDO2.
For example, in certain embodiments, a IDO2 nucleic acid includes a
DNA sequence encoding IDO2, an RNA sequence transcribed from DNA
encoding IDO2 (including genomic DNA comprising introns and exons),
and an mRNA sequence encoding IDO2. "IDO2 mRNA" means an mRNA
encoding an IDO2 protein.
[0041] "Inhibiting PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2,
CEACAM1, OX40, and/or OX40L mRNA or protein expression" means
reducing expression of PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2,
CEACAM1, OX40, and/or OX40L mRNA and/or protein levels in the
presence of a gene silencing compound according to the invention as
compared to expression of PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2,
CEACAM1, OX40, and/or OX40L mRNA and/or protein levels in the
absence of a gene silencing compound according to the
invention.
[0042] The term "kinase inhibitor" generally refers to molecules
that antagonize or inhibit phosphorylation-dependent cell signaling
and/or growth pathways in a cell. Kinase inhibitors may be
naturally occurring or synthetic and include small molecules that
have the potential to be administered as oral therapeutics. Kinase
inhibitors have the ability to rapidly and specifically inhibit the
activation of the target kinase molecules. Protein kinases are
attractive drug targets, in part because they regulate a wide
variety of signaling and growth pathways and include many different
proteins. As such, they have great potential in the treatment of
diseases involving kinase signaling, including cancer,
cardiovascular disease, inflammatory disorders, diabetes, macular
degeneration and neurological disorders. A non-limiting example of
a kinase inhibitor is sorafenib.
[0043] "LAG3 nucleic acid" means any nucleic acid encoding LAG3.
For example, in certain embodiments, a LAG3 nucleic acid includes a
DNA sequence encoding LAG3, an RNA sequence transcribed from DNA
encoding LAG3 (including genomic DNA comprising introns and exons),
and an mRNA sequence encoding LAG3. "LAG3 mRNA" means an mRNA
encoding a LAG3 protein.
[0044] The term "linear synthesis" generally refers to a synthesis
that starts at one end of an oligonucleotide and progresses
linearly to the other end. Linear synthesis permits incorporation
of either identical or non-identical (in terms of length, base
composition and/or chemical modifications incorporated) monomeric
units into an oligonucleotide.
[0045] The term "mammal" is expressly intended to include warm
blooded, vertebrate animals, including, without limitation, humans,
non-human primates, rats, mice, cats, dogs, horses, cattle, cows,
pigs, sheep and rabbits.
[0046] The term "nucleoside" generally refers to compounds
consisting of a sugar, usually ribose, deoxyribose, pentose,
arabinose or hexose, and a purine or pyrimidine base.
[0047] The term "nucleotide" generally refers to a nucleoside
comprising a phosphorous-containing group attached to the
sugar.
[0048] The term "modified nucleoside" or "nucleotide derivative"
generally is a nucleoside that includes a modified heterocyclic
base, a modified sugar moiety, or any combination thereof. In some
embodiments, the modified nucleoside or nucleotide derivative is a
non-natural pyrimidine or purine nucleoside, as herein described.
For purposes of the invention, a modified nucleoside or nucleotide
derivative, a pyrimidine or purine analog or non-naturally
occurring pyrimidine or purine can be used interchangeably and
refers to a nucleoside that includes a non-naturally occurring base
and/or non-naturally occurring sugar moiety. For purposes of the
invention, a base is considered to be non-natural if it is not
guanine, cytosine, adenine, thymine or uracil and a sugar is
considered to be non-natural if it is not .beta.-ribo-furanoside or
2'-deoxyribo-furanoside.
[0049] The term "modified oligonucleotide" as used herein describes
an oligonucleotide in which at least two of its nucleotides are
covalently linked via a synthetic linkage, i.e., a linkage other
than a phosphodiester linkage between the 5' end of one nucleotide
and the 3' end of another nucleotide in which the 5' nucleotide
phosphate has been replaced with any number of chemical groups. The
term "modified oligonucleotide" also encompasses
2'-O,4'-C-methylene-b-D-ribofuranosyl nucleic acids, arabinose
nucleic acids, substituted arabinose nucleic acids, hexose nucleic
acids, peptide nucleic acids, morpholino, and oligonucleotides
having at least one nucleotide with a modified base and/or sugar,
such as a 2'-O-substituted, a 5-methylcytosine and/or a
3'-O-substituted ribonucleotide.
[0050] The term "nucleic acid" encompasses a genomic region or an
RNA molecule transcribed therefrom. In some embodiments, the
nucleic acid is mRNA.
[0051] The term "linker" generally refers to any moiety that can be
attached to an oligonucleotide by way of covalent or non-covalent
bonding through a sugar, a base, or the backbone. The non-covalent
linkage may be, without limitation, electrostatic interactions,
hydrophobic interactions, .pi.-stacking interactions, hydrogen
bonding and combinations thereof. Non-limiting examples of such
non-covalent linkage includes Watson-Crick base pairing,
[0052] Hoogsteen base pairing, and base stacking. The linker can be
used to attach two or more nucleosides or can be attached to the 5'
and/or 3' terminal nucleotide in the oligonucleotide. Such linker
can be either a non-nucleotide linker or a nucleoside linker.
[0053] The term "non-nucleotide linker" generally refers to a
chemical moiety, other than a linkage directly between two
nucleotides that can be attached to an oligonucleotide by way of
covalent or non-covalent bonding. Preferably such non-nucleotide
linker is from about 2 angstroms to about 200 angstroms in length,
and may be either in a cis or trans orientation.
[0054] The term "internucleotide linkage" generally refer to a
chemical linkage to join two nucleosides through their sugars (e.g.
3'-3', 2'-3', 2'-5', 3'-5', 5'-5') consisting of a phosphorous atom
and a charged, or neutral group (e.g., phosphodiester,
phosphorothioate, phosphorodithioate or methylphosphonate) between
adjacent nucleosides.
[0055] The term "oligonucleotide" refers to a polynucleoside formed
from a plurality of linked nucleoside units, which may include, for
example, deoxyribonucleotides or ribonucleotides, synthetic or
natural nucleotides, phosphodiester or modified linkages, natural
bases or modified bases natural sugars or modified sugars, or
combinations of these components. The nucleoside units may be part
of viruses, bacteria, cell debris or oligonucleotide-based
compositions (for example, siRNA and microRNA). Such
oligonucleotides can also be obtained from existing nucleic acid
sources, including genomic or cDNA, but are preferably produced by
synthetic methods. In certain embodiments each nucleoside unit
includes a heterocyclic base and a pentofuranosyl, trehalose,
arabinose, 2'-deoxy-2'-substituted nucleoside,
2'-deoxy-2'-substituted arabinose, 2'-O-substituted arabinose or
hexose sugar group. The nucleoside residues can be coupled to each
other by any of the numerous known internucleoside linkages. Such
internucleoside linkages include, without limitation,
phosphodiester, phosphorothioate, phosphorodithioate,
methylphosphonate, alkylphosphonate, alkylphosphonothioate,
phosphotriester, phosphoramidate, siloxane, carbonate, carboalkoxy,
acetamidate, carbamate, morpholino, borano, thioether, bridged
phosphoramidate, bridged methylene phosphonate, bridged
phosphorothioate, and sulfone internucleoside linkages. The term
"oligonucleotide" also encompasses polynucleosides having one or
more stereospecific internucleoside linkage (e.g., (R.sub.P)- or
(S.sub.P)-phosphorothioate, alkylphosphonate, or phosphotriester
linkages). As used herein, the terms "oligonucleotide" and
"dinucleotide" are expressly intended to include polynucleosides
and dinucleosides having any such internucleoside linkage, whether
or not the linkage comprises a phosphate group. In certain
exemplary embodiments, these internucleoside linkages may be
phosphodiester, phosphorothioate or phosphorodithioate linkages, or
combinations thereof. In exemplary embodiments, the nucleotides of
the synthetic oligonucleotides are linked by at least one
phosphorothioate internucleotide linkage. The phosphorothioate
linkages may be mixed Rp and Sp enantiomers, or they may be
stereoregular or substantially stereoregular in either Rp or Sp
form (see Iyer et al. (1995) Tetrahedron Asymmetry 6:1051-1054). In
certain embodiments, one or more of the oligonucleotides within the
antisense compositions of the invention contain one or more
2'-O,4'-C-methylene-b-D-ribofuranosyl nucleic acids, wherein the
ribose is modified with a bond between the 2' and 4' carbons, which
fixes the ribose in the 3'-endo structural conformation.
[0056] "OX40 nucleic acid" means any nucleic acid encoding OX40.
For example, in certain embodiments, a OX40 nucleic acid includes a
DNA sequence encoding OX40, an RNA sequence transcribed from DNA
encoding OX40 (including genomic DNA comprising introns and exons),
and an mRNA sequence encoding OX40. "OX40 mRNA" means an mRNA
encoding an OX40 protein.
[0057] "OX40L nucleic acid" means any nucleic acid encoding OX40L.
For example, in certain embodiments, a OX40L nucleic acid includes
a DNA sequence encoding OX40L, an RNA sequence transcribed from DNA
encoding OX40L (including genomic DNA comprising introns and
exons), and an mRNA sequence encoding OX40L. "OX40L mRNA" means an
mRNA encoding an OX40L protein.
[0058] "PD1 nucleic acid" means any nucleic acid encoding PD1. For
example, in certain embodiments, a PD1 nucleic acid includes a DNA
sequence encoding PD1, an RNA sequence transcribed from DNA
encoding PD1 (including genomic DNA comprising introns and exons),
and an mRNA sequence encoding PD1. "PD1 mRNA" means an mRNA
encoding a PD1 protein.
[0059] "PDL1 nucleic acid" means any nucleic acid encoding PDL1.
For example, in certain embodiments, a PDL1 nucleic acid includes a
DNA sequence encoding PDL1, an RNA sequence transcribed from DNA
encoding PDL1 (including genomic DNA comprising introns and exons),
and an mRNA sequence encoding PDL1. "PDL1 mRNA" means an mRNA
encoding a PDL1 protein.
[0060] The term "peptide" generally refers to oligomers or polymers
of amino acids that are of sufficient length and composition to
affect a biological response, for example, antibody production or
cytokine activity whether or not the peptide is a hapten. The term
"peptide" may include modified amino acids (whether or not
naturally or non-naturally occurring), where such modifications
include, but are not limited to, phosphorylation, glycosylation,
pegylation, lipidization, and methylation.
[0061] The term "pharmaceutically acceptable" means a non-toxic
material that does not interfere with the effectiveness of a
compound according to the invention or the biological activity of a
compound according to the invention.
[0062] The term "physiologically acceptable" refers to a non-toxic
material that is compatible with a biological system such as a
cell, cell culture, tissue, or organism. Preferably, the biological
system is a living organism, such as a mammal, particularly a
human.
[0063] The term "prophylactically effective amount" generally
refers to an amount sufficient to prevent or reduce the development
of an undesired biological effect.
[0064] "Portion" means a defined number of contiguous (i.e.,
linked) nucleobases of a nucleic acid. In certain embodiments, a
portion is a defined number of contiguous nucleobases of a target
nucleic acid. In certain embodiments, a portion is a defined number
of contiguous nucleobases of an antisense compound.
[0065] "Single-stranded oligonucleotide" means an oligonucleotide
which is not hybridized to a complementary strand.
[0066] "Specifically hybridizable" refers to a gene silencing
compound having a sufficient degree of complementarity between an
antisense oligonucleotide and a target nucleic acid to induce a
desired effect, while exhibiting minimal or no effects on
non-target nucleic acids under conditions in which specific binding
is desired, i.e., under physiological conditions in the case of in
vivo assays and therapeutic treatments.
[0067] "Targeting" or "targeted" means the process of design and
selection of a gene silencing compound that will specifically
hybridize to a target nucleic acid and induce a desired effect.
[0068] "Target nucleic acid," "target RNA," "target mRNA," and
"target RNA transcript" all refer to a nucleic acid capable of
being targeted by gene silencing compounds.
[0069] "Target segment" means the sequence of nucleotides of a
target nucleic acid to which a gene silencing compound is targeted.
"5' target site" refers to the 5'-most nucleotide of a target
segment. "3' target site" refers to the 3'-most nucleotide of a
target segment.
[0070] The term "therapeutically effective amount" or
"pharmaceutically effective amount" generally refers to an amount
sufficient to affect a desired biological effect, such as a
beneficial result, including, without limitation, prevention,
diminution, amelioration or elimination of signs or symptoms of a
disease or disorder. Thus, the total amount of each active
component of the pharmaceutical composition or method is sufficient
to show a meaningful patient benefit, for example, but not limited
to, healing of chronic conditions characterized by immune
stimulation. Thus, a "pharmaceutically effective amount" will
depend upon the context in which it is being administered. A
pharmaceutically effective amount may be administered in one or
more prophylactic or therapeutic administrations. When applied to
an individual active ingredient, administered alone, the term
refers to that ingredient alone. When applied to a combination, the
term refers to combined amounts of the active ingredients that
result in the therapeutic effect, whether administered in
combination, serially or simultaneously.
[0071] "TIM3 nucleic acid" means any nucleic acid encoding TIM3.
For example, in certain embodiments, a TIM3 nucleic acid includes a
DNA sequence encoding TIM3, an RNA sequence transcribed from DNA
encoding TIM3 (including genomic DNA comprising introns and exons),
and an mRNA sequence encoding TIM3. "TIM3 mRNA" means an mRNA
encoding a TIM3 protein.
[0072] The term "treatment" generally refers to an approach
intended to obtain a beneficial or desired result, which may
include alleviation of symptoms, or delaying or ameliorating a
disease progression.
[0073] The term "gene expression" generally refers to process by
which information from a gene is used in the synthesis of a
functional gene product, which may be a protein. The process may
involve transcription, RNA splicing, translation, and
post-translational modification of a protein, and may include mRNA,
preRNA, ribosomal RNA, and other templates for protein
synthesis.
[0074] In certain embodiments provided are methods, compounds, and
compositions for inhibiting PD1, PDL1, IDO1, LAG3, TIM3, CTLA4,
IDO2, CEACAM1, OX40, or OX40L mRNA or protein expression. In
certain embodiments the compounds are antisense oligonucleotides,
double stranded or single-stranded siRNA compounds, or gene
silencing compounds.
[0075] As used herein, gene silencing compounds according to the
invention comprise two or more single-stranded antisense
oligonucleotides linked at their 5' ends, wherein the compounds
have two or more accessible 3' ends. The general structure of the
oligonucleotide-based compounds of the invention may be described
by the following formula I:
3'-Nn . . . N1N2N3N4-5'-L-5'-N8N7N6N5 . . . Nm-3' (Formula I),
wherein L is a nucleotide linker or non-nucleotide linker; N1-N8,
at each occurrence, is independently a nucleotide or nucleotide
derivative; Nm and Nn, at each occurrence, are independently a
nucleotide or nucleotide derivative; and wherein m and n are
independently numbers from 0 to about 40.
[0076] The linkage at the 5' ends of the component oligonucleotides
is independent of the other oligonucleotide linkages and may be
directly via 5', 3' or 2' hydroxyl groups, or indirectly, via a
non-nucleotide linker or a nucleoside, utilizing either the 2' or
3' hydroxyl positions of the nucleoside. Linkages may also utilize
a functionalized sugar or nucleobase of a 5' terminal
nucleotide.
[0077] In certain embodiments provided are gene silencing compounds
targeted to a mouse or human PD1 nucleic acid. In certain
embodiments, the mouse PD1 nucleic acid is the sequence set forth
in GENBANK Accession No. NM_008798 (incorporated herein as SEQ ID
NO: 387) or the human PD1 nucleic acid is the sequence set forth in
GENBANK Accession No. NM_005018 (incorporated herein as SEQ ID NO:
388).
[0078] In certain embodiments provided are gene silencing compounds
targeted to a mouse or human PDL1 nucleic acid. In certain
embodiments, the mouse PDL1 nucleic acid is the sequence set forth
in GENBANK Accession No. NM_021893 (incorporated herein as SEQ ID
NO: 389) or the human PDL1 nucleic acid is the sequence set forth
in GENBANK Accession No. NM_014143 (incorporated herein as SEQ ID
NO: 390).
[0079] In certain embodiments provided are gene silencing compounds
targeted to a mouse or human IDO1 nucleic acid. In certain
embodiments, the mouse IDO1 nucleic acid is the sequence set forth
in GENBANK Accession No. NM_008324 (incorporated herein as SEQ ID
NO: 391) or the human IDO1 nucleic acid is the sequence set forth
in GENBANK Accession No. NM_002164 (incorporated herein as SEQ ID
NO: 392).
[0080] In certain embodiments provided are gene silencing compounds
targeted to a mouse or human LAG3 nucleic acid. In certain
embodiments, the mouse LAG3 nucleic acid is the sequence set forth
in GENBANK Accession No. NM_008479 (incorporated herein as SEQ ID
NO: 393) or the human LAG3 nucleic acid is the sequence set forth
in GENBANK Accession No. NM_002286 (incorporated herein as SEQ ID
NO: 394).
[0081] In certain embodiments provided are gene silencing compounds
targeted to a mouse or human TIM3 nucleic acid. In certain
embodiments, the mouse TIM3 nucleic acid is the sequence set forth
in GENBANK Accession No. NM_134250 (incorporated herein as SEQ ID
NO: 395) or the human TIM3 nucleic acid is the sequence set forth
in GENBANK Accession No. NM_032782 (incorporated herein as SEQ ID
NO: 396).
[0082] In certain embodiments provided are gene silencing compounds
targeted to a mouse or human CTLA4 nucleic acid. In certain
embodiments, the mouse CTLA4 nucleic acid is the sequence set forth
in GENBANK Accession No. NM_009843 (incorporated herein as SEQ ID
NO: 397) or the human CTLA4 nucleic acid is the sequence set forth
in GENBANK Accession No. NM_005214 (incorporated herein as SEQ ID
NO: 398).
[0083] In certain embodiments provided are gene silencing compounds
targeted to a mouse or human IDO2 nucleic acid. In certain
embodiments, the mouse IDO2 nucleic acid is the sequence set forth
in GENBANK Accession No. NM_145949 (incorporated herein as SEQ ID
NO: 399) or the human IDO2 nucleic acid is the sequence set forth
in GENBANK Accession No. NM_194294 (incorporated herein as SEQ ID
NO: 400).
[0084] In certain embodiments provided are gene silencing compounds
targeted to a mouse or human CEACAM1 nucleic acid. In certain
embodiments, the mouse CEACAM1 nucleic acid is the sequence set
forth in GENBANK Accession No. NM_001039187 (incorporated herein as
SEQ ID NO: 401) or the human CEACAM1 nucleic acid is the sequence
set forth in GENBANK Accession No. NM_001205344 (incorporated
herein as SEQ ID NO: 402).
[0085] In certain embodiments provided are gene silencing compounds
targeted to a mouse or human OX40 nucleic acid. In certain
embodiments, the mouse OX40 nucleic acid is the sequence set forth
in GENBANK Accession No. NM_011659 (incorporated herein as SEQ ID
NO: 403) or the human OX40 nucleic acid is the sequence set forth
in GENBANK Accession No. NM_003327 (incorporated herein as SEQ ID
NO: 404).
[0086] In certain embodiments provided are gene silencing compounds
targeted to a mouse or human OX40L nucleic acid. In certain
embodiments, the mouse OX40L nucleic acid is the sequence set forth
in GENBANK Accession No. NM_009452 (incorporated herein as SEQ ID
NO: 405) or the human OX40L nucleic acid is the sequence set forth
in GENBANK Accession No. NM_003326 (incorporated herein as SEQ ID
NO: 406).
[0087] Certain embodiments provide gene silencing compounds
comprising two oligonucleotides each, independently, consisting of
12 to 30 nucleotides having a nucleobase sequence comprising a
portion of at least 12 contiguous nucleobases complementary to an
equal length portion of SEQ ID NO: 387, SEQ ID NO: 388, SEQ ID NO:
389, SEQ ID NO: 390, SEQ ID NO: 391, SEQ ID NO: 392, SEQ ID NO:
393, SEQ ID NO: 394, SEQ ID NO: 395, SEQ ID NO: 396, SEQ ID NO:
397, SEQ ID NO: 398, SEQ ID NO: 399, SEQ ID NO: 400, SEQ ID NO:
401, SEQ ID NO: 402, SEQ ID NO: 403, SEQ ID NO: 404, SEQ ID NO:
405, or SEQ ID NO: 406. Certain embodiments provide compounds
comprising two oligonucleotides each, independently, consisting of
15 to 25 nucleotides having a nucleobase sequence comprising a
portion of at least 12 contiguous nucleobases complementary to an
equal length portion of SEQ ID NO: 387, SEQ ID NO: 388, SEQ ID NO:
389, SEQ ID NO: 390, SEQ ID NO: 391, SEQ ID NO: 392, SEQ ID NO:
393, SEQ ID NO: 394, SEQ ID NO: 395, SEQ ID NO: 396, SEQ ID NO:
397, SEQ ID NO: 398, SEQ ID NO: 399, SEQ ID NO: 400, SEQ ID NO:
401, SEQ ID NO: 402, SEQ ID NO: 403, SEQ ID NO: 404, SEQ ID NO:
405, or SEQ ID NO: 406. Certain embodiments provide compounds
comprising a modified oligonucleotide consisting of 18 to 21
nucleotides having a nucleobase sequence comprising a portion of at
least 12 contiguous nucleobases complementary to an equal length
portion of SEQ ID NO: 387, SEQ ID NO: 388, SEQ ID NO: 389, SEQ ID
NO: 390, SEQ ID NO: 391, SEQ ID NO: 392, SEQ ID NO: 393, SEQ ID NO:
394, SEQ ID NO: 395, SEQ ID NO: 396, SEQ ID NO: 397, SEQ ID NO:
398, SEQ ID NO: 399, SEQ ID NO: 400, SEQ ID NO: 401, SEQ ID NO:
402, SEQ ID NO: 403, SEQ ID NO: 404, SEQ ID NO: 405, or SEQ ID NO:
406. In certain embodiments, the two oligonucleotide of the gene
silencing compound each, independently, comprise at least 9, at
least 10, at least 11, at least 12, at least 13, at least 14, at
least 15, at least 16, at least 17, at least 18, at least 19, at
least 20, or at least 21 contiguous nucleobases complementary to an
equal length portion of SEQ ID NO: 387, SEQ ID NO: 388, SEQ ID NO:
389, SEQ ID NO: 390, SEQ ID NO: 391, SEQ ID NO: 392, SEQ ID NO:
393, SEQ ID NO: 394, SEQ ID NO: 395, SEQ ID NO: 396, SEQ ID NO:
397, SEQ ID NO: 398, SEQ ID NO: 399, SEQ ID NO: 400, SEQ ID NO:
401, SEQ ID NO: 402, SEQ ID NO: 403, SEQ ID NO: 404, SEQ ID NO:
405, or SEQ ID NO: 406.
[0088] Certain embodiments provide gene silencing compounds
comprising two oligonucleotides each, independently, consisting of
12 to 30 nucleotides having a nucleobase sequence comprising a
portion of at least 12 contiguous nucleobases complementary to an
equal length portion of SEQ ID NO: 387, SEQ ID NO: 389, SEQ ID NO:
391, SEQ ID NO: 393, SEQ ID NO: 395, SEQ ID NO: 397, SEQ ID NO:
399, SEQ ID NO: 401, SEQ ID NO: 403, or SEQ ID NO: 405. Certain
embodiments provide compounds comprising two oligonucleotides each,
independently, consisting of 15 to 25 nucleotides having a
nucleobase sequence comprising a portion of at least 12 contiguous
nucleobases complementary to an equal length portion of SEQ ID NO:
387, SEQ ID NO: 389, SEQ ID NO: 391, SEQ ID NO: 393, SEQ ID NO:
395, SEQ ID NO: 397, SEQ ID NO: 399, SEQ ID NO: 401, SEQ ID NO:
403, or SEQ ID NO: 405. Certain embodiments provide compounds
comprising a modified oligonucleotide consisting of 18 to 21
nucleotides having a nucleobase sequence comprising a portion of at
least 12 contiguous nucleobases complementary to an equal length
portion of SEQ ID NO: 387, SEQ ID NO: 389, SEQ ID NO: 391, SEQ ID
NO: 393, SEQ ID NO: 395, SEQ ID NO: 397, SEQ ID NO: 399, SEQ ID NO:
401, SEQ ID NO: 403, or SEQ ID NO: 405. In certain embodiments, the
two oligonucleotide of the gene silencing compound each,
independently, comprise at least 9, at least 10, at least 11, at
least 12, at least 13, at least 14, at least 15, at least 16, at
least 17, at least 18, at least 19, at least 20, or at least 21
contiguous nucleobases complementary to an equal length portion of
SEQ ID NO: 387, SEQ ID NO: 389, SEQ ID NO: 391, SEQ ID NO: 393, SEQ
ID NO: 395, SEQ ID NO: 397, SEQ ID NO: 399, SEQ ID NO: 401, SEQ ID
NO: 403, or SEQ ID NO: 405.
[0089] Certain embodiments provide gene silencing compounds
comprising two oligonucleotides each, independently, consisting of
12 to 30 nucleotides having a nucleobase sequence comprising a
portion of at least 12 contiguous nucleobases complementary to an
equal length portion of SEQ ID NO: 388, SEQ ID NO: 390, SEQ ID NO:
392, SEQ ID NO: 394, SEQ ID NO: 396, SEQ ID NO: 398, SEQ ID NO:
400, SEQ ID NO: 402, SEQ ID NO: 404, or SEQ ID NO: 406. Certain
embodiments provide compounds comprising two oligonucleotides each,
independently, consisting of 15 to 25 nucleotides having a
nucleobase sequence comprising a portion of at least 12 contiguous
nucleobases complementary to an equal length portion of SEQ ID NO:
388, SEQ ID NO: 390, SEQ ID NO: 392, SEQ ID NO: 394, SEQ ID NO:
396, SEQ ID NO: 398, SEQ ID NO: 400, SEQ ID NO: 402, SEQ ID NO:
404, or SEQ ID NO: 406. Certain embodiments provide compounds
comprising a modified oligonucleotide consisting of 18 to 21
nucleotides having a nucleobase sequence comprising a portion of at
least 12 contiguous nucleobases complementary to an equal length
portion of SEQ ID NO: 388, SEQ ID NO: 390, SEQ ID NO: 392, SEQ ID
NO: 394, SEQ ID NO: 396, SEQ ID NO: 398, SEQ ID NO: 400, SEQ ID NO:
402, SEQ ID NO: 404, or SEQ ID NO: 406. In certain embodiments, the
two oligonucleotide of the gene silencing compound each,
independently, comprise at least 9, at least 10, at least 11, at
least 12, at least 13, at least 14, at least 15, at least 16, at
least 17, at least 18, at least 19, at least 20, or at least 21
contiguous nucleobases complementary to an equal length portion of
SEQ ID NO: 388, SEQ ID NO: 390, SEQ ID NO: 392, SEQ ID NO: 394, SEQ
ID NO: 396, SEQ ID NO: 398, SEQ ID NO: 400, SEQ ID NO: 402, SEQ ID
NO: 404, or SEQ ID NO: 406.
[0090] Certain embodiments provide gene silencing compounds
comprising two oligonucleotides each, independently, consisting of
12 to 30 nucleotides having a nucleobase sequence comprising a
portion of at least 12 contiguous nucleobases complementary to an
equal length portion of SEQ ID NO: 387. Certain embodiments provide
compounds comprising two oligonucleotides each, independently,
consisting of 15 to 25 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 387. Certain
embodiments provide compounds comprising a modified oligonucleotide
consisting of 18 to 21 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 387. In
certain embodiments, the two oligonucleotide of the gene silencing
compound each, independently, comprise at least 9, at least 10, at
least 11, at least 12, at least 13, at least 14, at least 15, at
least 16, at least 17, at least 18, at least 19, at least 20, or at
least 21 contiguous nucleobases complementary to an equal length
portion of SEQ ID NO: 387.
[0091] Certain embodiments provide gene silencing compounds
comprising two oligonucleotides each, independently, consisting of
12 to 30 nucleotides having a nucleobase sequence comprising a
portion of at least 12 contiguous nucleobases complementary to an
equal length portion of SEQ ID NO: 388. Certain embodiments provide
compounds comprising two oligonucleotides each, independently,
consisting of 15 to 25 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 388. Certain
embodiments provide compounds comprising a modified oligonucleotide
consisting of 18 to 21 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 388. In
certain embodiments, the two oligonucleotide of the gene silencing
compound each, independently, comprise at least 9, at least 10, at
least 11, at least 12, at least 13, at least 14, at least 15, at
least 16, at least 17, at least 18, at least 19, at least 20, or at
least 21 contiguous nucleobases complementary to an equal length
portion of SEQ ID NO: 388.
[0092] Certain embodiments provide gene silencing compounds
comprising two oligonucleotides each, independently, consisting of
12 to 30 nucleotides having a nucleobase sequence comprising a
portion of at least 12 contiguous nucleobases complementary to an
equal length portion of SEQ ID NO: 389. Certain embodiments provide
compounds comprising two oligonucleotides each, independently,
consisting of 15 to 25 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 389. Certain
embodiments provide compounds comprising a modified oligonucleotide
consisting of 18 to 21 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 389. In
certain embodiments, the two oligonucleotide of the gene silencing
compound each, independently, comprise at least 9, at least 10, at
least 11, at least 12, at least 13, at least 14, at least 15, at
least 16, at least 17, at least 18, at least 19, at least 20, or at
least 21 contiguous nucleobases complementary to an equal length
portion of SEQ ID NO: 389.
[0093] Certain embodiments provide gene silencing compounds
comprising two oligonucleotides each, independently, consisting of
12 to 30 nucleotides having a nucleobase sequence comprising a
portion of at least 12 contiguous nucleobases complementary to an
equal length portion of SEQ ID NO: 390. Certain embodiments provide
compounds comprising two oligonucleotides each, independently,
consisting of 15 to 25 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 390. Certain
embodiments provide compounds comprising a modified oligonucleotide
consisting of 18 to 21 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 390. In
certain embodiments, the two oligonucleotide of the gene silencing
compound each, independently, comprise at least 9, at least 10, at
least 11, at least 12, at least 13, at least 14, at least 15, at
least 16, at least 17, at least 18, at least 19, at least 20, or at
least 21 contiguous nucleobases complementary to an equal length
portion of SEQ ID NO: 390.
[0094] Certain embodiments provide gene silencing compounds
comprising two oligonucleotides each, independently, consisting of
12 to 30 nucleotides having a nucleobase sequence comprising a
portion of at least 12 contiguous nucleobases complementary to an
equal length portion of SEQ ID NO: 391. Certain embodiments provide
compounds comprising two oligonucleotides each, independently,
consisting of 15 to 25 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 391. Certain
embodiments provide compounds comprising a modified oligonucleotide
consisting of 18 to 21 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 391. In
certain embodiments, the two oligonucleotide of the gene silencing
compound each, independently, comprise at least 9, at least 10, at
least 11, at least 12, at least 13, at least 14, at least 15, at
least 16, at least 17, at least 18, at least 19, at least 20, or at
least 21 contiguous nucleobases complementary to an equal length
portion of SEQ ID NO: 391.
[0095] Certain embodiments provide gene silencing compounds
comprising two oligonucleotides each, independently, consisting of
12 to 30 nucleotides having a nucleobase sequence comprising a
portion of at least 12 contiguous nucleobases complementary to an
equal length portion of SEQ ID NO: 392. Certain embodiments provide
compounds comprising two oligonucleotides each, independently,
consisting of 15 to 25 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 392. Certain
embodiments provide compounds comprising a modified oligonucleotide
consisting of 18 to 21 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 392. In
certain embodiments, the two oligonucleotide of the gene silencing
compound each, independently, comprise at least 9, at least 10, at
least 11, at least 12, at least 13, at least 14, at least 15, at
least 16, at least 17, at least 18, at least 19, at least 20, or at
least 21 contiguous nucleobases complementary to an equal length
portion of SEQ ID NO: 392.
[0096] Certain embodiments provide gene silencing compounds
comprising two oligonucleotides each, independently, consisting of
12 to 30 nucleotides having a nucleobase sequence comprising a
portion of at least 12 contiguous nucleobases complementary to an
equal length portion of SEQ ID NO: 393. Certain embodiments provide
compounds comprising two oligonucleotides each, independently,
consisting of 15 to 25 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 393. Certain
embodiments provide compounds comprising a modified oligonucleotide
consisting of 18 to 21 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 393. In
certain embodiments, the two oligonucleotide of the gene silencing
compound each, independently, comprise at least 9, at least 10, at
least 11, at least 12, at least 13, at least 14, at least 15, at
least 16, at least 17, at least 18, at least 19, at least 20, or at
least 21 contiguous nucleobases complementary to an equal length
portion of SEQ ID NO: 393.
[0097] Certain embodiments provide gene silencing compounds
comprising two oligonucleotides each, independently, consisting of
12 to 30 nucleotides having a nucleobase sequence comprising a
portion of at least 12 contiguous nucleobases complementary to an
equal length portion of SEQ ID NO: 394. Certain embodiments provide
compounds comprising two oligonucleotides each, independently,
consisting of 15 to 25 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 394. Certain
embodiments provide compounds comprising a modified oligonucleotide
consisting of 18 to 21 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 394. In
certain embodiments, the two oligonucleotide of the gene silencing
compound each, independently, comprise at least 9, at least 10, at
least 11, at least 12, at least 13, at least 14, at least 15, at
least 16, at least 17, at least 18, at least 19, at least 20, or at
least 21 contiguous nucleobases complementary to an equal length
portion of SEQ ID NO: 394.
[0098] Certain embodiments provide gene silencing compounds
comprising two oligonucleotides each, independently, consisting of
12 to 30 nucleotides having a nucleobase sequence comprising a
portion of at least 12 contiguous nucleobases complementary to an
equal length portion of SEQ ID NO: 395. Certain embodiments provide
compounds comprising two oligonucleotides each, independently,
consisting of 15 to 25 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 395. Certain
embodiments provide compounds comprising a modified oligonucleotide
consisting of 18 to 21 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 395. In
certain embodiments, the two oligonucleotide of the gene silencing
compound each, independently, comprise at least 9, at least 10, at
least 11, at least 12, at least 13, at least 14, at least 15, at
least 16, at least 17, at least 18, at least 19, at least 20, or at
least 21 contiguous nucleobases complementary to an equal length
portion of SEQ ID NO: 395.
[0099] Certain embodiments provide gene silencing compounds
comprising two oligonucleotides each, independently, consisting of
12 to 30 nucleotides having a nucleobase sequence comprising a
portion of at least 12 contiguous nucleobases complementary to an
equal length portion of SEQ ID NO: 396. Certain embodiments provide
compounds comprising two oligonucleotides each, independently,
consisting of 15 to 25 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 396. Certain
embodiments provide compounds comprising a modified oligonucleotide
consisting of 18 to 21 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 396. In
certain embodiments, the two oligonucleotide of the gene silencing
compound each, independently, comprise at least 9, at least 10, at
least 11, at least 12, at least 13, at least 14, at least 15, at
least 16, at least 17, at least 18, at least 19, at least 20, or at
least 21 contiguous nucleobases complementary to an equal length
portion of SEQ ID NO: 396.
[0100] Certain embodiments provide gene silencing compounds
comprising two oligonucleotides each, independently, consisting of
12 to 30 nucleotides having a nucleobase sequence comprising a
portion of at least 12 contiguous nucleobases complementary to an
equal length portion of SEQ ID NO: 397. Certain embodiments provide
compounds comprising two oligonucleotides each, independently,
consisting of 15 to 25 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 397. Certain
embodiments provide compounds comprising a modified oligonucleotide
consisting of 18 to 21 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 397. In
certain embodiments, the two oligonucleotide of the gene silencing
compound each, independently, comprise at least 9, at least 10, at
least 11, at least 12, at least 13, at least 14, at least 15, at
least 16, at least 17, at least 18, at least 19, at least 20, or at
least 21 contiguous nucleobases complementary to an equal length
portion of SEQ ID NO: 397.
[0101] Certain embodiments provide gene silencing compounds
comprising two oligonucleotides each, independently, consisting of
12 to 30 nucleotides having a nucleobase sequence comprising a
portion of at least 12 contiguous nucleobases complementary to an
equal length portion of SEQ ID NO: 398. Certain embodiments provide
compounds comprising two oligonucleotides each, independently,
consisting of 15 to 25 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 398. Certain
embodiments provide compounds comprising a modified oligonucleotide
consisting of 18 to 21 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 398. In
certain embodiments, the two oligonucleotide of the gene silencing
compound each, independently, comprise at least 9, at least 10, at
least 11, at least 12, at least 13, at least 14, at least 15, at
least 16, at least 17, at least 18, at least 19, at least 20, or at
least 21 contiguous nucleobases complementary to an equal length
portion of SEQ ID NO: 398.
[0102] Certain embodiments provide gene silencing compounds
comprising two oligonucleotides each, independently, consisting of
12 to 30 nucleotides having a nucleobase sequence comprising a
portion of at least 12 contiguous nucleobases complementary to an
equal length portion of SEQ ID NO: 399. Certain embodiments provide
compounds comprising two oligonucleotides each, independently,
consisting of 15 to 25 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 399. Certain
embodiments provide compounds comprising a modified oligonucleotide
consisting of 18 to 21 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 399. In
certain embodiments, the two oligonucleotide of the gene silencing
compound each, independently, comprise at least 9, at least 10, at
least 11, at least 12, at least 13, at least 14, at least 15, at
least 16, at least 17, at least 18, at least 19, at least 20, or at
least 21 contiguous nucleobases complementary to an equal length
portion of SEQ ID NO: 399.
[0103] Certain embodiments provide gene silencing compounds
comprising two oligonucleotides each, independently, consisting of
12 to 30 nucleotides having a nucleobase sequence comprising a
portion of at least 12 contiguous nucleobases complementary to an
equal length portion of SEQ ID NO: 400. Certain embodiments provide
compounds comprising two oligonucleotides each, independently,
consisting of 15 to 25 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 400. Certain
embodiments provide compounds comprising a modified oligonucleotide
consisting of 18 to 21 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 400. In
certain embodiments, the two oligonucleotide of the gene silencing
compound each, independently, comprise at least 9, at least 10, at
least 11, at least 12, at least 13, at least 14, at least 15, at
least 16, at least 17, at least 18, at least 19, at least 20, or at
least 21 contiguous nucleobases complementary to an equal length
portion of SEQ ID NO: 400.
[0104] Certain embodiments provide gene silencing compounds
comprising two oligonucleotides each, independently, consisting of
12 to 30 nucleotides having a nucleobase sequence comprising a
portion of at least 12 contiguous nucleobases complementary to an
equal length portion of SEQ ID NO: 401. Certain embodiments provide
compounds comprising two oligonucleotides each, independently,
consisting of 15 to 25 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 401. Certain
embodiments provide compounds comprising a modified oligonucleotide
consisting of 18 to 21 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 401. In
certain embodiments, the two oligonucleotide of the gene silencing
compound each, independently, comprise at least 9, at least 10, at
least 11, at least 12, at least 13, at least 14, at least 15, at
least 16, at least 17, at least 18, at least 19, at least 20, or at
least 21 contiguous nucleobases complementary to an equal length
portion of SEQ ID NO: 401.
[0105] Certain embodiments provide gene silencing compounds
comprising two oligonucleotides each, independently, consisting of
12 to 30 nucleotides having a nucleobase sequence comprising a
portion of at least 12 contiguous nucleobases complementary to an
equal length portion of SEQ ID NO: 402. Certain embodiments provide
compounds comprising two oligonucleotides each, independently,
consisting of 15 to 25 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 402. Certain
embodiments provide compounds comprising a modified oligonucleotide
consisting of 18 to 21 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 402. In
certain embodiments, the two oligonucleotide of the gene silencing
compound each, independently, comprise at least 9, at least 10, at
least 11, at least 12, at least 13, at least 14, at least 15, at
least 16, at least 17, at least 18, at least 19, at least 20, or at
least 21 contiguous nucleobases complementary to an equal length
portion of SEQ ID NO: 402.
[0106] Certain embodiments provide gene silencing compounds
comprising two oligonucleotides each, independently, consisting of
12 to 30 nucleotides having a nucleobase sequence comprising a
portion of at least 12 contiguous nucleobases complementary to an
equal length portion of SEQ ID NO: 403. Certain embodiments provide
compounds comprising two oligonucleotides each, independently,
consisting of 15 to 25 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 403. Certain
embodiments provide compounds comprising a modified oligonucleotide
consisting of 18 to 21 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 403. In
certain embodiments, the two oligonucleotide of the gene silencing
compound each, independently, comprise at least 9, at least 10, at
least 11, at least 12, at least 13, at least 14, at least 15, at
least 16, at least 17, at least 18, at least 19, at least 20, or at
least 21 contiguous nucleobases complementary to an equal length
portion of SEQ ID NO: 403.
[0107] Certain embodiments provide gene silencing compounds
comprising two oligonucleotides each, independently, consisting of
12 to 30 nucleotides having a nucleobase sequence comprising a
portion of at least 12 contiguous nucleobases complementary to an
equal length portion of SEQ ID NO: 404. Certain embodiments provide
compounds comprising two oligonucleotides each, independently,
consisting of 15 to 25 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 404. Certain
embodiments provide compounds comprising a modified oligonucleotide
consisting of 18 to 21 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 404. In
certain embodiments, the two oligonucleotide of the gene silencing
compound each, independently, comprise at least 9, at least 10, at
least 11, at least 12, at least 13, at least 14, at least 15, at
least 16, at least 17, at least 18, at least 19, at least 20, or at
least 21 contiguous nucleobases complementary to an equal length
portion of SEQ ID NO: 404.
[0108] Certain embodiments provide gene silencing compounds
comprising two oligonucleotides each, independently, consisting of
12 to 30 nucleotides having a nucleobase sequence comprising a
portion of at least 12 contiguous nucleobases complementary to an
equal length portion of SEQ ID NO: 405. Certain embodiments provide
compounds comprising two oligonucleotides each, independently,
consisting of 15 to 25 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 405. Certain
embodiments provide compounds comprising a modified oligonucleotide
consisting of 18 to 21 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 405. In
certain embodiments, the two oligonucleotide of the gene silencing
compound each, independently, comprise at least 9, at least 10, at
least 11, at least 12, at least 13, at least 14, at least 15, at
least 16, at least 17, at least 18, at least 19, at least 20, or at
least 21 contiguous nucleobases complementary to an equal length
portion of SEQ ID NO: 405.
[0109] Certain embodiments provide gene silencing compounds
comprising two oligonucleotides each, independently, consisting of
12 to 30 nucleotides having a nucleobase sequence comprising a
portion of at least 12 contiguous nucleobases complementary to an
equal length portion of SEQ ID NO: 406. Certain embodiments provide
compounds comprising two oligonucleotides each, independently,
consisting of 15 to 25 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 406. Certain
embodiments provide compounds comprising a modified oligonucleotide
consisting of 18 to 21 nucleotides having a nucleobase sequence
comprising a portion of at least 12 contiguous nucleobases
complementary to an equal length portion of SEQ ID NO: 406. In
certain embodiments, the two oligonucleotide of the gene silencing
compound each, independently, comprise at least 9, at least 10, at
least 11, at least 12, at least 13, at least 14, at least 15, at
least 16, at least 17, at least 18, at least 19, at least 20, or at
least 21 contiguous nucleobases complementary to an equal length
portion of SEQ ID NO: 406.
[0110] In certain embodiments, the nucleobase sequence of the
oligonucleotides of the gene silencing compound are, independently,
at least 90% complementary over its entire length to a nucleobase
sequence of SEQ ID NO: 387, 388, 389, 390, 391, 392, 393, 394, 395,
396, 397, 398, 399, 400, 401, 402, 403, 404, 405, or 406. In
certain embodiments, the nucleobase sequence of the
oligonucleotides of the gene silencing compound are, independently,
at least 95% complementary over its entire length to a nucleobase
sequence of SEQ ID NO: 387, 388, 389, 390, 391, 392, 393, 394, 395,
396, 397, 398, 399, 400, 401, 402, 403, 404, 405, or 406. In
certain embodiments, the oligonucleotides of the gene silencing
compound are at least 99% complementary over its entire length to
SEQ ID NO: 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397,
398, 399, 400, 401, 402, 403, 404, 405, or 406. In certain
embodiments, the nucleobase sequence of the oligonucleotides of the
gene silencing compound are 100% complementary over its entire
length to a nucleobase sequence of SEQ ID NO: 387, 388, 389, 390,
391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403,
404, 405, or 406.
[0111] In certain embodiments, the oligonucleotides of the gene
silencing compound are, independently, 12 to 30 nucleotides in
length. In other words, the oligonucleotides are from 12 to 30
linked nucleobases. In other embodiments, the oligonucleotides,
independently, consist of 15 to 28, 18 to 24, 19 to 22, or 20
linked nucleobases. In certain such embodiments, the
oligonucleotides, independently, consist of 8, 9, 10, 11, 12, 13,
14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30
linked nucleobases in length, or a range defined by any two of the
above values.
[0112] In certain embodiments, a target region is a structurally
defined region of the target nucleic acid. For example, a target
region may encompass a 3' UTR, a 5' UTR, an exon, an intron, an
exon/intron junction, a coding region, a translation initiation
region, translation termination region, or other defined nucleic
acid region. The structurally defined regions for PD1, PDL1, IDO1,
LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, or OX40L can be obtained by
accession number from sequence databases such as NCB' and such
information is incorporated herein by reference. In certain
embodiments, a target region may encompass the sequence from a 5'
target site of one target segment within the target region to a 3'
target site of another target segment within the same target
region.
[0113] Certain embodiments provide a composition comprising a 3GA
compound as described herein, or a salt thereof, and a
pharmaceutically acceptable carrier or diluent. Certain embodiments
provide a composition comprising two or more 3GA compounds as
described herein, or a salt thereof, and a pharmaceutically
acceptable carrier or diluent. The two or more 3GA compounds can
inhibit the mRNA or protein expression of the same target or can
inhibit the mRNA or protein expression of different targets.
[0114] In certain embodiments, the 3GA compounds according to the
invention comprise two identical or different sequences linked at
their 5'-5' ends via a phosphodiester, phosphorothioate or
non-nucleoside linker. 3GA compounds according to the invention
that comprise identical sequences are able to bind to a specific
mRNA via Watson-Crick hydrogen bonding interactions and inhibit
mRNA and protein expression. Gene silencing compounds according to
the invention that comprise different sequences are able to bind to
two or more different regions of one or more mRNA target and
inhibit mRNA and protein expression. Such compounds are comprised
of heteronucleotide sequences complementary to target mRNA and form
stable duplex structures through Watson-Crick hydrogen bonding.
[0115] In certain embodiments, gene silencing compounds according
to the invention are useful in treating and/or preventing diseases
wherein inhibiting PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2,
CEACAM1, OX40, or OX40L expression would be beneficial. Gene
silencing compounds according to the invention include, but are not
limited to, antisense oligonucleotides comprising naturally
occurring nucleotides, modified nucleotides, modified
oligonucleotides and/or backbone modified oligonucleotides.
[0116] The oligonucleotides of the 3GA compounds are linked through
their 5'-ends to allow the presence of two or more accessible
3'-ends. In certain embodiments, the oligonucleotides are linked
through one or more of the non-nucleotide linkers listed in Table
1. In certain embodiments, a single linker listed in Table 1 is
used to link the oligonucleotides of the gene silencing compounds.
In certain embodiments, the linker is small molecule linker such as
glycerol or a glycerol homolog of the formula
HO--(CH.sub.2).sub.o--CH(OH)--(CH.sub.2).sub.p--OH, wherein o and p
independently are integers from 1 to about 6, from 1 to about 4 or
from 1 to about 3. In some other embodiments, the small molecule
linker is a derivative of 1,3-diamino-2-hydroxypropane. Some such
derivatives have the formula
HO--(CH.sub.2).sub.m--C(O)NH--CH.sub.2--CH(OH)--CH.sub.2--NHC(O)--(CH.sub-
.2).sub.m--OH, wherein m is an integer from 0 to about 10, from 0
to about 6, from 2 to about 6 or from 2 to about 4. Representative
non-nucleotide linkers are set forth in Table 1.
TABLE-US-00001 TABLE 1 Representative Non-Nucleotide Linkers
##STR00001## Glycerol (1,2,3-Propanetriol) ##STR00002##
1,2,4-Butanetriol ##STR00003## 2-(hydroxymethyl)-1,3-propanediol
##STR00004## 2-(hydroxymethyl)1,4-butanediol ##STR00005##
1,3,5-Pentanetriol ##STR00006## 1,1,1-Tris(hydroxymethyl)ethane
##STR00007## 1,1,1-Tris(hydroxymethyl)nitromethane ##STR00008##
1,1,1-Tris(hydroxymethyl)propane ##STR00009## 1,2,6-Hexanetriol
##STR00010## 3-Methyl-1,3,5-pentanetriol ##STR00011##
1,2,3-Heptanetriol ##STR00012##
2-Amino-2-(hydroxymethyl)-1,3-propanediol ##STR00013##
N-[Tris(hydroxymethyl)methyl]acrylamide ##STR00014##
cis-1,3,5-Cyclohexanetriol ##STR00015##
cis-1,3,5-Tri(hydroxymethyl)cyclohexane ##STR00016##
1,3,5-Trihydroxyl-benzene ##STR00017## 3,5,-Di(hydroxymethyl)phenol
##STR00018## 1,3,5,-Tri(hydroxymethyl)benzene ##STR00019##
1,3-Di(hydroxyethoxy)-2-hydroxyl-propane ##STR00020##
1,3-Di(hydroxypropoxy)-2-hydroxyl-propane ##STR00021##
2-Deoxy-D-ribose ##STR00022## 1,2,4,-Trihydroxyl-benzene
##STR00023## D-Galactoal ##STR00024## 1,6-anhydro-.beta.-D-Glucose
##STR00025## 1,3,5-Tris(2-hydroxyethyl)-Cyanuric acid ##STR00026##
Gallic acid ##STR00027## 3,5,7-Trihydroxyflavone ##STR00028##
4,6-Nitropyrogallol ##STR00029## Ethylene glycol ##STR00030##
1,3-Propanediol ##STR00031## 1,2-Propanediol ##STR00032##
1,4-Butanediol ##STR00033## 1,3-Butanediol ##STR00034##
2,3-Butanediol ##STR00035## 1,4-Butanediol ##STR00036##
1,5-Pentanediol ##STR00037## 2,4-Pentanediol ##STR00038##
1,6-Hexanediol ##STR00039## 1,2-Hexanediol ##STR00040##
1,5-Hexanediol ##STR00041## 2,5-Hexanediol ##STR00042##
1,7-Heptanediol ##STR00043## 1,8-Octanediol ##STR00044##
1,2-Octanediol ##STR00045## 1,9-Nonanediol ##STR00046##
1,12-Dodecanediol ##STR00047## Triethylene glycol ##STR00048##
Tetraethylene glycol ##STR00049## Hexaethylene glycol ##STR00050##
2-(1-Aminopropyl)-1,3-propanediol ##STR00051##
1,2-Dideoxyribose
[0117] In some embodiments, the small molecule linker is glycerol
or a glycerol homolog of the formula
HO--(CH.sub.2).sub.o--CH(OH)--(CH.sub.2).sub.p--OH, wherein o and p
independently are integers from 1 to about 6, from 1 to about 4 or
from 1 to about 3. In some other embodiments, the small molecule
linker is a derivative of 1,3-diamino-2-hydroxypropane. Some such
derivatives have the formula
HO--(CH.sub.2).sub.m--C(O)NH--CH.sub.2--CH(OH)--CH.sub.2--NHC(O)--(CH.sub-
.2).sub.m--OH, wherein m is an integer from 0 to about 10, from 0
to about 6, from 2 to about 6 or from 2 to about 4.
[0118] In certain embodiments, the two or more oligonucleotides of
the gene silencing compounds of the invention can be linked as
shown in Table 2.
TABLE-US-00002 TABLE 2 Oligoribonucleotide Formulas II-V Formula II
##STR00052## Formula III ##STR00053## Formula IV ##STR00054##
Formula V ##STR00055##
[0119] In certain embodiments of Formulas II and/or V, L is a
linker or a nucleotide linkage and Domain A and/or Domain B are
antisense oligonucleotides that are designed to selectively
hybridize to the same target RNA sequence or different target RNA
sequences.
[0120] In certain embodiments of Formulas II, III, IV or V, L is a
linker and Domain A and/or Domain B and/or Domain C and/or Domain D
are antisense oligonucleotides that are designed to selectively
hybridize to the same target RNA sequence or different target RNA
sequences. For example, in one embodiment, Domain A and/or Domain B
and/or Domain C of Formulas II and/or III are antisense
oligonucleotides that are designed to selectively hybridize to the
same target RNA sequence. In this embodiment, Domain A and/or
Domain B and/or Domain C can be designed to hybridize to the same
region on the target RNA sequence or to different regions of the
same target RNA sequence.
[0121] In a further embodiment of this aspect of the invention,
Domain A, Domain B, Domain C, and Domain D are independently RNA or
DNA-based oligonucleotides. In certain aspects of this embodiment,
the oligonucleotides comprise mixed backbone oligonucleotides.
[0122] In another embodiment, one or more of Domain A and/or Domain
B and/or Domain C and/or Domain D is an antisense oligonucleotide
that is designed to selectively hybridize to one target RNA
sequence and one or more of the remaining Domain A and/or Domain B
and/or Domain C and/or Domain D is an antisense oligonucleotide
that is designed to selectively hybridized to a different target
RNA sequence.
[0123] In another embodiment, one or more of Domain A and/or Domain
B and/or Domain C and/or Domain D is an RNA-based oligonucleotide
hybridized to a complimentary RNA-based oligonucleotide such that
the domain comprises an siRNA molecule.
[0124] These gene silencing compounds of the invention can be
prepared by the art recognized methods such as phosphoramidate or
H-phosphonate chemistry which can be carried out manually or by an
automated synthesizer. The synthetic antisense oligonucleotides of
the invention may also be modified in a number of ways without
compromising their ability to hybridize to mRNA. Such modifications
may include at least one internucleotide linkage of the
oligonucleotide being an alkylphosphonate, phosphorothioate,
phosphorodithioate, methylphosphonate, phosphate ester,
alkylphosphonothioate, phosphoramidate, carbamate, carbonate,
phosphate hydroxyl, acetamidate or carboxymethyl ester or a
combination of these and other internucleotide linkages between the
5' end of one nucleotide and the 3' end of another nucleotide in
which the 5' nucleotide phosphodiester linkage has been replaced
with any number of chemical groups.
[0125] The synthetic antisense oligonucleotides of the invention
may comprise combinations of internucleotide linkages. For example,
U.S. Pat. No. 5,149,797 describes traditional chimeric
oligonucleotides having a phosphorothioate core region interposed
between methylphosphonate or phosphoramidate flanking regions.
Additionally, U.S. Pat. No. 5,652,356 discloses "inverted" chimeric
oligonucleotides comprising one or more nonionic oligonucleotide
region (e.g. alkylphosphonate and/or phosphoramidate and/or
phosphotriester internucleoside linkage) flanked by one or more
region of oligonucleotide phosphorothioate. Various synthetic
antisense oligonucleotides with modified internucleotide linkages
can be prepared according to standard methods. In certain
embodiments, the phosphorothioate linkages may be mixed Rp and Sp
enantiomers, or they may be made stereoregular or substantially
stereoregular in either Rp or Sp form.
[0126] Other modifications of gene silencing compounds of the
invention include those that are internal or at the end(s) of the
oligonucleotide molecule and include additions to the molecule of
the internucleoside phosphate linkages, such as cholesterol,
cholesteryl, or diamine compounds with varying numbers of carbon
residues between the amino groups and terminal ribose, deoxyribose
and phosphate modifications which cleave, or crosslink to the
opposite chains or to associated enzymes or other proteins which
bind to the genome. Examples of such modified oligonucleotides
include oligonucleotides with a modified base and/or sugar such as
2'-O,4'-C-methylene-b-D-ribofuranosyl, or arabinose instead of
ribose, or a 3', 5'-substituted oligonucleotide having a sugar
which, at both its 3' and 5' positions, is attached to a chemical
group other than a hydroxyl group (at its 3' position) and other
than a phosphate group (at its 5' position).
[0127] Other examples of modifications to sugars of the
oligonucleotide-based compounds of the invention include
modifications to the 2' position of the ribose moiety which include
but are not limited to 2'-O-substituted with an -O-alkyl group
containing 1-6 saturated or unsaturated carbon atoms, or with an
-O-aryl, or -O-allyl group having 2-6 carbon atoms wherein such
-O-alkyl, -0-aryl or -O-allyl group may be unsubstituted or may be
substituted, for example with halo, hydroxyl, trifluoromethyl,
cyano, nitro, acyl, acyloxy, alkoxy, carboxy, carbalkoxyl or amino
groups. None of these substitutions are intended to exclude the
presence of other residues having native 2'-hydroxyl group in the
case of ribose or 2' H- in the case of deoxyribose.
[0128] The gene silencing compounds according to the invention can
comprise one or more ribonucleotides. For example, U.S. Pat No.
5,652,355 discloses traditional hybrid oligonucleotides having
regions of 2'-O-substituted ribonucleotides flanking a DNA core
region. U.S. Pat. No. 5,652,356 discloses an "inverted" hybrid
oligonucleotide that includes an oligonucleotide comprising a
2'-O-substituted (or 2' OH, unsubstituted) RNA region which is in
between two oligodeoxyribonucleotide regions, a structure that
"inverted relative to the "traditional" hybrid oligonucleotides.
Non-limiting examples of particularly useful oligonucleotides of
the invention have 2'-O-alkylated ribonucleotides at their 3', 5',
or 3' and 5' termini, with at least four, and in some exemplary
embodiments five, contiguous nucleotides being so modified.
Non-limiting examples of 2'-O-alkylated groups include 2'-O-methyl,
2'-O-ethyl, 2'-O-propyl, 2'-O-butyls and 2'-O-methoxy-ethyl.
[0129] The oligonucleotide-based compounds of the invention may
conveniently be synthesized using an automated synthesizer and
phosphoramidite approach further described in Example 1. In some
embodiments, the oligonucleotide-based compounds of the invention
are synthesized by a linear synthesis approach.
[0130] An alternative mode of synthesis is "parallel synthesis", in
which synthesis proceeds outward from a central linker moiety. A
solid support attached linker can be used for parallel synthesis,
as is described in U.S. Pat. No. 5,912,332. Alternatively, a
universal solid support (such as phosphate attached controlled pore
glass) support can be used.
[0131] Parallel synthesis of the oligonucleotide-based compounds of
the invention has several advantages over linear synthesis: (1)
parallel synthesis permits the incorporation of identical monomeric
units; (2) unlike in linear synthesis, both (or all) the monomeric
units are synthesized at the same time, thereby the number of
synthetic steps and the time required for the synthesis is the same
as that of a monomeric unit; and (3) the reduction in synthetic
steps improves purity and yield of the final immune modulatory
oligoribonucleotide product.
[0132] At the end of the synthesis by either linear synthesis or
parallel synthesis protocols, the oligonucleotide-based compounds
of the invention may conveniently be deprotected with concentrated
ammonia solution or as recommended by the phosphoramidite supplier,
if a modified nucleoside is incorporated. The product
oligonucleotide-based compounds is preferably purified by reversed
phase HPLC, detritylated, desalted and dialyzed.
[0133] In certain embodiments, the oligonucleotides of the gene
silencing compound according to the invention are selected from the
non-limiting list of the oligonucleotides shown in Table 3 below.
The oligonucleotides shown in Table 3 have phosphorothioate (PS)
linkages, but may also include phosphodiester linkages. Those
skilled in the art will recognize, however, that other linkages,
based on phosphodiester or non-phosphodiester moieties may be
included.
TABLE-US-00003 TABLE 3 Oligo #/ SEQ ID Target NO: Target Species
Site Sequence 5' .fwdarw. 3' 1 PD1 Mouse 58 GCCGGACCCACATGCCCAG 2
PD1 Mouse 65 GGTACCTGCCGGACCCACA 3 PD1 Mouse 115
GCCACCCTGATTGCCAGCT 4 PD1 Mouse 198 GGTGGCATTTGCTCCCTCT 5 PD1 Mouse
755 GGTGTCTTCTCTCGTCCCT 6 PD1 Mouse 848 GCTGAGCCCCTACGTCCCA 7 PD1
Mouse 1161 CCCCAGCTCTGCACCTTGT 8 PD1 Mouse 1589 CTAGCTCTGCTGGTTCCCT
9 PD1 Human 69 GCGCCTGTGGGATCTGCAT 10 PD1 Human 108
GCCAGCCCAGTTGTAGCAC 11 PD1 Human 285 GCTTGTCCGTCTGGTTGCT 12 PD1
Human 495 CCCTTCTCTCTGTCACCCT 13 PD1 Human 496 GCCCTTCTCTCTGTCACCC
14 PD1 Human 497 TGCCCTTCTCTCTGTCACC 15 PD1 Human 616
GCCAGGACCCAGACTAGCA 16 PD1 Human 620 GACGGCCAGGACCCAGACT 17 PD1
Human 895 CCATCCTCAGGCCTCAGTG 18 PD1 Human 897 GTCCATCCTCAGGCCTCAG
19 PD1 Human 899 GTGTCCATCCTCAGGCCTC 20 PD1 Human 901
CAGTGTCCATCCTCAGGCC 21 PD1 Human 1003 GCACCCTGCCTGCTTCTCC 22 PD1
Human 1005 CTGCACCCTGCCTGCTTCT 23 PD1 Human 1137
GTGACACCTGCTGCCTGGG 24 PD1 Human 1161 ATCTGGCCCTCCCTGTAGG 25 PD1
Human 1163 GCATCTGGCCCTCCCTGTA 26 PD1 Human 1165
CTGCATCTGGCCCTCCCTG 27 PD1 Human 1167 GACTGCATCTGGCCCTCCC 28 PD1
Human 1169 GTGACTGCATCTGGCCCTC 29 PD1 Human 1412
CTCCTGTGCCCAGTCTTGG 30 PD1 Human 1512 CCCACCACAGCCAGGAGCT 31 PD1
Human 1513 GCCCACCACAGCCAGGAGC 32 PD1 Human 1563
GCCTGAGGTGCTGCCTGGG 33 PD1 Human 1591 CTGCCTCAGCTTCCCTGCC 34 PD1
Human 1592 ACTGCCTCAGCTTCCCTGC 35 PD1 Human 1615
CCTCCAGCTCTGCCTGCCC 36 PD1 Human 1616 GCCTCCAGCTCTGCCTGCC 37 PD1
Human 1720 GCCCTCCTGACCTTGGGAC 38 PD1 Human 1722
CTGCCCTCCTGACCTTGGG 39 PD1 Human 1724 CCCTGCCCTCCTGACCTTG 40 PD1
Human 1894 CCTTCCCACCCAGGCCCTG 41 PD1 Human 1896
TACCTTCCCACCCAGGCCC 42 PD1 Human 1898 TGTACCTTCCCACCCAGGC 43 PD1
Human 1900 CCTGTACCTTCCCACCCAG 44 PD1 Human 1996
CTGGATGCTGGTGGCCCTG 45 PD1 Human 1997 CCTGGATGCTGGTGGCCCT 46 PD1
Human 2024 CCCAGCCACTCAGGTGCCT 47 PD1 Human 2032
TCCCTTGTCCCAGCCACTC 48 PD1 Human 2034 GATCCCTTGTCCCAGCCAC 49 PDL1
Mouse 219 CAAGCAGGTCCAGCTCCCG 50 PDL1 Mouse 316 CTCCCCCTGAAGTTGCTGT
51 PDL1 Mouse 436 TTGTAGTCCGCACCACCGT 52 PDL1 Mouse 1399
GGTGACCTCTGTGTTCCCT 53 PDL1 Mouse 2152 GCCTGCCTCTGCCTCCCTA 54 PDL1
Mouse 3311 GCCCAGCCTGTTCCTTCAG 55 PDL1 Human 571
GGTAGCCCTCAGCCTGACA 56 PDL1 Human 892 CCATCATTCTCCCTTTTCT 57 PDL1
Human 1075 ATTGCCTGCATCCCACGGG 58 PDL1 Human 1080
CCCACATTGCCTGCATCCC 59 PDL1 Human 1103 TTCAGTGCTTGGGCCTTTT 60 PDL1
Human 1163 GGCTCCCTGTTTGACTCCA 61 PDL1 Human 1182
GTATCAAGGTCTCCCTCCA 62 PDL1 Human 1230 TCCTTTCTCCCTGTCACAG 63 PDL1
Human 1296 ATTCTCAACCCGTCTTCCT 64 PDL1 Human 1855
TCTGTTTGCTTCCTCAGCT 65 PDL1 Human 1904 GGGTGGCAGTCTGAGGTCT 66 PDL1
Human 1911 GGACAGTGGGTGGCAGTCT 67 PDL1 Human 2142
TTCCCCTCGCATCATCCTT 68 PDL1 Human 2192 TCCCAGACCACATTGGCCT 69 PDL1
Human 2901 TGCACCCTGGAGAGCCCAT 70 PDL1 Human 3128
GCTGGTGGCATTCAAGGGT 71 PDL1 Human 3173 CGAAACCTCCAGGAAGCCT 72 PDL1
Human 3196 GATCTCCCAGGGCATCTGA 73 PDL1 Human 3397
GCCTTGCTCAGCCACAATT 74 PDL1 Human 3402 TATGTGCCTTGCTCAGCCA 75 IDO1
Mouse 138 CTAGCCACAAGGACCCAGG 76 IDO1 Mouse 264 ATGTACCCCAGGGCCAGGT
77 IDO1 Mouse 295 ATCCCCTCGGTTCCACACA 78 IDO1 Mouse 492
CCCTTGTCGCAGTCCCCAC 79 IDO1 Mouse 817 GAAGATGCTGCTCTGGCCT 80 IDO1
Mouse 1145 CAGTCCCTCTGCTTTCCAC 81 IDO1 Human 172
GCAGAGCAAAGCCCACTTC 82 IDO1 Human 184 CCTGTGGATTTGGCAGAGC 83 IDO1
Human 388 CTCCATGACCTTTGCCCCA 84 IDO1 Human 507 CTTTTTCTTCCAGTTTGCC
85 IDO1 Human 619 CAGCTGCTATTTCCACCAA 86 IDO1 Human 816
GTTGCCTTTCCAGCCAGAC 87 IDO1 Human 823 GCTGGGGGTTGCCTTTCCA 88 IDO1
Human 849 CCCTTCATACACCAGACCG 89 IDO1 Human 956 TGTCCTCCACCAGCAGTCT
90 IDO1 Human 1138 GCAGATGGTAGCTCCTCAG 91 IDO1 Human 1187
TCCTTTGGCTGCTGGCTTG 92 IDO1 Human 1239 GCCTCCAGTTCCTTTGGCT 93 IDO1
Human 1246 AATCAGTGCCTCCAGTTCC 94 IDO1 Human 1327
GTGCTCTTGTTGGGTTACA 95 IDO1 Human 1627 GCCTCGGCCTCCCAAAGTG 96 IDO1
Human 1745 TAGCTGGGACTACAGGTGC 97 IDO1 Human 1767
TCTCCTGCCTCAGCCTCCC 98 IDO1 Human 1774 ACGCCATTCTCCTGCCTCA 99 IDO1
Human 1792 GCTCCGCCTCCCAGGTTCA 100 IDO1 Human 1815
GGCACAATCTTGGCTCACT 101 LAG3 Mouse 25 GCTCCTCCAGACCCAGTCC 102 LAG3
Mouse 321 GGCCTCCCCAGCCCTCCAA 103 LAG3 Mouse 355
GGAGCAGGTCCTCCCTCAT 104 LAG3 Mouse 422 AGCTCTTTCCCAGGCCCTG 105 LAG3
Mouse 585 CCCCTGGTGAAGGTCAAGG 106 LAG3 Mouse 590
GGCATCCCCTGGTGAAGGT 107 LAG3 Mouse 601 GTCTAGGCGAGGGCATCCC 108 LAG3
Mouse 953 GGCACTCGGTTCTGGCCCT 109 LAG3 Mouse 1044
GACACAGCCCCAGGTCCCA 110 LAG3 Mouse 1108 GCTCCAGACCCAGAACCTT 111
LAG3 Mouse 1161 GGGCAGCTCCACCCTAGAA 112 LAG3 Mouse 1260
GCCACTCTTTCCAGCCACG 113 LAG3 Mouse 1295 GCCAGACCCACAGCCTCAA 114
LAG3 Mouse 1316 CAGGTGTAGGTCCCAGCCT 115 LAG3 Mouse 1349
GCATTGAGCTGCTGTCCCT 116 LAG3 Mouse 1524 GGCCTCCTGAATCTCCAGC 117
LAG3 Mouse 1573 GCCTCTGGCCCTCGTACAG 118 LAG3 Mouse 1819
CCAGCTCCTCTATCTTCCT 119 LAG3 Mouse 1918 CTGCCTCGGCTCCAGGTCA 120
LAG3 Mouse 1936 GCTGCTGAGACCTGCTGGC 121 LAG3 Mouse/ 1315
AGGTGTAGGTCCCAGCCTG Human
122 LAG3 Mouse/ 1822 GCTCCAGCTCCTCTATCTT Human 123 LAG3 Mouse/ 1062
GCCATCTCTGTAGGTGAGG Human 124 LAG3 Mouse/ 1356 GACAGTGGCATTGAGCTGC
Human 125 LAG3 Human 3 TCTCTGGGCCTTCACCCCT 126 LAG3 Human 123
CTGGGCAGATCAGGCAGCC 127 LAG3 Human 167 GGGAGGGATGACCAGAGGC 128 LAG3
Human 229 GGGAGGTGGAGGAAGGGGT 129 LAG3 Human 346
CTGAGCCTCCCACATCTCT 130 LAG3 Human 395 GCTTCACTGGAGCCACCCA 131 LAG3
Human 494 GGCTGAGATCCTGGAGGGG 132 LAG3 Human 524
GCTGCCAAGTGACCCCTGC 133 LAG3 Human 648 GGACCCACGCTCAGCACCG 134 LAG3
Human 736 CCATAGCGAGAAGTCCCCG 135 LAG3 Human 834
TGGCCCAGGCGCAGACGGA 136 LAG3 Human 1034 CCATGGGGCTGACTTGGGG 137
LAG3 Human 1359 TTGAGCTGCTGTTCCTGCA 138 LAG3 Human 1433
GCAGCTTCCCCAGGGATCC 139 LAG3 Human 1499 GGGATGGGGTGTCCAGAGA 140
LAG3 Human 1554 TGGGAAAGGAGCTGGGCCT 141 LAG3 Human 1593
AGAAGCCTCTCCCCCTGGT 142 LAG3 Human 1636 GGCACCTGGGCTAGACAGC 143
LAG3 Human 1848 GGTTCTTGCTCCAGCTCCT 144 LAG3 Human 1940
GCTGAGATCTGCTGGCTGC 145 LAG3 Human/ 1972 GCTGCTGACAGGGAGTTTA Mouse
146 LAG3 Human/ 642 ACGCTCAGCACCGTGTAGC Mouse 147 LAG3 Human/ 1234
AGGAGGAGTCCACTTGGCA Mouse 148 LAG3 Human/ 1366 AGTGGCATTGAGCTGCTGT
Mouse 149 TIM3 Mouse 222 AATCCCTTGCCCCAGCACA 150 TIM3 Mouse 319
GAGATCGCCCTTTAGCTGG 151 TIM3 Mouse 386 TGCAGCAGTAGGTCCCATG 152 TIM3
Mouse 462 GGAGTGACCTTGGCTGCTT 153 TIM3 Mouse 661
CCCAGCAGAGACTCCCACT 154 TIM3 Mouse 782 CATTTGCCAACCCTCCTGG 155 TIM3
Mouse 887 GCTGGCTGTTGACGTAGCA 156 TIM3 Mouse 1273
TTAGCCCTTTATTCCCCCT 157 TIM3 Mouse 1416 CCTCCTGCCTAAGGTTCCC 158
TIM3 Mouse 1425 ACTTATCACCCTCCTGCCT 159 TIM3 Mouse 1517
GAGCCTCATCTCCAGCCTC 160 TIM3 Mouse 1526 TCACTGTCCGAGCCTCATC 161
TIM3 Mouse 1668 CTGACTGCACGCAAGCCCC 162 TIM3 Mouse 1767
GAGCAGAGGACAACCCCCA 163 TIM3 Mouse 1953 CTGCTCTGCCATGCTCCCA 164
TIM3 Mouse 2138 GTCAGTTCCCCTTGAGCAC 165 TIM3 Mouse 2220
CTGCCTTCGTATGTCCCAG 166 TIM3 Mouse 2461 CACAGTTGCTCCCCAATGC 167
TIM3 Mouse 2570 AGCCAGGACCTCCACAGCT 168 TIM3 Mouse 2596
GTCTCCCTTCCATACCCAC 169 TIM3 Human 59 CTGCCAGGTCTACAGTCAC 170 TIM3
Human 281 CAGCAGCAGCAGCAGGACA 171 TIM3 Human 338
GGCATTCTGACCGACCTCC 172 TIM3 Human 457 TCCCTTTCATCAGTCCTGA 173 TIM3
Human 740 GAGGCTCCCCAGTGTCTGT 174 TIM3 Human 803
GGCCAATCTAGAGTCCCGT 175 TIM3 Human 1110 GTGAGGGTTGCTGCCTGCT 176
TIM3 Human 1235 GCAGTGGACAGAACCTCCA 177 TIM3 Human 1304
CAGTGCAGGTCCCAGTTCA 178 TIM3 Human 1442 GAGCTCCAGAGACCCCACG 179
TIM3 Human 1456 GCCCGAATTTCCTGGAGCT 180 TIM3 Human 1506
CAGCACCCAGTTTTCCCTA 181 TIM3 Human 1549 GCCCCTTTAGACTTTCTGT 182
TIM3 Human 1640 TGCCATTGCACTCCAGCCT 183 TIM3 Human 1716
ATCCCAGCCACTCAGGAGG 184 TIM3 Human 1725 ATGCCTGTAATCCCAGCCA 185
TIM3 Human 1863 GCTCACGCCTGTAATCCCA 186 TIM3 Human 1877
GGCTGGATGTGGTGGCTCA 187 TIM3 Human 2053 GCCACATCTCAGCCCTGCA 188
TIM3 Human 2246 GCCTTTGCCTTCTTTCCAC 189 CTLA4 Mouse 106
GGTCCTCAGGGAGCAGAGT 190 CTLA4 Mouse 191 AGGCCAAGTCCTAGAAGGC 191
CTLA4 Mouse 253 TGGGTCACCTGTATGGCTT 192 CTLA4 Mouse 344
AGTCACCCGGACCTCATCA 193 CTLA4 Mouse 416 GCCCACTGTATTCTTCTCT 194
CTLA4 Mouse 497 GTCAACAGCTCTCAGTCCT 195 CTLA4 Mouse 563
GTTGCCCATGCCCACAAAG 196 CTLA4 Mouse 567 TCCCGTTGCCCATGCCCAC 197
CTLA4 Mouse 647 CCCCAAGCTAACTGCGACA 198 CTLA4 Mouse 735
TCACATAGACCCCTGTTGT 199 CTLA4 Mouse 760 CATTCTGGCTCTGTTGGGG 200
CTLA4 Mouse 1084 CCTTGACCCCACACCATAA 201 CTLA4 Mouse 1135
CTCTTCCTTCACCCCCTTC 202 CTLA4 Mouse 1434 CTCCCCAGCCAAACCTCCC 203
CTLA4 Mouse 1436 AGCTCCCCAGCCAAACCTC 204 CTLA4 Mouse 1470
GACCTCGAGTCCAACCTGA 205 CTLA4 Mouse 1484 GCCAGTTGGTGCAGGACCT 206
CTLA4 Mouse 1542 ACTCCATCACCATCGGTTT 207 CTLA4 Mouse 1552
CCCAGTTTACACTCCATCA 208 CTLA4 Mouse 1794 TCCCATCCTACCATCTGCT 209
CTLA4 Human 129 GGGAGCGGTGTTCAGGTCT 210 CTLA4 Human 211
AGGAGAGTGCAGGGCCAGG 211 CTLA4 Human 346 CGGACCTCAGTGGCTTTGC 212
CTLA4 Human 504 CCATGGCCCTCAGTCCTTG 213 CTLA4 Human 574
CCGTTGCCTATGCCCAGGT 214 CTLA4 Human 953 GGGTTCCGCATCCAACTTT 215
CTLA4 Human 1007 CATCCCAGCTCTGTCTTTC 216 CTLA4 Human 1067
GCATCCCCATATTAATCCC 217 CTLA4 Human 1136 CTCCCTGCCTTTTCCTTCT 218
CTLA4 Human 1308 ACCTTTAGCATCACTGGCT 219 CTLA4 Human 1514
AGTGTCCTGAGCTCCTCCA 220 CTLA4 Human 1537 CCTTGTGTTCTACCTGGTG 221
CTLA4 Human 1570 CCTCATCCAGTTTCCAAGC 222 CTLA4 Human 1606
CTCAGCACAATTCCACGCA 223 CTLA4 Human 1632 AGCCCCAAAGCACATGTCA 224
CTLA4 Human 1747 ATACCTGTGGGTCTCCTGG 225 CTLA4 Human 1822
GCCTTCTTCTGTCCATGGC 226 CTLA4 Human 1844 GCACCCCATTCTGCCACCT 227
CTLA4 Human/ 744 TCACATAGACCCCTGTTGT Mouse 228 CTLA4 Human/ 1117
TTGGGCTGTGCCATTCCCT Mouse 229 IDO2 Mouse 49 TGCCCCAGAGGAATGCCCA 230
IDO2 Mouse 127 GTGGTATCTCCCCAAGGAC 231 IDO2 Mouse 279
CAGTCCAGGAGAGGCATCC 232 IDO2 Mouse 440 GGAGTCCCAAGTTCCTGGA 233 IDO2
Mouse 510 TCCAACGGTCCTTCTGGGT 234 IDO2 Mouse 639
GCCTCCATTCCCTGAACCA 235 IDO2 Mouse 801 GGATTGTCCTTCCACCCAG 236 IDO2
Mouse 873 GCTGCACTTCCTCCAGAGT 237 IDO2 Mouse 971
GCGGCATGTAGTCCCTCAT 238 IDO2 Mouse 1047 CCAGGACCAGAGGCCAGTA 239
IDO2 Mouse 1215 GTACCCCCAGTGCCCCTGT 240 IDO2 Mouse 1280
CACCAGGACACAGGAGGGC 241 IDO2 Mouse 1617 GCTCCCACGGGACCTGACT 242
IDO2 Mouse 1782 TGAGGAGGTCATGGCTGCA
243 IDO2 Mouse 1911 GGGACGAGGGAGGTAGGGA 244 IDO2 Mouse 2058
GTTTGAGGCCCATCAGACC 245 IDO2 Mouse 2345 GCTCAGTGGCTCATCCCTG 246
IDO2 Mouse 2638 GGCTGTCCCAGGTCACAGA 247 IDO2 Mouse 2748
GGTGACTTCCAGGTCTGCA 248 IDO2 Mouse 2756 CCCGTGCTGGTGACTTCCA 249
IDO2 Human 156 GGTGTCCATTGCCTTCTGT 250 IDO2 Human 214
GCCTGGTGGGTGAAGTGTC 251 IDO2 Human 222 TTGTGGTGGCCTGGTGGGT 252 IDO2
Human 284 ATTCGGTCTGTGGGGCTCC 253 IDO2 Human 561
CTCCTTCCTGCCAGACATA 254 IDO2 Human 633 GCCCCAAGTTCCTGGAGAC 255 IDO2
Human 713 CCCAATTTCCAGGAATCCG 256 IDO2 Human 722
CTCCAGGTTCCCAATTTCC 257 IDO2 Human 757 TGCAGGCTCTCTCCCCCAG 258 IDO2
Human 802 GGCACTGCTTCTTTCTCTA 259 IDO2 Human 1137
AGTCACCACTTTCCTTGCT 260 IDO2 Human 1207 GGTGCTGAGTGGATGTCTT 261
IDO2 Human 1253 CAGCAAGTGGTCCTGTCCA 262 IDO2 Human 1363
GGCTTCCCATGCTTTGCCT 263 IDO2 Human 1415 TCCACCTGTGCCCCTGTCT 264
IDO2 Human 1464 ACTCCAAGGTCTTATCCCT 265 IDO2 Human 1573
TGATCCCAGGCAGAACCCT 266 IDO2 Human 1593 GGGCTGAGATCCTTCCTGG 267
IDO2 Human 1745 TGGGGGTTCTGCATGAGGA 268 IDO2 Human 1752
ACTCCTCTGGGGGTTCTGC 269 IDO2 Human 1837 AGTAATGTATCCCCAGGCA 270
IDO2 Human 1945 AAGAGGGCTGGTCTGGGAC 271 CEACAM1 Mouse 291
GTAGTGTTTCCCTTGTACC 272 CEACAM1 Mouse 294 GCCGTAGTGTTTCCCTTGT 273
CEACAM1 Mouse 299 CTATAGCCGTAGTGTTTCC 274 CEACAM1 Mouse 1110
GTGAGGAACAGAATCCGGG 275 CEACAM1 Mouse 1526 TTCCTGCTTCTGGTTTGTT 276
CEACAM1 Mouse 1530 CCATTTCCTGCTTCTGGTT 277 CEACAM1 Mouse 1531
GCCATTTCCTGCTTCTGGT 278 CEACAM1 Mouse 2474 CCATGCTGGAACTCTGTCT 279
CEACAM1 Mouse 2485 CTGCACAGGCTCCATGCTG 280 CEACAM1 Mouse 2486
CCTGCACAGGCTCCATGCT 281 CEACAM1 Mouse 2500 CTGTGGGATTGAAACCTGC 282
CEACAM1 Mouse 2507 GGTGTTACTGTGGGATTGA 283 CEACAM1 Mouse 2513
GCAGAAGGTGTTACTGTGG 284 CEACAM1 Mouse 2533 GTCTGAGCAGGTGGGGTGC 285
CEACAM1 Mouse 2536 GCAGTCTGAGCAGGTGGGG 286 CEACAM1 Mouse 2568
TGTCCAGGTAGCCAGGCCT 287 CEACAM1 Mouse 2570 AATGTCCAGGTAGCCAGGC 288
CEACAM1 Human 103 GCCCTGTCTTCACCTGTGG 289 CEACAM1 Human 111
TCCTGCTGGCCCTGTCTTC 290 CEACAM1 Human 126 GTGCCCCATGGTGTCTCCT 291
CEACAM1 Human 1021 TGGCGTGGCAGGTATAGGA 292 CEACAM1 Human 1403
GCCCCAGGTGAGAGGCCAT 293 CEACAM1 Human 1440 AACCAGGGCCACTACTCCA 294
CEACAM1 Human 1463 GCCAGGGCTACTGCTATCA 295 CEACAM1 Human 1851
GGTTTCCTACAGACTCCCA 296 CEACAM1 Human 1908 GTTCTGGTCCCTCTTTCCC 297
CEACAM1 Human 2230 GGTGCTTAGACCCTGATCC 298 CEACAM1 Human 2396
CTGCCTTGAACAGAGCCCA 299 CEACAM1 Human 2414 AACCCCTCCCTCTCAGCAC 300
CEACAM1 Human 2436 GCTGGTTCCCTCCTGAAGC 301 CEACAM1 Human 2473
CCTTTCCCAAGTTCCTAGC 302 CEACAM1 Human 2489 GGGCAGCTCTCTGATTCCT 303
CEACAM1 Human 2700 GCTCCTGACCAAGGGACCT 304 CEACAM1 Human 2894
AGCAGAGGCCAAGGTTTCC 305 CEACAM1 Human 2924 CTCCCACTTCTCAAGGACC 306
CEACAM1 Human 3019 TCACAGCCCCATTTCCCCA 307 CEACAM1 Human 3323
GCACAGTCCGTGTCAGGGT 308 OX40 Mouse 20 GTATGCAGAGTCCCATGAT 309 OX40
Mouse 121 CCTTGCAGGGTGTGGCTAT 310 OX40 Mouse 161
CCTTGTCTGCTTTCTGCCT 311 OX40 Mouse 270 TGTGACCACTGGGGTAGGT 312 OX40
Mouse 495 GAGGTTGGGTGCCTGGTCT 313 OX40 Mouse 509
GCCGCTGTCCTGCCGAGGT 314 OX40 Mouse 544 GGAGGGCAGGGAACACAGT 315 OX40
Mouse 572 CTGGTTGTTGCCTGGAGAA 316 OX40 Mouse 593
ATTGGTCCAGGGCTTGCAG 317 OX40 Mouse 642 CCAAGCTGTCACTGGCTGG 318 OX40
Mouse 693 GGGTCTCCCAGAGCAGTGT 319 OX40 Mouse 845
AGTCAAGGGAGCCAGCAGG 320 OX40 Mouse 904 GGTTTGGGAGTGTTAGGCA 321 OX40
Mouse 941 CTCCTGGATCGGGGTCCTG 322 OX40 Mouse 1010
GCCCCATAAAATCCACTCC 323 OX40 Mouse 1021 GGGTTGTCCGTGCCCCATA 324
OX40 Mouse 1038 GGCAGGCATCAGGATATGG 325 OX40 Mouse 1069
GCCCAGCACCTAGAACGGT 326 OX40 Mouse 1080 GCCCAGAGCCAGCCCAGCA 327
OX40 Mouse 1126 TTAGGAGCACCACCAGGCA 328 OX40 Human 82
CCCAGGAGGAGCAGAGCCG 329 OX40 Human 192 TGCAGCGGCTCACCATCCC 330 OX40
Human 273 AGGGCTTGCACGGCTTGGA 331 OX40 Human 300
TCCCACTTCTGAGGTTACA 332 OX40 Human 312 GCTTCCGCTCACTCCCACT 333 OX40
Human 342 AGACTGTGTCCTGTGTGGC 334 OX40 Human 347
GCGGCAGACTGTGTCCTGT 335 OX40 Human 401 GGCACAGTCAACTCCAGGC 336 OX40
Human 462 AGTTGGTCCAGGGCTTGCA 337 OX40 Human 485
GGTGTGCTTCCCAGCCAAG 338 OX40 Human 746 CCGGAGCAGGTACAGGGCC 339 OX40
Human 762 GCAGCCTCTGGTCCCTCCG 340 OX40 Human 763
GGCAGCCTCTGGTCCCTCC 341 OX40 Human 823 TGCTCCTCTTGGATGGGGG 342 OX40
Human 865 GGCCCAGGTCAGATCTTGG 343 OX40 Human 967
GTTGGCCCAGGAGCGTGGC 344 OX40 Human 1036 GCAGGAGGTATGCATGGCA 345
OX40 Human 1058 GTTTTTATTGTGGTCCCGC 346 OX40 Human 1075
GACTCCCGTCTGCCAAGGT 347 OX40L Mouse 141 CCCTTCCCCTTCCATCTCT 348
OX40L Mouse 167 TCCAGATTCTCATCCAGGG 349 OX40L Mouse 182
GGCCTTGATCCGTTTTCCA 350 OX40L Mouse 218 ACCACCAGCCTTAGCGTCT 351
OX40L Mouse 226 TCCCAGAGACCACCAGCCT 352 OX40L Mouse 240
CCCTGCTCCCTTGATCCCA 353 OX40L Mouse 303 TGGAGGGTCCTTTGCCGGA 354
OX40L Mouse 399 GTTCTGCACCTCCATAGTT 355 OX40L Mouse 454
AGGAGCCCTTCAGGTAGAT 356 OX40L Mouse 565 CCAAAGAGGCCACCACAGT 357
OX40L Mouse 650 ACAATCAGCTCCCCATCAT 358 OX40L Mouse 753
CCTGTGTCCCGTCCACCCT 359 OX40L Mouse 817 AGGGTAGGCTCTGCATTCA 360
OX40L Mouse 895 GCAGGCTCAAGGCAATCCT 361 OX40L Mouse 1069
TGGACACCACCCTTTCCAT 362 OX40L Mouse 1157 CCCCCATGAGATGAGAGAC 363
OX40L Mouse 1173 AATCTTCTTTCCAAGCCCC 364 OX40L Mouse 1193
AGTCCTGCTTTCCACGGGG 365 OX40L Mouse 1298 GGTGGGTATCATAGTCCCT 366
OX40L Mouse 1439 CCTTCTTGGCCTTTATCCT 367 OX40L Human 494
GGGCTCCTCATCCTTCTGG 368 OX40L Human 712 GTTCATGCTGGTGCCTGGT
369 OX40L Human 814 GGGAGGGCCAGGATCTGCT 370 OX40L Human 1104
CCTTCACTCCTTGCTCCTC 371 OX40L Human 1120 GATTCATAACCCCACTCCT 372
OX40L Human 1139 GTTCATACCACCTTTGGCA 373 OX40L Human 1276
GGCTCTCTTCAAGTCCTGA 374 OX40L Human 1378 CACATCCCCAGACAGTTCT 375
OX40L Human 1383 AGCATCACATCCCCAGACA 376 OX40L Human 1492
GTCCAGTTCCCTGCTATCC 377 OX40L Human 1569 TGCTTTGCCTGTCTGTGGC 378
OX40L Human 1577 GCATGTGTTGCTTTGCCTG 379 OX40L Human 1828
ATTCCATTGAAGCCCTGGC 380 OX40L Human 2127 CAGCCCTCCACCTTTCTGG 381
OX40L Human 2367 GTCCACAGTAGGCCCTCCA 382 OX40L Human 2376
CAGTGCCTGGTCCACAGTA 383 OX40L Human 2387 AGTATTTAGCCCAGTGCCT 384
OX40L Human 2729 CCCAAAGCGAGTGAGCACC 385 OX40L Human 2754
ACATGGGAAGAGCAGGCCA 386 OX40L Human 2808 GGTGGAGTGAGGCTGGTGC
[0134] Compound names for the 3.sup.rd generation antisense (3GA)
compounds according to the invention are based on the target and
oligonucleotide target site(s) as depicted Table 3. For example,
"3GA 384" comprises two copies of Oligo # 384 linked at their 5'
ends (e.g., 3'-CCACGAGTGAGCGAAACCC-5'-X-5'-CCCAAAGCGAGTGAGCACC-3',
wherein X represents a non-nucleotidic linker). Alternatively, a
3GA compound comprising two different oligonucleotides such as
Oligo # 385 and Oligo # 386 (e.g.,
3'-ACCGGACGAGAAGGGTACA-5'-X-5'-GGTGGAGTGAGGCTGGTGC-3', wherein X
represents a non-nucleotidic linker) will be referred to herein,
for example, as "3GA 385/386".
[0135] Certain embodiments provide gene silencing compounds
comprising two oligonucleotides independently selected from the
oligonucleotides listed in Table 3. In certain embodiments, the
gene silencing compounds comprise two oligonucleotides each,
independently, comprising a portion of at least 12 contiguous
nucleobases of SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,
13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,
30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,
47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63,
64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80,
81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97,
98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111,
112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124,
125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137,
138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150,
151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163,
164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176,
177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189,
190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202,
203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215,
216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228,
229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241,
242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254,
255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267,
268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280,
281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293,
294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306,
307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319,
320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332,
333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345,
346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358,
359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371,
372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384,
385, or 386, or combinations thereof. In certain embodiments, the
oligonucleotides of the gene silencing compound are the same. In
certain embodiments, the oligonucleotides of the gene silencing
compounds are different.
[0136] In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 1, 2,
3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,
21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,
38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54,
55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71,
72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88,
89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103,
104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116,
117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129,
130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142,
143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155,
156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168,
169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181,
182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194,
195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207,
208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220,
221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233,
234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246,
247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259,
260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272,
273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285,
286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298,
299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311,
312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324,
325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337,
338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350,
351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363,
364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376,
377, 378, 379, 380, 381, 382, 383, 384, 385, or 386, and is at
least 80% complimentary to its target site with SEQ ID NO: 387, SEQ
ID NO: 388,
[0137] SEQ ID NO: 389, SEQ ID NO: 390, SEQ ID NO: 391, SEQ ID NO:
392, SEQ ID NO: 393, SEQ ID NO: 394, SEQ ID NO: 395, SEQ ID NO:
396, SEQ ID NO: 397, SEQ ID NO: 398, SEQ ID NO: 399, SEQ ID NO:
400, SEQ ID NO: 401, SEQ ID NO: 402, SEQ ID NO: 403, SEQ ID NO:
404, SEQ ID NO: 405, or SEQ ID NO: 406. In certain embodiments, the
gene silencing compounds comprise two oligonucleotides each,
independently, comprising a portion of at least 12 contiguous
nucleobases of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,
13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,
30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,
47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63,
64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80,
81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97,
98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111,
112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124,
125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137,
138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150,
151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163,
164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176,
177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189,
190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202,
203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215,
216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228,
229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241,
242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254,
255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267,
268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280,
281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293,
294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306,
307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319,
320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332,
333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345,
346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358,
359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371,
372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384,
385, or 386, and is at least 85% complimentary to its target site
with SEQ ID NO: 387, SEQ ID NO: 388, SEQ ID NO: 389, SEQ ID NO:
390, SEQ ID NO: 391, SEQ ID NO: 392, SEQ ID NO: 393, SEQ ID NO:
394, SEQ ID NO: 395, SEQ ID NO: 396, SEQ ID NO: 397, SEQ ID NO:
398, SEQ ID NO: 399, SEQ ID NO: 400, SEQ ID NO: 401, SEQ ID NO:
402, SEQ ID NO: 403, SEQ ID NO: 404, SEQ ID NO: 405, or SEQ ID NO:
406. In certain embodiments, the gene silencing compounds comprise
two oligonucleotides each, independently, comprising a portion of
at least 12 contiguous nucleobases of SEQ ID NOs: 1, 2, 3, 4, 5, 6,
7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,
24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,
41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57,
58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74,
75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91,
92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106,
107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119,
120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132,
133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145,
146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158,
159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171,
172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184,
185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197,
198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210,
211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223,
224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236,
237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249,
250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262,
263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275,
276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288,
289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301,
302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314,
315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327,
328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340,
341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353,
354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366,
367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379,
380, 381, 382, 383, 384, 385, or 386, and is at least 90%
complimentary to its target site with SEQ ID NO: 387, SEQ ID NO:
388, SEQ ID NO: 389, SEQ ID NO: 390, SEQ ID NO: 391, SEQ ID NO:
392, SEQ ID NO: 393, SEQ ID NO: 394, SEQ ID NO: 395, SEQ ID NO:
396, SEQ ID NO: 397, SEQ ID NO: 398, SEQ ID NO: 399, SEQ ID NO:
400, SEQ ID NO: 401, SEQ ID NO: 402, SEQ ID NO: 403, SEQ ID NO:
404, SEQ ID NO: 405, or SEQ ID NO: 406. In certain embodiments, the
gene silencing compounds comprise two oligonucleotides each,
independently, comprising a portion of at least 12 contiguous
nucleobases of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,
13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,
30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,
47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63,
64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80,
81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97,
98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111,
112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124,
125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137,
138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150,
151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163,
164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176,
177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189,
190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202,
203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215,
216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228,
229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241,
242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254,
255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267,
268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280,
281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293,
294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306,
307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319,
320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332,
333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345,
346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358,
359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371,
372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384,
385, or 386, and is at least 95% complimentary to its target site
with SEQ ID NO: 387, SEQ ID NO: 388, SEQ ID NO: 389, SEQ ID NO:
390, SEQ ID NO: 391, SEQ ID NO: 392, SEQ ID NO: 393, SEQ ID NO:
394, SEQ ID NO: 395, SEQ ID NO: 396, SEQ ID NO: 397, SEQ ID NO:
398, SEQ ID NO: 399, SEQ ID NO: 400, SEQ ID NO: 401, SEQ ID NO:
402, SEQ ID NO: 403, SEQ ID NO: 404, SEQ ID NO: 405, or SEQ ID NO:
406.
[0138] In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 1, 2,
3, 4, 5, 6, 7, 8, 49, 50, 51, 52, 53, 54, 75, 76, 77, 78, 79, 80,
101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113,
114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 149, 150,
151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163,
164, 165, 166, 167, 168, 189, 190, 191, 192, 193, 194, 195, 196,
197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 229,
230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242,
243, 244, 245, 246, 247, 248, 271, 272, 273, 274, 275, 276, 277,
278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 308, 309, 310,
311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323,
324, 325, 326, 327, 347, 348, 349, 350, 351, 352, 353, 354, 355,
356, 357, 358, 359, 360, 361, 362, 363, 364, or 365, and is at
least 80% complimentary to its target site with SEQ ID NO: 387, SEQ
ID NO: 389, SEQ ID NO: 391, SEQ ID NO: 393, SEQ ID NO: 395, SEQ ID
NO: 397, SEQ ID NO: 399, SEQ ID NO: 401, SEQ ID NO: 403, or SEQ ID
NO: 405. In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 1, 2,
3, 4, 5, 6, 7, 8, 49, 50, 51, 52, 53, 54, 75, 76, 77, 78, 79,
80,101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113,
114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 149, 150,
151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163,
164, 165, 166, 167, 168, 189, 190, 191, 192, 193, 194, 195, 196,
197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 229,
230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242,
243, 244, 245, 246, 247, 248, 271, 272, 273, 274, 275, 276, 277,
278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 308, 309, 310,
311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323,
324, 325, 326, 327, 347, 348, 349, 350, 351, 352, 353, 354, 355,
356, 357, 358, 359, 360, 361, 362, 363, 364, or 365, and is at
least 85% complimentary to its target site with SEQ ID NO: 387, SEQ
ID NO: 389, SEQ ID NO: 391, SEQ ID NO: 393, SEQ ID NO: 395, SEQ ID
NO: 397, SEQ ID NO: 399, SEQ ID NO: 401, SEQ ID NO: 403, or SEQ ID
NO: 405. In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 1, 2,
3, 4, 5, 6, 7, 8, 49, 50, 51, 52, 53, 54, 75, 76, 77, 78, 79,
80,101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113,
114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 149, 150,
151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163,
164, 165, 166, 167, 168, 189, 190, 191, 192, 193, 194, 195, 196,
197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 229,
230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242,
243, 244, 245, 246, 247, 248, 271, 272, 273, 274, 275, 276, 277,
278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 308, 309, 310,
311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323,
324, 325, 326, 327, 347, 348, 349, 350, 351, 352, 353, 354, 355,
356, 357, 358, 359, 360, 361, 362, 363, 364, or 365, and is at
least 90% complimentary to its target site with SEQ ID NO: 387, SEQ
ID NO: 389, SEQ ID NO: 391, SEQ ID NO: 393, SEQ ID NO: 395, SEQ ID
NO: 397, SEQ ID NO: 399, SEQ ID NO: 401, SEQ ID NO: 403, or SEQ ID
NO: 405. In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 1, 2,
3, 4, 5, 6, 7, 8, 49, 50, 51, 52, 53, 54, 75, 76, 77, 78, 79,
80,101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113,
114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 149, 150,
151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163,
164, 165, 166, 167, 168, 189, 190, 191, 192, 193, 194, 195, 196,
197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 229,
230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242,
243, 244, 245, 246, 247, 248, 271, 272, 273, 274, 275, 276, 277,
278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 308, 309, 310,
311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323,
324, 325, 326, 327, 347, 348, 349, 350, 351, 352, 353, 354, 355,
356, 357, 358, 359, 360, 361, 362, 363, 364, or 365, and is at
least 95% complimentary to its target site with SEQ ID NO: 387, SEQ
ID NO: 389, SEQ ID NO: 391, SEQ ID NO: 393, SEQ ID NO: 395, SEQ ID
NO: 397, SEQ ID NO: 399, SEQ ID NO: 401, SEQ ID NO: 403, or SEQ ID
NO: 405.
[0139] In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,
28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,
45, 46, 47, 48, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67,
68, 69, 70, 71, 72, 73, 74, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90,
91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 125, 126, 127, 128, 129,
130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142,
143, 144, 145, 146, 147, 148, 169, 170, 171, 172, 173, 174, 175,
176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188,
209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221,
222, 223, 224, 225, 226, 227, 228, 249, 250, 251, 252, 253, 254,
255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267,
268, 269, 270, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297,
298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 328, 329, 330,
331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343,
344, 345, 346, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375,
376, 377, 378, 379, 380, 381, 382, 383, 384, 385, or 386, and is at
least 80% complimentary to its target site within SEQ ID NO: 388,
SEQ ID NO: 390, SEQ ID NO: 392, SEQ ID NO: 394, SEQ ID NO: 396, SEQ
ID NO: 398, SEQ ID NO: 400, SEQ ID NO: 402, SEQ ID NO: 404, or SEQ
ID NO: 406. In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,
28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,
45, 46, 47, 48, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67,
68, 69, 70, 71, 72, 73, 74, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90,
91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 125, 126, 127, 128, 129,
130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142,
143, 144, 145, 146, 147, 148, 169, 170, 171, 172, 173, 174, 175,
176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188,
209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221,
222, 223, 224, 225, 226, 227, 228, 249, 250, 251, 252, 253, 254,
255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267,
268, 269, 270, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297,
298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 328, 329, 330,
331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343,
344, 345, 346, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375,
376, 377, 378, 379, 380, 381, 382, 383, 384, 385, or 386, and is at
least 85% complimentary to its target site within SEQ ID NO: 388,
SEQ ID NO: 390, SEQ ID NO: 392, SEQ ID NO: 394, SEQ ID NO: 396, SEQ
ID NO: 398, SEQ ID NO: 400, SEQ ID NO: 402, SEQ ID NO: 404, or SEQ
ID NO: 406. In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,
28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,
45, 46, 47, 48, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67,
68, 69, 70, 71, 72, 73, 74, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90,
91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 125, 126, 127, 128, 129,
130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142,
143, 144, 145, 146, 147, 148, 169, 170, 171, 172, 173, 174, 175,
176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188,
209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221,
222, 223, 224, 225, 226, 227, 228, 249, 250, 251, 252, 253, 254,
255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267,
268, 269, 270, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297,
298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 328, 329, 330,
331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343,
344, 345, 346, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375,
376, 377, 378, 379, 380, 381, 382, 383, 384, 385, or 386, and is at
least 90% complimentary to its target site within SEQ ID NO: 388,
SEQ ID NO: 390, SEQ ID NO: 392, SEQ ID NO: 394, SEQ ID NO: 396, SEQ
ID NO: 398, SEQ ID NO: 400, SEQ ID NO: 402, SEQ ID NO: 404, or SEQ
ID NO: 406. In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,
28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,
45, 46, 47, 48, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67,
68, 69, 70, 71, 72, 73, 74, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90,
91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 125, 126, 127, 128, 129,
130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142,
143, 144, 145, 146, 147, 148, 169, 170, 171, 172, 173, 174, 175,
176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188,
209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221,
222, 223, 224, 225, 226, 227, 228, 249, 250, 251, 252, 253, 254,
255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267,
268, 269, 270, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297,
298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 328, 329, 330,
331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343,
344, 345, 346, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375,
376, 377, 378, 379, 380, 381, 382, 383, 384, 385, or 386, and is at
least 95% complimentary to its target site within SEQ ID NO: 388,
SEQ ID NO: 390, SEQ ID NO: 392, SEQ ID NO: 394, SEQ ID NO: 396, SEQ
ID NO: 398, SEQ ID NO: 400, SEQ ID NO: 402, SEQ ID NO: 404, or SEQ
ID NO: 406.
[0140] In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 1, 2,
3, 4, 5, 6, 7, or 8, and is at least 80% complimentary to SEQ ID
NO: 387. In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 1, 2,
3, 4, 5, 6, 7, or 8, and is at least 85% complimentary to SEQ ID
NO: 387. In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 1, 2,
3, 4, 5, 6, 7, or 8, and is at least 90% complimentary to SEQ ID
NO: 387. In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 1, 2,
3, 4, 5, 6, 7, or 8, and is at least 95% complimentary to SEQ ID
NO: 387.
[0141] In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,
28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,
45, 46, 47, 48, and is at least 80% complimentary to SEQ ID NO:
388. In certain embodiments, the gene silencing compounds comprise
two oligonucleotides each, independently, comprising a portion of
at least 12 contiguous nucleobases of SEQ ID NOs: 9, 10, 11, 12,
13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,
30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,
47, 48, and is at least 85% complimentary to SEQ ID NO: 388. In
certain embodiments, the gene silencing compounds comprise two
oligonucleotides each, independently, comprising a portion of at
least 12 contiguous nucleobases of SEQ ID NOs: 9, 10, 11, 12, 13,
14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,
31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47,
48, and is at least 90% complimentary to SEQ ID NO: 388. In certain
embodiments, the gene silencing compounds comprise two
oligonucleotides each, independently, comprising a portion of at
least 12 contiguous nucleobases of SEQ ID NOs: 9, 10, 11, 12, 13,
14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,
31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47,
48, and is at least 95% complimentary to SEQ ID NO: 388.
[0142] In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 49,
50, 51, 52, 53, 54, and is at least 80% complimentary to SEQ ID NO:
389. In certain embodiments, the gene silencing compounds comprise
two oligonucleotides each, independently, comprising a portion of
at least 12 contiguous nucleobases of SEQ ID NOs: 49, 50, 51, 52,
53, 54, and is at least 85% complimentary to SEQ ID NO: 389. In
certain embodiments, the gene silencing compounds comprise two
oligonucleotides each, independently, comprising a portion of at
least 12 contiguous nucleobases of SEQ ID NOs: 49, 50, 51, 52, 53,
54, and is at least 90% complimentary to SEQ ID NO: 389. In certain
embodiments, the gene silencing compounds comprise two
oligonucleotides each, independently, comprising a portion of at
least 12 contiguous nucleobases of SEQ ID NOs: 49, 50, 51, 52, 53,
54, and is at least 95% complimentary to SEQ ID NO: 389.
[0143] In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 55,
56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,
73, 74, and is at least 80% complimentary to SEQ ID NO: 390. In
certain embodiments, the gene silencing compounds comprise two
oligonucleotides each, independently, comprising a portion of at
least 12 contiguous nucleobases of SEQ ID NOs: 55, 56, 57, 58, 59,
60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, and is
at least 85% complimentary to SEQ ID NO: 390. In certain
embodiments, the gene silencing compounds comprise two
oligonucleotides each, independently, comprising a portion of at
least 12 contiguous nucleobases of SEQ ID NOs: 55, 56, 57, 58, 59,
60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, and is
at least 90% complimentary to SEQ ID NO: 390. In certain
embodiments, the gene silencing compounds comprise two
oligonucleotides each, independently, comprising a portion of at
least 12 contiguous nucleobases of SEQ ID NOs: 55, 56, 57, 58, 59,
60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, and is
at least 95% complimentary to SEQ ID NO: 390.
[0144] In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 75,
76, 77, 78, 79, 80, and is at least 80% complimentary to SEQ ID NO:
391. In certain embodiments, the gene silencing compounds comprise
two oligonucleotides each, independently, comprising a portion of
at least 12 contiguous nucleobases of SEQ ID NOs: 75, 76, 77, 78,
79, 80, and is at least 85% complimentary to SEQ ID NO: 391. In
certain embodiments, the gene silencing compounds comprise two
oligonucleotides each, independently, comprising a portion of at
least 12 contiguous nucleobases of SEQ ID NOs: 75, 76, 77, 78, 79,
80, and is at least 90% complimentary to SEQ ID NO: 391. In certain
embodiments, the gene silencing compounds comprise two
oligonucleotides each, independently, comprising a portion of at
least 12 contiguous nucleobases of SEQ ID NOs: 75, 76, 77, 78, 79,
80, and is at least 95% complimentary to SEQ ID NO: 391.
[0145] In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 81,
82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98,
99, 100, and is at least 80% complimentary to SEQ ID NO: 392. In
certain embodiments, the gene silencing compounds comprise two
oligonucleotides each, independently, comprising a portion of at
least 12 contiguous nucleobases of SEQ ID NOs: 81, 82, 83, 84, 85,
86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, and is
at least 85% complimentary to SEQ ID NO: 392. In certain
embodiments, the gene silencing compounds comprise two
oligonucleotides each, independently, comprising a portion of at
least 12 contiguous nucleobases of SEQ ID NOs: 81, 82, 83, 84, 85,
86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, and is
at least 90% complimentary to SEQ ID NO: 392. In certain
embodiments, the gene silencing compounds comprise two
oligonucleotides each, independently, comprising a portion of at
least 12 contiguous nucleobases of SEQ ID NOs: 81, 82, 83, 84, 85,
86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, and is
at least 95% complimentary to SEQ ID NO: 392.
[0146] In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 101,
102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114,
115, 116, 117, 118, 119, 120, 121, 122, 123, 124, and is at least
80% complimentary to SEQ ID NO: 393. In certain embodiments, the
gene silencing compounds comprise two oligonucleotides each,
independently, comprising a portion of at least 12 contiguous
nucleobases of SEQ ID NOs: 101, 102, 103, 104, 105, 106, 107, 108,
109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121,
122, 123, 124, and is at least 85% complimentary to SEQ ID NO: 393.
In certain embodiments, the gene silencing compounds comprise two
oligonucleotides each, independently, comprising a portion of at
least 12 contiguous nucleobases of SEQ ID NOs: 101, 102, 103, 104,
105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117,
118, 119, 120, 121, 122, 123, 124, and is at least 90%
complimentary to SEQ ID NO: 393. In certain embodiments, the gene
silencing compounds comprise two oligonucleotides each,
independently, comprising a portion of at least 12 contiguous
nucleobases of SEQ ID NOs: 101, 102, 103, 104, 105, 106, 107, 108,
109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121,
122, 123, 124, and is at least 95% complimentary to SEQ ID NO:
393.
[0147] In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 125,
126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138,
139, 140, 141, 142, 143, 144, 145, 146, 147, 148, and is at least
80% complimentary to SEQ ID NO: 394. In certain embodiments, the
gene silencing compounds comprise two oligonucleotides each,
independently, comprising a portion of at least 12 contiguous
nucleobases of SEQ ID NOs: 125, 126, 127, 128, 129, 130, 131, 132,
133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145,
146, 147, 148, and is at least 85% complimentary to SEQ ID NO: 394.
In certain embodiments, the gene silencing compounds comprise two
oligonucleotides each, independently, comprising a portion of at
least 12 contiguous nucleobases of SEQ ID NOs: 125, 126, 127, 128,
129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141,
142, 143, 144, 145, 146, 147, 148, and is at least 90%
complimentary to SEQ ID NO: 394. In certain embodiments, the gene
silencing compounds comprise two oligonucleotides each,
independently, comprising a portion of at least 12 contiguous
nucleobases of SEQ ID NOs: 125, 126, 127, 128, 129, 130, 131, 132,
133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145,
146, 147, 148, and is at least 95% complimentary to SEQ ID NO:
394.
[0148] In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 149,
150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162,
163, 164, 165, 166, 167, 168, and is at least 80% complimentary to
SEQ ID NO: 395. In certain embodiments, the gene silencing
compounds comprise two oligonucleotides each, independently,
comprising a portion of at least 12 contiguous nucleobases of SEQ
ID NOs: 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160,
161, 162, 163, 164, 165, 166, 167, 168, and is at least 85%
complimentary to SEQ ID NO: 395. In certain embodiments, the gene
silencing compounds comprise two oligonucleotides each,
independently, comprising a portion of at least 12 contiguous
nucleobases of SEQ ID NOs: 149, 150, 151, 152, 153, 154, 155, 156,
157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, and is
at least 90% complimentary to SEQ ID NO: 395. In certain
embodiments, the gene silencing compounds comprise two
oligonucleotides each, independently, comprising a portion of at
least 12 contiguous nucleobases of SEQ ID NOs: 149, 150, 151, 152,
153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165,
166, 167, 168, and is at least 95% complimentary to SEQ ID NO:
395.
[0149] In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 169,
170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182,
183, 184, 185, 186, 187, 188, and is at least 80% complimentary to
SEQ ID NO: 396. In certain embodiments, the gene silencing
compounds comprise two oligonucleotides each, independently,
comprising a portion of at least 12 contiguous nucleobases of SEQ
ID NOs: 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180,
181, 182, 183, 184, 185, 186, 187, 188, and is at least 85%
complimentary to SEQ ID NO: 396. In certain embodiments, the gene
silencing compounds comprise two oligonucleotides each,
independently, comprising a portion of at least 12 contiguous
nucleobases of SEQ ID NOs: 169, 170, 171, 172, 173, 174, 175, 176,
177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, and is
at least 90% complimentary to SEQ ID NO: 396. In certain
embodiments, the gene silencing compounds comprise two
oligonucleotides each, independently, comprising a portion of at
least 12 contiguous nucleobases of SEQ ID NOs: 169, 170, 171, 172,
173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185,
186, 187, 188, and is at least 95% complimentary to SEQ ID NO:
396.
[0150] In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 189,
190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202,
203, 204, 205, 206, 207, 208, and is at least 80% complimentary to
SEQ ID NO: 397. In certain embodiments, the gene silencing
compounds comprise two oligonucleotides each, independently,
comprising a portion of at least 12 contiguous nucleobases of SEQ
ID NOs: 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200,
201, 202, 203, 204, 205, 206, 207, 208, and is at least 85%
complimentary to SEQ ID NO: 397. In certain embodiments, the gene
silencing compounds comprise two oligonucleotides each,
independently, comprising a portion of at least 12 contiguous
nucleobases of SEQ ID NOs: 189, 190, 191, 192, 193, 194, 195, 196,
197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, and is
at least 90% complimentary to SEQ ID NO: 397. In certain
embodiments, the gene silencing compounds comprise two
oligonucleotides each, independently, comprising a portion of at
least 12 contiguous nucleobases of SEQ ID NOs: 189, 190, 191, 192,
193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205,
206, 207, 208, and is at least 95% complimentary to SEQ ID NO:
397.
[0151] In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 209,
210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222,
223, 224, 225, 226, 227, 228, and is at least 80% complimentary to
SEQ ID NO: 398. In certain embodiments, the gene silencing
compounds comprise two oligonucleotides each, independently,
comprising a portion of at least 12 contiguous nucleobases of SEQ
ID NOs: 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220,
221, 222, 223, 224, 225, 226, 227, 228, and is at least 85%
complimentary to SEQ ID NO: 398. In certain embodiments, the gene
silencing compounds comprise two oligonucleotides each,
independently, comprising a portion of at least 12 contiguous
nucleobases of SEQ ID NOs: 209, 210, 211, 212, 213, 214, 215, 216,
217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, and is
at least 90% complimentary to SEQ ID NO: 398. In certain
embodiments, the gene silencing compounds comprise two
oligonucleotides each, independently, comprising a portion of at
least 12 contiguous nucleobases of SEQ ID NOs: 209, 210, 211, 212,
213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225,
226, 227, 228, and is at least 95% complimentary to SEQ ID NO:
398.
[0152] In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 229,
230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242,
243, 244, 245, 246, 247, 248, and is at least 80% complimentary to
SEQ ID NO: 399. In certain embodiments, the gene silencing
compounds comprise two oligonucleotides each, independently,
comprising a portion of at least 12 contiguous nucleobases of SEQ
ID NOs: 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240,
241, 242, 243, 244, 245, 246, 247, 248, and is at least 85%
complimentary to SEQ ID NO: 399. In certain embodiments, the gene
silencing compounds comprise two oligonucleotides each,
independently, comprising a portion of at least 12 contiguous
nucleobases of SEQ ID NOs: 229, 230, 231, 232, 233, 234, 235, 236,
237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, and is
at least 90% complimentary to SEQ ID NO: 399. In certain
embodiments, the gene silencing compounds comprise two
oligonucleotides each, independently, comprising a portion of at
least 12 contiguous nucleobases of SEQ ID NOs: 229, 230, 231, 232,
233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245,
246, 247, 248, and is at least 95% complimentary to SEQ ID NO:
399.
[0153] In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 249,
250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262,
263, 264, 265, 266, 267, 268, 269, 270, and is at least 80%
complimentary to SEQ ID NO: 400. In certain embodiments, the gene
silencing compounds comprise two oligonucleotides each,
independently, comprising a portion of at least 12 contiguous
nucleobases of SEQ ID NOs: 249, 250, 251, 252, 253, 254, 255, 256,
257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269,
270, and is at least 85% complimentary to SEQ ID NO: 400. In
certain embodiments, the gene silencing compounds comprise two
oligonucleotides each, independently, comprising a portion of at
least 12 contiguous nucleobases of SEQ ID NOs: 249, 250, 251, 252,
253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265,
266, 267, 268, 269, 270, and is at least 90% complimentary to SEQ
ID NO: 400. In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 249,
250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262,
263, 264, 265, 266, 267, 268, 269, 270, and is at least 95%
complimentary to SEQ ID NO: 400.
[0154] In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 271,
272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284,
285, 286, 287, and is at least 80% complimentary to SEQ ID NO: 401.
In certain embodiments, the gene silencing compounds comprise two
oligonucleotides each, independently, comprising a portion of at
least 12 contiguous nucleobases of SEQ ID NOs: 271, 272, 273, 274,
275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287,
and is at least 85% complimentary to SEQ ID NO: 401. In certain
embodiments, the gene silencing compounds comprise two
oligonucleotides each, independently, comprising a portion of at
least 12 contiguous nucleobases of SEQ ID NOs: 271, 272, 273, 274,
275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287,
and is at least 90% complimentary to SEQ ID NO: 401. In certain
embodiments, the gene silencing compounds comprise two
oligonucleotides each, independently, comprising a portion of at
least 12 contiguous nucleobases of SEQ ID NOs: 271, 272, 273, 274,
275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287,
and is at least 95% complimentary to SEQ ID NO: 401.
[0155] In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 288,
289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301,
302, 303, 304, 305, 306, 307, and is at least 80% complimentary to
SEQ ID NO: 402. In certain embodiments, the gene silencing
compounds comprise two oligonucleotides each, independently,
comprising a portion of at least 12 contiguous nucleobases of SEQ
ID NOs: 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299,
300, 301, 302, 303, 304, 305, 306, 307, and is at least 85%
complimentary to SEQ ID NO: 402. In certain embodiments, the gene
silencing compounds comprise two oligonucleotides each,
independently, comprising a portion of at least 12 contiguous
nucleobases of SEQ ID NOs: 288, 289, 290, 291, 292, 293, 294, 295,
296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, and is
at least 90% complimentary to SEQ ID NO: 402. In certain
embodiments, the gene silencing compounds comprise two
oligonucleotides each, independently, comprising a portion of at
least 12 contiguous nucleobases of SEQ ID NOs: 288, 289, 290, 291,
292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304,
305, 306, 307, and is at least 95% complimentary to SEQ ID NO:
402.
[0156] In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 308,
309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321,
322, 323, 324, 325, 326, 327, and is at least 80% complimentary to
SEQ ID NO: 403. In certain embodiments, the gene silencing
compounds comprise two oligonucleotides each, independently,
comprising a portion of at least 12 contiguous nucleobases of SEQ
ID NOs: 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319,
320, 321, 322, 323, 324, 325, 326, 327, and is at least 85%
complimentary to SEQ ID NO: 403. In certain embodiments, the gene
silencing compounds comprise two oligonucleotides each,
independently, comprising a portion of at least 12 contiguous
nucleobases of SEQ ID NOs: 308, 309, 310, 311, 312, 313, 314, 315,
316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, and is
at least 90% complimentary to SEQ ID NO: 403. In certain
embodiments, the gene silencing compounds comprise two
oligonucleotides each, independently, comprising a portion of at
least 12 contiguous nucleobases of SEQ ID NOs: 308, 309, 310, 311,
312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324,
325, 326, 327, and is at least 95% complimentary to SEQ ID NO:
403.
[0157] In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 328,
329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341,
342, 343, 344, 345, 346, and is at least 80% complimentary to SEQ
ID NO: 404. In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 328,
329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341,
342, 343, 344, 345, 346, and is at least 85% complimentary to SEQ
ID NO: 404. In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 328,
329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341,
342, 343, 344, 345, 346, and is at least 90% complimentary to SEQ
ID NO: 404. In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 328,
329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341,
342, 343, 344, 345, 346, and is at least 95% complimentary to SEQ
ID NO: 404.
[0158] In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 347,
348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360,
361, 362, 363, 364, 365, and is at least 80% complimentary to SEQ
ID NO: 405. In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 347,
348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360,
361, 362, 363, 364, 365, and is at least 85% complimentary to SEQ
ID NO: 405. In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 347,
348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360,
361, 362, 363, 364, 365, and is at least 90% complimentary to SEQ
ID NO: 405. In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 347,
348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360,
361, 362, 363, 364, 365, and is at least 95% complimentary to SEQ
ID NO: 405.
[0159] In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 366,
367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379,
380, 381, 382, 383, 384, 385, or 386, and is at least 80%
complimentary to SEQ ID NO: 406. In certain embodiments, the gene
silencing compounds comprise two oligonucleotides each,
independently, comprising a portion of at least 12 contiguous
nucleobases of SEQ ID NOs: 366, 367, 368, 369, 370, 371, 372, 373,
374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, or 386,
and is at least 85% complimentary to SEQ ID NO: 406. In certain
embodiments, the gene silencing compounds comprise two
oligonucleotides each, independently, comprising a portion of at
least 12 contiguous nucleobases of SEQ ID NOs: 366, 367, 368, 369,
370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382,
383, 384, 385, or 386, and is at least 90% complimentary to SEQ ID
NO: 406. In certain embodiments, the gene silencing compounds
comprise two oligonucleotides each, independently, comprising a
portion of at least 12 contiguous nucleobases of SEQ ID NOs: 366,
367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379,
380, 381, 382, 383, 384, 385, or 386, and is at least 95%
complimentary to SEQ ID NO: 406.
[0160] In certain embodiments, the invention provides a composition
comprising a 3GA compound according to the invention and one or
more vaccines, antigens, antibodies, cytotoxic agents,
chemotherapeutic agents (both traditional chemotherapy and modern
targeted therapies), kinase inhibitors, allergens, antibiotics,
agonist, antagonist, antisense oligonucleotides, ribozymes, RNAi
molecules, siRNA molecules, miRNA molecules, aptamers, proteins,
gene therapy vectors, DNA vaccines, adjuvants, co-stimulatory
molecules or combinations thereof.
[0161] In certain embodiments, the invention provides a method for
inhibiting PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40,
and/or OX40L mRNA or protein expression, the method comprising
contacting a cell with a gene silencing compound according to the
invention. In certain embodiments, the cell can be contacted with
two or more gene silencing compounds targeting different regions of
the same checkpoint. In certain embodiments, the cell can be
contacted with two or more gene silencing compounds targeting
different checkpoints.
[0162] Certain embodiments further provide a method to reduce PD1,
PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, and/or or OX40L
mRNA or protein expression in an animal comprising administering to
the animal a gene silencing compound or composition as described
herein to reduce PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1,
OX40, or OX40L mRNA or protein expression in the animal. In certain
embodiments, the animal is a human. In certain embodiments,
reducing PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40,
or OX40L mRNA or protein expression prevents, treats, ameliorates,
or slows progression of disease. In certain embodiments reducing
PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, or OX40L
mRNA or protein expression inhibits immune system tolerance. In
certain embodiments two or more gene silencing compounds targeting
different regions of the same checkpoint can be administered. In
certain embodiments two or more gene silencing compounds targeting
different checkpoints can be administered.
[0163] In certain embodiments provided are methods for inhibiting
immune system tolerance to tumors comprising administering to the
animal a gene silencing compound or composition as described herein
to reduce PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40,
and/or OX40L mRNA or protein expression in the animal. In certain
embodiments, the animal is a human. In certain embodiments, the
gene silencing compound or composition as described herein is
administered intratumorally. Thus, the inhibition of PD1, PDL1,
IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, or OX40L mRNA or
protein expression may provide a potentially useful immunotherapy
strategy for patients with cancer. In certain embodiments two or
more gene silencing compounds targeting different regions of the
same checkpoint can be administered. In certain embodiments two or
more gene silencing compounds targeting different checkpoints can
be administered.
[0164] In certain embodiments provided are methods for preventing
tumor growth and tumor volume. In certain embodiments provided are
methods for reducing tumor growth and tumor volume.
[0165] In certain embodiments provided are methods, compounds, and
compositions for the treatment, prevention, or amelioration of
diseases, disorders, and conditions associated with PD1, PDL1,
IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, or OX40L in an
individual in need thereof Also contemplated are methods and
compounds for the preparation of a medicament for the treatment,
prevention, or amelioration of a disease, disorder, or condition
associated with PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1,
OX40, or OX40L. In certain embodiments two or more gene silencing
compounds targeting different regions of the same checkpoint can be
administered. In certain embodiments two or more gene silencing
compounds targeting different checkpoints can be administered.
[0166] PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, or
OX40L associated diseases, disorders, and conditions include
hyperproliferative diseases, e.g., cancer, carcinomas, sarcomas,
lymphomas, and leukemias as well as associated malignancies and
metastases. PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1,
OX40, or OX40L associated diseases, disorders, and conditions can
also include autoimmune diseases and disorders.
[0167] In certain embodiments provided are PD1, PDL1, IDO1, LAG3,
TIM3, CTLA4, IDO2, CEACAM1, OX40, or OX40L gene silencing compounds
for use in treating, preventing, or ameliorating a PD1, PDL1, IDO1,
LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, or OX40L associated
disease. In certain embodiments, PD1, PDL1, IDO1, LAG3, TIM3,
CTLA4, IDO2, CEACAM1, OX40, or OX40L gene silencing compounds are
capable of inhibiting the expression of PD1, PDL1, IDO1, LAG3,
TIM3, CTLA4, IDO2, CEACAM1, OX40, or OX40L mRNA and/or PD1, PDL1,
IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, or OX40L protein in a
cell, tissue, or animal.
[0168] Certain embodiments provide methods comprising administering
to an animal a gene silencing compounds as described herein. In
certain embodiments two or more gene silencing compounds targeting
different regions of the same checkpoint can be administered. In
certain embodiments two or more gene silencing compounds targeting
different checkpoints can be administered.
[0169] Also provided are methods and gene silencing compounds for
the preparation of a medicament for the treatment, prevention, or
amelioration of disease.
[0170] Certain embodiments provide the use of gene silencing
compounds as described herein in the manufacture of a medicament
for treating, ameliorating, or preventing disease.
[0171] Certain embodiments provide gene silencing compounds as
described herein for use in treating, preventing, or ameliorating
disease as described herein by combination therapy with an
additional agent or therapy as described herein. Agents or
therapies can be co-administered or administered concomitantly.
[0172] Certain embodiments provide the use of a gene silencing
compound as described herein in the manufacture of a medicament for
treating, preventing, or ameliorating disease as described herein
by combination therapy with an additional agent or therapy as
described herein. Agents or therapies can be co-administered or
administered concomitantly.
[0173] Certain embodiments provide the use of a gene silencing
compound as described herein in the manufacture of a medicament for
treating, preventing, or ameliorating disease as described herein
in a patient who is subsequently administered an additional agent
or therapy as described herein.
[0174] In any of the methods according to the invention, the gene
silencing compound according to the invention can variously act by
producing direct gene expression modulation effects alone and/or in
combination with any other agent useful for treating or preventing
the disease or condition that does not diminish the gene expression
modulation effect of the gene silencing compound according to the
invention. In any of the methods according to the invention, the
agent(s) useful for treating or preventing the disease or condition
includes, but is not limited to, vaccines, antigens, antibodies,
preferably monoclonal antibodies, cytotoxic agents, kinase
inhibitors, allergens, antibiotics, siRNA molecules, antisense
oligonucleotides, TLR antagonist (e.g. antagonists of TLR3 and/or
TLR7 and/or antagonists of TLR8 and/or antagonists of TLR9),
chemotherapeutic agents (both traditional chemotherapy and modern
targeted therapies), targeted therapeutic agents, activated cells,
peptides, proteins, gene therapy vectors, peptide vaccines, protein
vaccines, DNA vaccines, adjuvants, and co-stimulatory molecules
(e.g. cytokines, chemokines, protein ligands, trans-activating
factors, peptides or peptides comprising modified amino acids), or
combinations thereof. For example, in the treatment of cancer, it
is contemplated that the oligonucleotide-based compound according
to the invention may be administered in combination with one or
more chemotherapeutic compound, targeted therapeutic agent and/or
monoclonal antibody. Alternatively, the agent can include DNA
vectors encoding for antigen or allergen. Alternatively, the gene
silencing compound according to the invention can be administered
in combination with other compounds (for example lipids or
liposomes) to enhance the specificity or magnitude of the gene
expression modulation of the oligonucleotide-based compound
according to the invention.
[0175] In any of the methods according to the invention,
administration of gene silencing compounds according to the
invention, alone or in combination with any other agent, can be by
any suitable route, including, without limitation, parenteral,
mucosal, oral, sublingual, intratumoral, transdermal, topical,
inhalation, intrathecal, intranasal, aerosol, intraocular,
intratracheal, intrarectal, vaginal, by gene gun, dermal patch or
in eye drop or mouthwash form. In any of the methods according to
the invention, administration of gene silencing compounds according
to the invention, alone or in combination with any other agent, can
be directly to a tissue or organ such as, but not limited to, the
bladder, liver, lung, kidney or lung. In certain embodiments,
administration of gene silencing compounds according to the
invention, alone or in combination with any other agent, is by
intratumoral administration. In certain embodiments, administration
of gene silencing compounds according to the invention, alone or in
combination with any other agent, is by mucosal administration. In
certain embodiments, administration of gene silencing compounds
according to the invention, alone or in combination with any other
agent, is by oral administration. In certain embodiments,
administration of gene silencing compounds according to the
invention, alone or in combination with any other agent, is by
intrarectal administration. In certain embodiments, administration
of gene silencing compounds according to the invention, alone or in
combination with any other agent, is by intrathecal administration.
In certain embodiments, administration of gene silencing compounds
according to the invention, alone or in combination with any other
agent, is directly to the bladder. In certain embodiments,
administration of gene silencing compounds according to the
invention, alone or in combination with any other agent, is
directly to the lung.
[0176] Administration of the therapeutic compositions of gene
silencing compounds according to the invention can be carried out
using known procedures using an effective amount and for periods of
time effective to reduce symptoms or surrogate markers of the
disease. For example, an effective amount of a gene silencing
compound according to the invention for treating a disease and/or
disorder could be that amount necessary to alleviate or reduce the
symptoms, or delay or ameliorate the disease and/or disorder. In
the context of administering a composition that modulates gene
expression, an effective amount of a gene silencing compound
according to the invention is an amount sufficient to achieve the
desired modulation as compared to the gene expression in the
absence of the gene silencing compound according to the invention.
The effective amount for any particular application can vary
depending on such factors as the disease or condition being
treated, the particular compound being administered, the size of
the subject, or the severity of the disease or condition. One of
ordinary skill in the art can empirically determine the effective
amount of a particular compound without necessitating undue
experimentation.
[0177] When administered systemically, the therapeutic composition
is preferably administered at a sufficient dosage to attain a blood
level of gene silencing compound according to the invention from
about 0.0001 micromolar to about 10 micromolar. For localized
administration, much lower concentrations than this may be
effective, and much higher concentrations may be tolerated.
Preferably, a total dosage of gene silencing compound according to
the invention ranges from about 0.001 mg per patient per day to
about 200 mg per kg body weight per day. In certain embodiments,
the total dosage may be 0.08, 0.16, 0.32, 0.48, 0.32, 0.64, 1, 10
or 30 mg/kg body weight administered daily, twice weekly or weekly.
It may be desirable to administer simultaneously, or sequentially a
therapeutically effective amount of one or more of the therapeutic
compositions of the invention to an individual as a single
treatment episode.
[0178] The methods according to this aspect of the invention are
useful for model studies of gene expression. The methods are also
useful for the prophylactic or therapeutic treatment of human or
animal disease. For example, the methods are useful for pediatric
and veterinary inhibition of gene expression applications.
[0179] The examples below are intended to further illustrate
certain preferred embodiments of the invention, and are not
intended to limit the scope of the invention.
Example 1
Preparation of Oligonucleotide-Based Compounds
[0180] The oligonucleotide-based compounds of the invention were
chemically synthesized using phosphoramidite chemistry on automated
DNA/RNA synthesizer. TAC protected (Except U) 2'-O-TBDMS RNA
monomers, A, G, C and U, were purchased from Sigma-Aldrich.
7-deaza-G, inosine and loxoribine monomers were purchased from
ChemGenes Corporation. 0.25M 5-ethylthio-1H-tetrazole,
PAC-anhydride Cap A and Cap B were purchased from Glen Research. 3%
trichloroacetic acid (TCA) in dichloromethane (DCM) and 5%
3H-1,2-Benzodithiole-3-one-1,1-dioxide (Beaucage reagent) were made
in house.
[0181] Oligonucleotide-based compounds of the invention were
synthesized at 1-2 .mu.M scale using a standard RNA synthesis
protocol.
Cleavage and Base Deprotection
[0182] Oligonucleotide-based compounds of the invention were
cleaved from solid support and the solution was further heated at
65.degree. C. to removing protecting groups of exo cyclic-amines.
The resulting solution was dried completely in a SpeedVac.
IE HPLC Purification
[0183] Oligonucleotide-based compounds of the invention were
purified by ion exchange HPLC.
[0184] Column: Dionex DNAPac 100 column (22.times.250)
[0185] Column Heater: ChromTech TL-105 HPLC column heater,
temperature is set to 80.degree. C.
[0186] Buffer A: 20 mM Tris-HCl, pH 7.0, 20% acetinitrile
[0187] Buffer B: 3.0 M NaCl, 20 mM Tris-HCl, pH 7.0, 20%
acetonitrile
[0188] Flow rate: 10 ml/min
[0189] Gradient: [0190] 0-2 min: 0% B [0191] 2-11 min: 0% B to 35%
B [0192] 11-41 min: 35% B to 90% B [0193] 41-45 min: 100% B
[0194] Crude solution of oligonucleotide-based compounds of the
invention was injected into HPLC. Above gradient is performed and
the fractions were collected. All fractions containing more than
90% desired product were mixed, and then the solution was
concentrated to almost dry by RotoVap. RNAse-free water was added
to make final volume of 10 ml.
C-18 Reversed Phase Desalting
[0195] CC-18 Sep-Pak cartridge purchased from Waters was first
conditioned with 10 ml of acetonitrile followed by 10 ml of 0.5 M
sodium acetate. 10 ml of the solution of oligonucleotide-based
compounds of the invention was loaded. 15 ml of water was then used
to wash out the salt. The oligonucleotide-based compounds of the
invention was eluted out by 1 ml of 50% acetonitrile in water.
[0196] The solution is placed in SpeedVac for 30 minutes. The
remaining solution was filter through a 0.2 micro filter and then
was lyophilized to dryness. The solid was then re-dissolved in
water to make the desired concentration.
[0197] The final solution was stored below 0.degree. C.
Capillary Electrophoresis
[0198] Oligonucleotide-based compounds of the invention were
analyzed by capillary electrophoresis according to the following
conditions.
[0199] Instrument: Beckman 5010
[0200] Capillary: 62 cm ssDNA capillary
[0201] Sample preparation: 0.2 OD of oligonucleotide-based
composition according to the invention was dissolved in 200ul of
RNAse-free water.
[0202] Injection: electro-kinetic injection at 5KV for 5
seconds.
[0203] Running condition: 14KV for 50 minutes at 30.degree. C.
Ion Exchange HPLC Analysis
[0204] Oligonucleotide-based compounds of the invention were
analyzed by ion exchange HPLC according to the following
conditions:
[0205] Column: Dionex DNAPac guard column (22.times.250)
[0206] Column Heater: ChromTech TL-105 HPLC column heater,
temperature is set to 80.degree. C.
[0207] Buffer A: 100 mM Tris-HCl, pH 8.0, 20% acetinitrile
[0208] Buffer B: 2.0 M LiCl, 100 mM Tris-HCl, pH 8.0, 20%
acetonitrile
[0209] Flow rate: 2 ml/min
[0210] Gradient: [0211] 0-2 min: 0% B [0212] 2-10 min: 0% B to 100%
B [0213] 10-15 min: 100% B
PAGE Analysis
[0214] 0.3 OD of oligonucleotide-based compounds of the invention
was loaded on 20% polyacrylamide gel and was running at constant
power of 4 watts for approximately 5 hours. The gel was viewed
under short wavelength UV light.
Dual Luciferase Reporter System Assay
[0215] Hepa 1-6 cells are co-transfected with GSO and target
plasmid simultaneously using LIPOFECTAMINE.RTM. 2000 on day one
(20,000 c/well). RLuc siRNA was used as the positive control and
GSO mu/hu universal control was used as the negative control. On
day two (24 hours post-transfection), luminescence measurements for
both reporter genes are taken separately: Firefly luciferase:
expression serves as the normalizer for the assay; Renilla
luciferase: substrate includes a "stop" reagent to quench
luminescence from firefly. Separate luminescence measurements are
taken to correspond to renilla-target transcript expression.
Substrate includes DTT to lyse cells. Results are shown in Table 4A
and Table 4B.
TABLE-US-00004 TABLE 4A % KD Luciferase 3GA Screen # GSO sequence
(25 nM) 1 3'-GACCGTACACCCAGGCCG-5'-X- 72.80
5'-GCCGGACCCACATGCCCAG-3' 2 3'-ACACCCAGGCCGTCCATGG-5'-X- 74.00
5'-GGTACCTGCCGGACCCACA-3' 3 3'-TCGACCGTTAGTCCCACCG-5'-X- 73.10
5'-GCCACCCTGATTGCCAGCT-3' 4 3'-TCTCCCTCGTTTACGGTGG-5'-X- 62.60
5'-GGTGGCATTTGCTCCCTCT-3' 5 3'-TCCCTGCTCTCTTCTGTGG-5'-X- 20.80
5'-GGTGTCTTCTCTCGTCCCT-3' 6 3'-ACCCTGCATCCCCGAGTCG-5'-X- 52.80
5'-GCTGAGCCCCTACGTCCCA-3' 7 3'-TGTTCCACGTCTCGACCCC-5'-X- 76.50
5'-CCCCAGCTCTGCACCTTGT-3' 8 3'-TCCCTTGGTCGTCTCGATC-5'-X- 71.50
5'-CTAGCTCTGCTGGTTCCCT-3' 9 3'-TACGTCTAGGGTGTCCGCG-5'-X- 76.32
5'-GCGCCTGTGGGATCTGCAT-3' 10 3'-CACGATGTTGACCCGACCG-5'-X- 80.51
5'-GCCAGCCCAGTTGTAGCAC-3' 11 3'-TCGTTGGTCTGCCTGTTCG-5'-X- 64.70
5'-GCTTGTCCGTCTGGTTGCT-3' 12 3'-TCCCACTGTCTCTCTTCCC-5'-X- 63.00
5'-CCCTTCTCTCTGTCACCCT-3' 13 3'-CCCACTGTCTCTCTTCCCG-5'-X- 71.30
5'-GCCCTTCTCTCTGTCACCC-3' 14 3'-CCACTGTCTCTCTTCCCGT-5'-X- 61.91
5'-TGCCCTTCTCTCTGTCACC-3' 15 3'-ACGATCAGACCCAGGACCG-5'-X- 53.22
5'-GCCAGGACCCAGACTAGCA-3' 16 3'-TCAGACCCAGGACCGGCAG-5'-X- 73.38
5'-GACGGCCAGGACCCAGACT-3' 17 3'-GTGACTCCGGACTCCTACC-5'-X- 53.02
5'-CCATCCTCAGGCCTCAGTG-3' 18 3'-GACTCCGGACTCCTACCTG-5'-X- 51.62
5'-GTCCATCCTCAGGCCTCAG-3' 19 3'-CTCCGGACTCCTACCTGTG-5'-X- 56.13
5'-GTGTCCATCCTCAGGCCTC-3' 20 3'CCGGACTCCTACCTGTGAC-5'-X- 46.22
5'-CAGTGTCCATCCTCAGGCC-3' 21 3'-CCTCTTCGTCCGTCCCACG-5'-X- 68.62
5'-GCACCCTGCCTGCTTCTCC-3' 22 3'-TCTTCGTCCGTCCCACGTC-5'-X- 73.88
5'-CTGCACCCTGCCTGCTTCT-3' 23 3'-GGGTCCGTCGTCCACAGTG-5'-X- 61.92
5'-GTGACACCTGCTGCCTGGG-3' 24 3'-GGATGTCCCTCCCGGTCTA-5'-X- 40.93
5'-ATCTGGCCCTCCCTGTAGG-3' 25 3'-ATGTCCCTCCCGGTCTACG-5'-X- 41.82
5'-GCATCTGGCCCTCCCTGTA-3' 26 3'-GTCCCTCCCGGTCTACGTC-5'-X- 57.94
5'-CTGCATCTGGCCCTCCCTG-3' 27 3'-CCCTCCCGGTCTACGTCAG-5'-X- 58.14
5'-GACTGCATCTGGCCCTCCC-3' 28 3'-CTCCCGGTCTACGTCAGTG-5'-X- 63.13
5'-GTGACTGCATCTGGCCCTC-3' 29 3'-GGTTCTGACCCGTGTCCTC-5'-X- 59.63
5'-CTCCTGTGCCCAGTCTTGG-3' 30 3'-TCGAGGACCGACACCACCC-5'-X- 77.64
5'-CCCACCACAGCCAGGAGCT-3' 31 3'-CGAGGACCGACACCACCCG-5'-X- 80.53
5'-GCCCACCACAGCCAGGAGC-3' 32 3'-GGGTCCGTCGTGGAGTCCG-5'-X- 62.62
5'-GCCTGAGGTGCTGCCTGGG-3' 33 3'-CCGTCCCTTCGACTCCGTC-5'-X- 73.27
5'-CTGCCTCAGCTTCCCTGCC-3' 34 3'-CGTCCCTTCGACTCCGTCA-5'-X- 78.22
5'-ACTGCCTCAGCTTCCCTGC-3' 35 3'-CCCGTCCGTCTCGACCTCC-5'-X- 60.58
5'-CCTCCAGCTCTGCCTGCCC-3' 36 3'-CCGTCCGTCTCGACCTCCG-5'-X- 54.52
5'-GCCTCCAGCTCTGCCTGCC-3' 37 3'-CAGGGTTCCAGTCCTCCCG-5'-X- 71.63
5'-GCCCTCCTGACCTTGGGAC-3' 38 3'-GGGTTCCAGTCCTCCCGTC-5'-X- 69.94
5'-CTGCCCTCCTGACCTTGGG-3' 39 3'-GTTCCAGTCCTCCCGTCCC-5'-X- 71.58
5'-CCCTGCCCTCCTGACCTTG-3' 40 3'-GTCCCGGACCCACCCTTCC-5'-X- 57.15
5'-CCTTCCCACCCAGGCCCTG-3' 41 3'-CCCGGACCCACCCTTCCAT-5'-X- 51.93
5'-TACCTTCCCACCCAGGCCC-3' 42 3'-CGGACCCACCCTTCCATGT-5'-X- 31.04
5'-TGTACCTTCCCACCCAGGC-3' 43 3'GACCCACCCTTCCATGTCC-5'-X- 44.89
5'-CCTGTACCTTCCCACCCAG-3' 44 3'-GTCCCGGTGGTCGTAGGTC-5'-X- 61.72
5'-CTGGATGCTGGTGGCCCTG-3' 45 3'-TCCCGGTGGTCGTAGGTCC-5'-X- 52.12
5'-CCTGGATGCTGGTGGCCCT-3' 46 3'TCCGTGGACTCACCGACCC-5'-X- 76.87
5'-CCCAGCCACTCAGGTGCCT-3' 47 3'-CTCACCGACCCTGTTCCCT-5'-X- 68.50
5'-TCCCTTGTCCCAGCCACTC-3' 48 3'-CACCGACCCTGTTCCCTAG-5'-X- 74.30
5'-GATCCCTTGTCCCAGCCAC-3' 49 3'-GCCCTCGACCTGGACGAAC-5'-X- 67.80
5'-CAAGCAGGTCCAGCTCCCG-3' 50 3'-TGTCGTTGAAGTCCCCCTC-5'-X- 76.40
5'-CTCCCCCTGAAGTTGCTGT-3' 51 3'-TGCCACCACGCCTGATGTT-5'-X- 84.40
5'-TTGTAGTCCGCACCACCGT-3' 52 3'-TCCCTTGTGTCTCCAGTGG-5'-X- 58.30
5'-GGTGACCTCTGTGTTCCCT-3' 53 3'-ATCCCTCCGTCTCCGTCCG-5'-X- 76.10
5'-GCCTGCCTCTGCCTCCCTA-3' 54 3'-GACTTCCTTGTCCGACCCG-5'-X- 70.30
5'-GCCCAGCCTGTTCCTTCAG-3' Where X is glycerol
TABLE-US-00005 TABLE 4B % KD Luciferase Screen 3GA # (25 nM) 55
72.55 56 16.18 57 68.59 58 82.08 59 64.04 60 61.19 61 55.65 62
29.88 63 44.00 64 73.27 65 69.04 66 76.39 67 67.30 68 84.30 69
61.65 70 59.28 71 60.44 72 49.61 73 65.21 74 52.34 75 82.43 76
68.25 77 83.97 78 82.25 79 67.84 80 41.54 81 80.09 82 53.95 83
74.05 84 2.78 85 53.89 86 53.70 87 34.15 88 77.07 89 23.27 90 41.99
91 41.36 92 60.45 93 58.99 94 74.51 95 10.33 96 9.46 97 42.36 98
27.05 99 24.30 100 10.54 101 85.55 102 60.69 103 63.04 104 59.83
105 57.80 106 71.35 107 74.39 108 74.04 109 80.27 110 89.98 111
86.33 112 88.35 113 84.67 114 57.13 115 56.03 116 77.36 117 72.63
118 74.24 119 79.93 120 86.42 121 57.13 122 49.63 123 65.62 124
72.63 125 96.00 126 71.45 127 -0.08 128 4.49 129 60.37 130 67.01
131 10.42 132 72.11 133 66.46 134 58.22 135 40.56 136 75.82 137
69.22 138 69.06 139 79.03 140 10.17 141 25.50 142 84.19 143 81.61
144 70.57 145 78.67 146 66.46 147 58.98 148 69.06 149 97.18 150
81.25 151 30.14 152 73.42 153 79.87 154 63.67 155 71.18 156 64.26
157 84.39 158 91.96 159 87.62 160 85.37 161 90.51 162 90.48 163
88.20 164 82.16 165 79.86 166 88.55 167 91.35 168 81.98 169 94.67
170 84.41 171 82.59 172 31.12 173 67.25 174 36.58 175 55.38 176
73.10 177 77.05 178 91.25 179 83.86 180 85.21 181 72.85 182 61.27
183 81.35 184 68.97 185 67.13 186 57.30 187 79.41 188 41.38 189
50.80 190 52.18 191 63.14 192 82.52 193 41.99 194 73.39 195 76.17
196 85.66 197 98.60 198 47.11 199 42.47 200 87.17 201 74.36 202
58.24 203 59.21 204 42.36 205 74.17 206 76.54 207 30.41 208 68.55
209 69.73 210 59.73 211 54.92 212 56.90 213 69.09 214 77.40 215
39.73 216 39.23 217 41.13 218 23.48 219 79.92 220 29.57 221 64.50
222 73.89 223 81.38 224 70.29 225 69.92 226 81.70 227 59.46 228
81.39 229 88.01 230 75.84 231 58.18 232 29.33 233 61.77 234 72.38
235 45.83 236 39.94 237 66.24 238 49.78 239 23.03 240 59.57 241
41.65 242 44.50 243 18.23 244 37.51 245 58.43 246 70.66 247 74.80
248 70.32 249 90.70 250 73.19 251 81.50 252 87.92 253 76.82 254
55.60 255 42.30 256 44.52 257 81.17 258 64.45 259 79.46 260 41.81
261 46.85 262 83.04 263 78.00 264 69.88 265 59.09 266 39.05 267
34.97 268 83.20 269 86.16 270 49.03 271 70.17 272 86.40 273 67.96
274 44.65 275 65.68 276 66.68 277 76.67 278 39.46 279 69.63 280
68.44 281 57.77 282 67.85 283 61.74 284 69.87 285 58.11 286 41.07
287 42.40 288 42.09* 289 61.77* 290 33.46* 291 49.08* 292 43.43*
293 40.08* 294 57.06* 295 87.34* 296 76.54*
297 36.96* 298 96.71* 299 70.53* 300 88.21* 301 76.86* 302 85.21*
303 74.25* 304 70.61* 305 83.52* 306 65.18* 307 84.36* 308 91.72
309 93.78 310 86.49 311 79.67 312 78.18 313 68.73 314 49.06 315
51.92 316 64.80 317 49.86 318 60.88 319 54.14 320 54.27 321 64.20
322 57.54 323 64.73 324 24.73 325 -3.86 326 58.29 327 85.58 328
38.27 329 54.35 330 37.69 331 42.71 332 77.86 333 34.95 334 29.20
335 41.76 336 55.25 337 56.23 338 44.34 339 42.26 340 33.54 341
32.88 342 46.91 343 25.39 344 53.54 345 68.08 346 65.26 347 70.49
348 33.62 349 78.29 350 87.30 351 92.56 352 82.30 353 62.64 354
84.10 355 72.48 356 87.25 357 68.93 358 77.23 359 74.70 360 43.71
361 86.31 362 52.57 363 38.62 364 64.49 365 66.70 366 77.24 367
89.81 368 77.82 369 62.31 370 80.21 371 58.76 372 71.34 373 65.23
374 65.58 375 78.67 376 67.01 377 32.15 378 49.07 379 53.07 380
58.24 381 72.09 382 63.90 383 68.54 384 15.69 385 25.43 386
40.49
For 3GA compounds numbers 55 through 386 listed in Table 4B,
glycerol is the non-nucleotidic linker.
Flow Cytometric Analysis
[0216] Whole blood samples with anticoagulant EDTA from mice in
study were stained for 30 minutes in the dark at room temperature
with the following labeled antibodies from BD Biosciences in the
presence of mouse Fc blocker (Affymetrix eBioscience, 14-0161): rat
anti-mouse CD3-Alexa Fluor 647 (557869), rat anti-mouse CD4-Alexa
Fluor 647 (557681), rat anti-mouse CD8-Alexa Fluor 488 (557668) or
the corresponding isotype controls. Red blood cells were lysed with
freshly prepared 1.times.RBC lysis buffer (eBioscience, 00-4300)
and washed with flow cytometry staining buffer (BD Biosciences,
554657). Resuspended cell suspensions in the flow cytometry
staining buffer were run on BD Accuri C6 to acquire data and
analyzed by FLOWJO (TreeStar).
IC50 Analysis
[0217] Hepa 1-6 cells are co-transfected with 3GA and target
plasmid simultaneously using LIPOFECTAMINE.RTM. 2000 on day one
(20,000 c/well). Concentration of 3GAs were ranging from 0.019 to
41.7 nM with a 3-fold increment. RLuc siRNA was used as the
positive control and 3GA mu/hu universal control was used as the
negative control. On day two (24 hours post-transfection),
luminescence measurements for both reporter genes are taken
separately: Firefly luciferase: expression serves as the normalizer
for the assay; Renilla luciferase: substrate includes a "stop"
reagent to quench luminescence from firefly. Separate luminescence
measurements are taken to correspond to renilla-target transcript
expression. Substrate includes DTT to lyse cells. IC50 of 3GAs was
calculated using GraphPad Prism 6. Results are shown in Table
5.
TABLE-US-00006 TABLE 5 3GA Target GSO Sequence IC.sub.50 # target
Site 5' to 3' (nM) 75 mIDO1 138 CTAGCCACAAGGACCCAGG 33.1 81 hIDO1
172 GCAGAGCAAAGCCCACTTC 3.49 92 1239 GCCTCCAGTTCCTTTGGCT 1.53 3
mPD1 115 GCCACCCTGATTGCCAGCT 59.0 10 hPD1 108 GCCAGCCCAGTTGTAGCAC
3.87 33 1591 CTGCCTCAGCTTCCCTGCC 1.57 46 2024 CCCAGCCACTCAGGTGCCT
3.16 54 mPD-L1 3311 GCCCAGCCTGTTCCTTCAG 14.4 55 hPD-L1 571
GGTAGCCCTCAGCCTGACA 5.00 58 1080 CCCACATTGCCTGCATCCC 2.42 64 1855
TCTGTTTGCTTCCTCAGCT 2.51 158 mTIM3 1425 ACTTATCACCCTCCTGCCT 5.55
169 hTIM3 59 CTGCCAGGTCTACAGTCAC 13.8 180 1506 CAGCACCCAGTTTTCCCTA
6.10 183 1716 ATCCCAGCCACTCAGGAGG 32.7 110 mLAG3 1108
GCTCCAGACCCAGAACCTT 6.49 124 hLAG3 1356/ GACAGTGGCATTGAGCTGC 11.9
1369 122 1822/ GCTCCAGCTCCTCTATCTT 9.10 1841 143 1848
GGTTCTTGCTCCAGCTCCT 5.03 195 mCTLA4 563 GTTGCCCATGCCCACAAAG 19.6
225 hCTLA4 1822 GCCTTCTTCTGTCCATGGC 1.71 247 mIDO2 2748
GGTGACTTCCAGGTCTGCA 0.247 249 hID02 156 GGTGTCCATTGCCTTCTGT 2.73
259 1137 AGTCACCACTTTCCTTGCT 3.36 262 1363 GGCTTCCCATGCTTTGCCT 1.28
361 mOX40L 1069 TGGACACCACCCTTTCCAT 0.673 368 hOX40L 712
TGGTCCGTGGTCGTACTTG 0.553 370 1104 CTCCTCGTTCCTCACTTCC 5.01
In Vivo Mouse Tumor Model
[0218] Colon tumor can be implanted in BALB/c mice by subcutaneous
injection of 10.sup.6 CT26.WT cells at right flank (Tumor 1) and
10.sup.6 CT26.CL25 cells at left flank (Tumor 2) on day 0.
Treatment can be initiated on day 6 or when tumor size reached to
70 to 80 mm.sup.3 by intra-tumor injection of gene silencing
compound according to the invention at various dosages (e.g., 2
mg/kg, 5 mg/kg, 12.5 mg/kg, or 25 mg/kg) on day 6, 10, 13, 16, 20,
and 22.
[0219] Tumor growth can be monitored twice per week throughout the
study period. The study can be terminated with blood, spleen and
tumor tissues collected for further evaluation. T lymphocyte
population in blood and spleen samples were detected and analyzed
by flow cytometry. Spleen IFN-.gamma.-producing cells were detected
with ELISPOT assay after culture of spleen cells for 24 hours with
tumor antigen beta-gal or AH1 peptide. Tumor tissues were analyzed
for gene expression by RT-PCR.
EQUIVALENTS
[0220] Those skilled in the art will recognize, or be able to
ascertain, using no more than routine experimentation, numerous
equivalents to the specific substances and procedures described
herein. For example, antisense oligonucleotides that overlap with
the oligonucleotides may be used. Such equivalents are considered
to be within the scope of this invention, and are covered by the
following claims.
Sequence CWU 1
1
406119DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1gccggaccca catgcccag 19219DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 2ggtacctgcc ggacccaca 19319DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 3gccaccctga ttgccagct 19419DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 4ggtggcattt gctccctct 19519DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 5ggtgtcttct ctcgtccct 19619DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 6gctgagcccc tacgtccca 19719DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 7ccccagctct gcaccttgt 19819DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 8ctagctctgc tggttccct 19919DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 9gcgcctgtgg gatctgcat 191019DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 10gccagcccag ttgtagcac 191119DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 11gcttgtccgt ctggttgct 191219DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 12cccttctctc tgtcaccct 191319DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 13gcccttctct ctgtcaccc 191419DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 14tgcccttctc tctgtcacc 191519DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 15gccaggaccc agactagca 191619DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 16gacggccagg acccagact 191719DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 17ccatcctcag gcctcagtg 191819DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 18gtccatcctc aggcctcag 191919DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 19gtgtccatcc tcaggcctc 192019DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 20cagtgtccat cctcaggcc 192119DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 21gcaccctgcc tgcttctcc 192219DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 22ctgcaccctg cctgcttct 192319DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 23gtgacacctg ctgcctggg 192419DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 24atctggccct ccctgtagg 192519DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 25gcatctggcc ctccctgta 192619DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 26ctgcatctgg ccctccctg 192719DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 27gactgcatct ggccctccc 192819DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 28gtgactgcat ctggccctc 192919DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 29ctcctgtgcc cagtcttgg 193019DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 30cccaccacag ccaggagct 193119DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 31gcccaccaca gccaggagc 193219DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 32gcctgaggtg ctgcctggg 193319DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 33ctgcctcagc ttccctgcc 193419DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 34actgcctcag cttccctgc 193519DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 35cctccagctc tgcctgccc 193619DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 36gcctccagct ctgcctgcc 193719DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 37gccctcctga ccttgggac 193819DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 38ctgccctcct gaccttggg 193919DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 39ccctgccctc ctgaccttg 194019DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 40ccttcccacc caggccctg 194119DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 41taccttccca cccaggccc 194219DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 42tgtaccttcc cacccaggc 194319DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 43cctgtacctt cccacccag 194419DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 44ctggatgctg gtggccctg 194519DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 45cctggatgct ggtggccct 194619DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 46cccagccact caggtgcct 194719DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 47tcccttgtcc cagccactc 194819DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 48gatcccttgt cccagccac 194919DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 49caagcaggtc cagctcccg 195019DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 50ctccccctga agttgctgt 195119DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 51ttgtagtccg caccaccgt 195219DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 52ggtgacctct gtgttccct 195319DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 53gcctgcctct gcctcccta 195419DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 54gcccagcctg ttccttcag 195519DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 55ggtagccctc agcctgaca 195619DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 56ccatcattct cccttttct 195719DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 57attgcctgca tcccacggg 195819DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 58cccacattgc ctgcatccc 195919DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 59ttcagtgctt gggcctttt 196019DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 60ggctccctgt ttgactcca 196119DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 61gtatcaaggt ctccctcca 196219DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 62tcctttctcc ctgtcacag 196319DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 63attctcaacc cgtcttcct 196419DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 64tctgtttgct tcctcagct 196519DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 65gggtggcagt ctgaggtct 196619DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 66ggacagtggg tggcagtct 196719DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 67ttcccctcgc atcatcctt 196819DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 68tcccagacca cattggcct 196919DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 69tgcaccctgg agagcccat 197019DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 70gctggtggca ttcaagggt 197119DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 71cgaaacctcc aggaagcct 197219DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 72gatctcccag ggcatctga 197319DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 73gccttgctca gccacaatt 197419DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 74tatgtgcctt gctcagcca 197519DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 75ctagccacaa ggacccagg 197619DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 76atgtacccca gggccaggt 197719DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 77atcccctcgg ttccacaca 197819DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 78cccttgtcgc agtccccac 197919DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 79gaagatgctg ctctggcct 198019DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 80cagtccctct gctttccac 198119DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 81gcagagcaaa gcccacttc 198219DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 82cctgtggatt tggcagagc 198319DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 83ctccatgacc tttgcccca 198419DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 84ctttttcttc cagtttgcc 198519DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 85cagctgctat ttccaccaa 198619DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 86gttgcctttc cagccagac 198719DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 87gctgggggtt gcctttcca 198819DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 88cccttcatac accagaccg 198919DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 89tgtcctccac cagcagtct 199019DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 90gcagatggta gctcctcag 199119DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 91tcctttggct gctggcttg 199219DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 92gcctccagtt cctttggct 199319DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 93aatcagtgcc tccagttcc 199419DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 94gtgctcttgt tgggttaca 199519DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 95gcctcggcct cccaaagtg 199619DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 96tagctgggac tacaggtgc 199719DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 97tctcctgcct cagcctccc 199819DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 98acgccattct cctgcctca 199919DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 99gctccgcctc ccaggttca 1910019DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 100ggcacaatct tggctcact 1910119DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 101gctcctccag acccagtcc 1910219DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 102ggcctcccca gccctccaa 1910319DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 103ggagcaggtc ctccctcat 1910419DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 104agctctttcc caggccctg 1910519DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 105cccctggtga aggtcaagg 1910619DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 106ggcatcccct ggtgaaggt 1910719DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 107gtctaggcga gggcatccc
1910819DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 108ggcactcggt tctggccct
1910919DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 109gacacagccc caggtccca
1911019DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 110gctccagacc cagaacctt
1911119DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 111gggcagctcc accctagaa
1911219DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 112gccactcttt ccagccacg
1911319DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 113gccagaccca cagcctcaa
1911419DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 114caggtgtagg tcccagcct
1911519DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 115gcattgagct gctgtccct
1911619DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 116ggcctcctga atctccagc
1911719DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 117gcctctggcc ctcgtacag
1911819DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 118ccagctcctc tatcttcct
1911919DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 119ctgcctcggc tccaggtca
1912019DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 120gctgctgaga cctgctggc
1912119DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 121aggtgtaggt cccagcctg
1912219DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 122gctccagctc ctctatctt
1912319DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 123gccatctctg taggtgagg
1912419DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 124gacagtggca ttgagctgc
1912519DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 125tctctgggcc ttcacccct
1912619DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 126ctgggcagat caggcagcc
1912719DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 127gggagggatg accagaggc
1912819DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 128gggaggtgga ggaaggggt
1912919DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 129ctgagcctcc cacatctct
1913019DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 130gcttcactgg agccaccca
1913119DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 131ggctgagatc ctggagggg
1913219DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 132gctgccaagt gacccctgc
1913319DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 133ggacccacgc tcagcaccg
1913419DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 134ccatagcgag aagtccccg
1913519DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 135tggcccaggc gcagacgga
1913619DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 136ccatggggct gacttgggg
1913719DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 137ttgagctgct gttcctgca
1913819DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 138gcagcttccc cagggatcc
1913919DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 139gggatggggt gtccagaga
1914019DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 140tgggaaagga gctgggcct
1914119DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 141agaagcctct ccccctggt
1914219DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 142ggcacctggg ctagacagc
1914319DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 143ggttcttgct ccagctcct
1914419DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 144gctgagatct gctggctgc
1914519DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 145gctgctgaca gggagttta
1914619DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 146acgctcagca ccgtgtagc
1914719DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 147aggaggagtc cacttggca
1914819DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 148agtggcattg agctgctgt
1914919DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 149aatcccttgc cccagcaca
1915019DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 150gagatcgccc tttagctgg
1915119DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 151tgcagcagta ggtcccatg
1915219DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 152ggagtgacct tggctgctt
1915319DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 153cccagcagag actcccact
1915419DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 154catttgccaa ccctcctgg
1915519DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 155gctggctgtt gacgtagca
1915619DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 156ttagcccttt attccccct
1915719DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 157cctcctgcct aaggttccc
1915819DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 158acttatcacc ctcctgcct
1915919DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 159gagcctcatc tccagcctc
1916019DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 160tcactgtccg agcctcatc
1916119DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 161ctgactgcac gcaagcccc
1916219DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 162gagcagagga caaccccca
1916319DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 163ctgctctgcc atgctccca
1916419DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 164gtcagttccc cttgagcac
1916519DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 165ctgccttcgt atgtcccag
1916619DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 166cacagttgct ccccaatgc
1916719DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 167agccaggacc tccacagct
1916819DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 168gtctcccttc catacccac
1916919DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 169ctgccaggtc tacagtcac
1917019DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 170cagcagcagc agcaggaca
1917119DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 171ggcattctga ccgacctcc
1917219DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 172tccctttcat cagtcctga
1917319DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 173gaggctcccc agtgtctgt
1917419DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 174ggccaatcta gagtcccgt
1917519DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 175gtgagggttg ctgcctgct
1917619DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 176gcagtggaca gaacctcca
1917719DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 177cagtgcaggt cccagttca
1917819DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 178gagctccaga gaccccacg
1917919DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 179gcccgaattt cctggagct
1918019DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 180cagcacccag ttttcccta
1918119DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 181gcccctttag actttctgt
1918219DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 182tgccattgca ctccagcct
1918319DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 183atcccagcca ctcaggagg
1918419DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 184atgcctgtaa tcccagcca
1918519DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 185gctcacgcct gtaatccca
1918619DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 186ggctggatgt ggtggctca
1918719DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 187gccacatctc agccctgca
1918819DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 188gcctttgcct tctttccac
1918919DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 189ggtcctcagg gagcagagt
1919019DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 190aggccaagtc ctagaaggc
1919119DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 191tgggtcacct gtatggctt
1919219DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 192agtcacccgg acctcatca
1919319DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 193gcccactgta ttcttctct
1919419DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 194gtcaacagct ctcagtcct
1919519DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 195gttgcccatg cccacaaag
1919619DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 196tcccgttgcc catgcccac
1919719DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 197ccccaagcta actgcgaca
1919819DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 198tcacatagac ccctgttgt
1919919DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 199cattctggct ctgttgggg
1920019DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 200ccttgacccc acaccataa
1920119DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 201ctcttccttc acccccttc
1920219DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 202ctccccagcc aaacctccc
1920319DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 203agctccccag ccaaacctc
1920419DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 204gacctcgagt ccaacctga
1920519DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 205gccagttggt gcaggacct
1920619DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 206actccatcac catcggttt
1920719DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 207cccagtttac actccatca
1920819DNAArtificial SequenceDescription of Artificial Sequence
Synthetic
oligonucleotide 208tcccatccta ccatctgct 1920919DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 209gggagcggtg ttcaggtct 1921019DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 210aggagagtgc agggccagg 1921119DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 211cggacctcag tggctttgc 1921219DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 212ccatggccct cagtccttg 1921319DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 213ccgttgccta tgcccaggt 1921419DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 214gggttccgca tccaacttt 1921519DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 215catcccagct ctgtctttc 1921619DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 216gcatccccat attaatccc 1921719DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 217ctccctgcct tttccttct 1921819DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 218acctttagca tcactggct 1921919DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 219agtgtcctga gctcctcca 1922019DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 220ccttgtgttc tacctggtg 1922119DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 221cctcatccag tttccaagc 1922219DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 222ctcagcacaa ttccacgca 1922319DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 223agccccaaag cacatgtca 1922419DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 224atacctgtgg gtctcctgg 1922519DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 225gccttcttct gtccatggc 1922619DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 226gcaccccatt ctgccacct 1922719DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 227tcacatagac ccctgttgt 1922819DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 228ttgggctgtg ccattccct 1922919DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 229tgccccagag gaatgccca 1923019DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 230gtggtatctc cccaaggac 1923119DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 231cagtccagga gaggcatcc 1923219DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 232ggagtcccaa gttcctgga 1923319DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 233tccaacggtc cttctgggt 1923419DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 234gcctccattc cctgaacca 1923519DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 235ggattgtcct tccacccag 1923619DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 236gctgcacttc ctccagagt 1923719DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 237gcggcatgta gtccctcat 1923819DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 238ccaggaccag aggccagta 1923919DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 239gtacccccag tgcccctgt 1924019DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 240caccaggaca caggagggc 1924119DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 241gctcccacgg gacctgact 1924219DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 242tgaggaggtc atggctgca 1924319DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 243gggacgaggg aggtaggga 1924419DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 244gtttgaggcc catcagacc 1924519DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 245gctcagtggc tcatccctg 1924619DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 246ggctgtccca ggtcacaga 1924719DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 247ggtgacttcc aggtctgca 1924819DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 248cccgtgctgg tgacttcca 1924919DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 249ggtgtccatt gccttctgt 1925019DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 250gcctggtggg tgaagtgtc 1925119DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 251ttgtggtggc ctggtgggt 1925219DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 252attcggtctg tggggctcc 1925319DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 253ctccttcctg ccagacata 1925419DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 254gccccaagtt cctggagac 1925519DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 255cccaatttcc aggaatccg 1925619DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 256ctccaggttc ccaatttcc 1925719DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 257tgcaggctct ctcccccag 1925819DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 258ggcactgctt ctttctcta 1925919DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 259agtcaccact ttccttgct 1926019DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 260ggtgctgagt ggatgtctt 1926119DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 261cagcaagtgg tcctgtcca 1926219DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 262ggcttcccat gctttgcct 1926319DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 263tccacctgtg cccctgtct 1926419DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 264actccaaggt cttatccct 1926519DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 265tgatcccagg cagaaccct 1926619DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 266gggctgagat ccttcctgg 1926719DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 267tgggggttct gcatgagga 1926819DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 268actcctctgg gggttctgc 1926919DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 269agtaatgtat ccccaggca 1927019DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 270aagagggctg gtctgggac 1927119DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 271gtagtgtttc ccttgtacc 1927219DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 272gccgtagtgt ttcccttgt 1927319DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 273ctatagccgt agtgtttcc 1927419DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 274gtgaggaaca gaatccggg 1927519DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 275ttcctgcttc tggtttgtt 1927619DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 276ccatttcctg cttctggtt 1927719DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 277gccatttcct gcttctggt 1927819DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 278ccatgctgga actctgtct 1927919DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 279ctgcacaggc tccatgctg 1928019DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 280cctgcacagg ctccatgct 1928119DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 281ctgtgggatt gaaacctgc 1928219DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 282ggtgttactg tgggattga 1928319DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 283gcagaaggtg ttactgtgg 1928419DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 284gtctgagcag gtggggtgc 1928519DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 285gcagtctgag caggtgggg 1928619DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 286tgtccaggta gccaggcct 1928719DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 287aatgtccagg tagccaggc 1928819DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 288gccctgtctt cacctgtgg 1928919DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 289tcctgctggc cctgtcttc 1929019DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 290gtgccccatg gtgtctcct 1929119DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 291tggcgtggca ggtatagga 1929219DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 292gccccaggtg agaggccat 1929319DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 293aaccagggcc actactcca 1929419DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 294gccagggcta ctgctatca 1929519DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 295ggtttcctac agactccca 1929619DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 296gttctggtcc ctctttccc 1929719DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 297ggtgcttaga ccctgatcc 1929819DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 298ctgccttgaa cagagccca 1929919DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 299aacccctccc tctcagcac 1930019DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 300gctggttccc tcctgaagc 1930119DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 301cctttcccaa gttcctagc 1930219DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 302gggcagctct ctgattcct 1930319DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 303gctcctgacc aagggacct 1930419DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 304agcagaggcc aaggtttcc 1930519DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 305ctcccacttc tcaaggacc 1930619DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 306tcacagcccc atttcccca 1930719DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 307gcacagtccg tgtcagggt 1930819DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 308gtatgcagag tcccatgat
1930919DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 309ccttgcaggg tgtggctat
1931019DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 310ccttgtctgc tttctgcct
1931119DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 311tgtgaccact ggggtaggt
1931219DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 312gaggttgggt gcctggtct
1931319DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 313gccgctgtcc tgccgaggt
1931419DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 314ggagggcagg gaacacagt
1931519DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 315ctggttgttg cctggagaa
1931619DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 316attggtccag ggcttgcag
1931719DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 317ccaagctgtc actggctgg
1931819DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 318gggtctccca gagcagtgt
1931919DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 319agtcaaggga gccagcagg
1932019DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 320ggtttgggag tgttaggca
1932119DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 321ctcctggatc ggggtcctg
1932219DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 322gccccataaa atccactcc
1932319DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 323gggttgtccg tgccccata
1932419DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 324ggcaggcatc aggatatgg
1932519DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 325gcccagcacc tagaacggt
1932619DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 326gcccagagcc agcccagca
1932719DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 327ttaggagcac caccaggca
1932819DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 328cccaggagga gcagagccg
1932919DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 329tgcagcggct caccatccc
1933019DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 330agggcttgca cggcttgga
1933119DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 331tcccacttct gaggttaca
1933219DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 332gcttccgctc actcccact
1933319DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 333agactgtgtc ctgtgtggc
1933419DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 334gcggcagact gtgtcctgt
1933519DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 335ggcacagtca actccaggc
1933619DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 336agttggtcca gggcttgca
1933719DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 337ggtgtgcttc ccagccaag
1933819DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 338ccggagcagg tacagggcc
1933919DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 339gcagcctctg gtccctccg
1934019DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 340ggcagcctct ggtccctcc
1934119DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 341tgctcctctt ggatggggg
1934219DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 342ggcccaggtc agatcttgg
1934319DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 343gttggcccag gagcgtggc
1934419DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 344gcaggaggta tgcatggca
1934519DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 345gtttttattg tggtcccgc
1934619DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 346gactcccgtc tgccaaggt
1934719DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 347cccttcccct tccatctct
1934819DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 348tccagattct catccaggg
1934919DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 349ggccttgatc cgttttcca
1935019DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 350accaccagcc ttagcgtct
1935119DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 351tcccagagac caccagcct
1935219DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 352ccctgctccc ttgatccca
1935319DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 353tggagggtcc tttgccgga
1935419DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 354gttctgcacc tccatagtt
1935519DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 355aggagccctt caggtagat
1935619DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 356ccaaagaggc caccacagt
1935719DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 357acaatcagct ccccatcat
1935819DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 358cctgtgtccc gtccaccct
1935919DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 359agggtaggct ctgcattca
1936019DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 360gcaggctcaa ggcaatcct
1936119DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 361tggacaccac cctttccat
1936219DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 362cccccatgag atgagagac
1936319DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 363aatcttcttt ccaagcccc
1936419DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 364agtcctgctt tccacgggg
1936519DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 365ggtgggtatc atagtccct
1936619DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 366ccttcttggc ctttatcct
1936719DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 367gggctcctca tccttctgg
1936819DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 368gttcatgctg gtgcctggt
1936919DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 369gggagggcca ggatctgct
1937019DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 370ccttcactcc ttgctcctc
1937119DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 371gattcataac cccactcct
1937219DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 372gttcatacca cctttggca
1937319DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 373ggctctcttc aagtcctga
1937419DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 374cacatcccca gacagttct
1937519DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 375agcatcacat ccccagaca
1937619DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 376gtccagttcc ctgctatcc
1937719DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 377tgctttgcct gtctgtggc
1937819DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 378gcatgtgttg ctttgcctg
1937919DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 379attccattga agccctggc
1938019DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 380cagccctcca cctttctgg
1938119DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 381gtccacagta ggccctcca
1938219DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 382cagtgcctgg tccacagta
1938319DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 383agtatttagc ccagtgcct
1938419DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 384cccaaagcga gtgagcacc
1938519DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 385acatgggaag agcaggcca
1938619DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 386ggtggagtga ggctggtgc 193871972DNAMus
musculus 387tgagcagcgg ggaggaggaa gaggagactg ctactgaagg cgacactgcc
aggggctctg 60ggcatgtggg tccggcaggt accctggtca ttcacttggg ctgtgctgca
gttgagctgg 120caatcagggt ggcttctaga ggtccccaat gggccctgga
ggtccctcac cttctaccca 180gcctggctca cagtgtcaga gggagcaaat
gccaccttca cctgcagctt gtccaactgg 240tcggaggatc ttatgctgaa
ctggaaccgc ctgagtccca gcaaccagac tgaaaaacag 300gccgccttct
gtaatggttt gagccaaccc gtccaggatg cccgcttcca gatcatacag
360ctgcccaaca ggcatgactt ccacatgaac atccttgaca cacggcgcaa
tgacagtggc 420atctacctct gtggggccat ctccctgcac cccaaggcaa
aaatcgagga gagccctgga 480gcagagctcg tggtaacaga gagaatcctg
gagacctcaa caagatatcc cagcccctcg 540cccaaaccag aaggccggtt
tcaaggcatg gtcattggta tcatgagtgc cctagtgggt 600atccctgtat
tgctgctgct ggcctgggcc ctagctgtct tctgctcaac aagtatgtca
660gaggccagag gagctggaag caaggacgac actctgaagg aggagccttc
agcagcacct 720gtccctagtg tggcctatga ggagctggac ttccagggac
gagagaagac accagagctc 780cctaccgcct gtgtgcacac agaatatgcc
accattgtct tcactgaagg gctgggtgcc 840tcggccatgg gacgtagggg
ctcagctgat ggcctgcagg gtcctcggcc tccaagacat 900gaggatggac
attgttcttg gcctctttga ccagattctt cagccattag catgctgcag
960accctccaca gagagcaccg gtccgtccct cagtcaagag gagcatgcag
gctacagttc 1020agccaaggct cccagggtct gagctagctg gagtgacagc
ccagcgcctg caccaattcc 1080agcacatgca ctgttgagtg agagctcact
tcaggtttac cacaagctgg gagcagcagg 1140cttcccggtt tcctattgtc
acaaggtgca gagctggggc ctaagcctat gtctcctgaa 1200tcctactgtt
gggcacttct agggacttga gacactatag ccaatggcct ctgtgggttc
1260tgtgcctgga aatggagaga tctgagtaca gcctgctttg aatggccctg
tgaggcaacc 1320ccaaagcaag ggggtccagg tatactatgg gcccagcacc
taaagccacc cttgggagat 1380gatactcagg tgggaaattc gtagactggg
ggactgaacc aatcccaaga tctggaaaag 1440ttttgatgaa gacttgaaaa
gctcctagct tcgggggtct gggaagcatg agcacttacc 1500aggcaaaagc
tccgtgagcg tatctgctgt ccttctgcat gcccaggtac ctcagttttt
1560ttcaacagca aggaaactag ggcaataaag ggaaccagca gagctagagc
cacccacaca 1620tccagggggc acttgactct ccctactcct cctaggaacc
aaaaggacaa agtccatgtt 1680gacagcaggg aaggaaaggg ggatataacc
ttgacgcaaa ccaacactgg ggtgttagaa 1740tctcctcatt cactctgtcc
tggagttggg ttctggctct ccttcacacc taggactctg 1800aaatgagcaa
gcacttcaga cagtcagggt agcaagagtc tagctgtctg gtgggcaccc
1860aaaatgacca gggcttaagt ccctttcctt tggtttaagc ccgttataat
taaatggtac 1920caaaagcttt aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa
aaaaaaaaaa aa 19723882115DNAHomo sapiens 388agtttccctt ccgctcacct
ccgcctgagc agtggagaag gcggcactct ggtggggctg 60ctccaggcat gcagatccca
caggcgccct ggccagtcgt ctgggcggtg ctacaactgg 120gctggcggcc
aggatggttc ttagactccc cagacaggcc ctggaacccc cccaccttct
180ccccagccct gctcgtggtg accgaagggg acaacgccac cttcacctgc
agcttctcca 240acacatcgga gagcttcgtg ctaaactggt accgcatgag
ccccagcaac cagacggaca 300agctggccgc cttccccgag gaccgcagcc
agcccggcca ggactgccgc ttccgtgtca 360cacaactgcc caacgggcgt
gacttccaca tgagcgtggt cagggcccgg cgcaatgaca 420gcggcaccta
cctctgtggg gccatctccc tggcccccaa ggcgcagatc aaagagagcc
480tgcgggcaga gctcagggtg acagagagaa gggcagaagt gcccacagcc
caccccagcc 540cctcacccag gccagccggc cagttccaaa ccctggtggt
tggtgtcgtg ggcggcctgc 600tgggcagcct ggtgctgcta gtctgggtcc
tggccgtcat ctgctcccgg gccgcacgag 660ggacaatagg agccaggcgc
accggccagc ccctgaagga ggacccctca gccgtgcctg 720tgttctctgt
ggactatggg gagctggatt tccagtggcg agagaagacc ccggagcccc
780ccgtgccctg tgtccctgag cagacggagt atgccaccat tgtctttcct
agcggaatgg 840gcacctcatc ccccgcccgc aggggctcag ctgacggccc
tcggagtgcc cagccactga 900ggcctgagga tggacactgc tcttggcccc
tctgaccggc ttccttggcc accagtgttc 960tgcagaccct ccaccatgag
cccgggtcag cgcatttcct caggagaagc aggcagggtg 1020caggccattg
caggccgtcc aggggctgag ctgcctgggg gcgaccgggg ctccagcctg
1080cacctgcacc aggcacagcc ccaccacagg actcatgtct caatgcccac
agtgagccca 1140ggcagcaggt gtcaccgtcc cctacaggga gggccagatg
cagtcactgc ttcaggtcct 1200gccagcacag agctgcctgc gtccagctcc
ctgaatctct gctgctgctg ctgctgctgc 1260tgctgctgcc tgcggcccgg
ggctgaaggc gccgtggccc tgcctgacgc cccggagcct
1320cctgcctgaa cttgggggct ggttggagat ggccttggag cagccaaggt
gcccctggca 1380gtggcatccc gaaacgccct ggacgcaggg cccaagactg
ggcacaggag tgggaggtac 1440atggggctgg ggactcccca ggagttatct
gctccctgca ggcctagaga agtttcaggg 1500aaggtcagaa gagctcctgg
ctgtggtggg cagggcagga aacccctcca cctttacaca 1560tgcccaggca
gcacctcagg ccctttgtgg ggcagggaag ctgaggcagt aagcgggcag
1620gcagagctgg aggcctttca ggcccagcca gcactctggc ctcctgccgc
cgcattccac 1680cccagcccct cacaccactc gggagaggga catcctacgg
tcccaaggtc aggagggcag 1740ggctggggtt gactcaggcc cctcccagct
gtggccacct gggtgttggg agggcagaag 1800tgcaggcacc tagggccccc
catgtgccca ccctgggagc tctccttgga acccattcct 1860gaaattattt
aaaggggttg gccgggctcc caccagggcc tgggtgggaa ggtacaggcg
1920ttcccccggg gcctagtacc cccgccgtgg cctatccact cctcacatcc
acacactgca 1980cccccactcc tggggcaggg ccaccagcat ccaggcggcc
agcaggcacc tgagtggctg 2040ggacaaggga tcccccttcc ctgtggttct
attatattat aattataatt aaatatgaga 2100gcatgctaag gaaaa
21153893653DNAMus musculus 389gaaatcgtgg tccccaagcc tcatgccagg
ctgcacttgc acgtcgcggg ccagtctcct 60cgcctgcaga tagttcccaa aacatgagga
tatttgctgg cattatattc acagcctgct 120gtcacttgct acgggcgttt
actatcacgg ctccaaagga cttgtacgtg gtggagtatg 180gcagcaacgt
cacgatggag tgcagattcc ctgtagaacg ggagctggac ctgcttgcgt
240tagtggtgta ctgggaaaag gaagatgagc aagtgattca gtttgtggca
ggagaggagg 300accttaagcc tcagcacagc aacttcaggg ggagagcctc
gctgccaaag gaccagcttt 360tgaagggaaa tgctgccctt cagatcacag
acgtcaagct gcaggacgca ggcgtttact 420gctgcataat cagctacggt
ggtgcggact acaagcgaat cacgctgaaa gtcaatgccc 480cataccgcaa
aatcaaccag agaatttccg tggatccagc cacttctgag catgaactaa
540tatgtcaggc cgagggttat ccagaagctg aggtaatctg gacaaacagt
gaccaccaac 600ccgtgagtgg gaagagaagt gtcaccactt cccggacaga
ggggatgctt ctcaatgtga 660ccagcagtct gagggtcaac gccacagcga
atgatgtttt ctactgtacg ttttggagat 720cacagccagg gcaaaaccac
acagcggagc tgatcatccc agaactgcct gcaacacatc 780ctccacagaa
caggactcac tgggtgcttc tgggatccat cctgttgttc ctcattgtag
840tgtccacggt cctcctcttc ttgagaaaac aagtgagaat gctagatgtg
gagaaatgtg 900gcgttgaaga tacaagctca aaaaaccgaa atgatacaca
attcgaggag acgtaagcag 960tgttgaaccc tctgatcgtc gattggcagc
ttgtggtctg tgaaagaaag ggcccatggg 1020acatgagtcc aaagactcaa
gatggaacct gagggagaga accaagaaag tgttgggaga 1080ggagcctgga
acaacggaca ttttttccag ggagacactg ctaagcaagt tgcccatcag
1140tcgtcttggg aaatggattg agggttcctg gcttagcagc tggtccttgc
acagtgacct 1200tttcctctgc tcagtgccgg gatgagagat ggagtcatga
gtgttgaaga ataagtgcct 1260tctatttatt ttgagtctgt gtgttctcac
tttgggcatg taattatgac tggtgaattc 1320tgacgacatg atagatctta
agatgtagtc accaaactca actgctgctt agcatcctcc 1380gtaactactg
atacaagcag ggaacacaga ggtcacctgc ttggtttgac aggctcttgc
1440tgtctgactc aaataatctt tatttttcag tcctcaaggc tcttcgatag
cagttgttct 1500gtatcagcct tataggtgtc aggtatagca ctcaacatct
catctcatta caatagcaac 1560cctcatcacc atagcaacag ctaacctctg
ttatcctcac ttcatagcca ggaagctgag 1620cgactaagtc acttgcccac
agagtatcag ctctcagatt tctgttcttc agccactgtc 1680ctttcaggat
agaatttgtc gttaagaaat taatttaaaa actgattatt gagtagcatt
1740gtatatcaat cacaacatgc cttgtgcact gtgctggcct ctgagcataa
agatgtacgc 1800cggagtaccg gtcggacatg tttatgtgtg ttaaatactc
agagaaatgt tcattaacaa 1860ggagcttgca ttttagagac actggaaagt
aactccagtt cattgtctag cattacattt 1920acctcatttg ctatccttgc
catacagtct cttgttctcc atgaagtgtc atgaatcttg 1980ttgaatagtt
cttttatttt ttaaatgttt ctatttaaat gatattgaca tctgaggcga
2040tagctcagtt ggtaaaaccc tttcctcaca agtgtgaaac cctgagtctt
atccctagaa 2100cccacataaa aaacagttgc gtatgtttgt gcatgctttt
gatcccagca ctagggaggc 2160agaggcaggc agatcctgag ctctcattga
ccacccagcc tagcctacat ggttagctcc 2220aggcctacag gagctggcag
agcctgaaaa acgatgccta gacacacaca cacacacaca 2280cacacacaca
cacacacaca cacaccatgt actcatagac ctaagtgcac cctcctacac
2340atgcacacac atacaattca aacacaaatc aacagggaat tgtctcagaa
tggtccccaa 2400gacaaagaag aagaaaaaca ccaaaccagc tctattccct
cagcctatcc tctctactcc 2460ttcctagaag caactactat tgtttttgta
tataaattta cccaacgaca gttaatatgt 2520agaatatata ttaaagtgtc
tgtcaatata tattatctct ttctttcttt cttcctttct 2580ttctttcttt
ctttctttct ttctttcttt ctttctttct ttcttccttc cttccttcct
2640tccttccttc cttccttcct ttctttcttt ctttcttttt ttctgtctat
ctgtacctaa 2700atggttgctc actatgcatt ttctgtgctc ttcgcccttt
ttatttaatg tatggatatt 2760tatgctgctt ccagaatgga tctaaagctc
tttgtttcta ggttttctcc cccatccttc 2820taggcatctc tcacactgtc
taggccagac accatgtctg ctgcctgaat ctgtagacac 2880catttataaa
gcacgtactc accgagtttg tatttggctt gttctgtgtc tgattaaagg
2940gagaccatga gtccccaggg tacactgagt taccccagta ccaaggggga
gccttgtttg 3000tgtctccatg gcagaagcag gcctggagcc attttggttt
cttccttgac ttctctcaaa 3060cacagacgcc tcacttgctc attacaggtt
ctcctttggg aatgtcagca ttgctccttg 3120actgctggct gccctggaag
gagcccatta gctctgtgtg agcccttgac agctactgcc 3180tctccttacc
acaggggcct ctaagatact gttacctaga ggtcttgagg atctgtgttc
3240tctgggggga ggaaaggagg aggaacccag aactttctta cagttttcct
tgttctgtca 3300catgtcaaga ctgaaggaac aggctgggct acgtagtgag
atcctgtctc aaaggaaaga 3360cgagcatagc cgaacccccg gtggaacccc
ctctgttacc tgttcacaca agcttattga 3420tgagtctcat gttaatgtct
tgtttgtatg aagtttaaga aaatatcggg ttgggcaaca 3480cattctattt
attcatttta tttgaaatct taatgccatc tcatggtgtt ggattggtgt
3540ggcactttat tcttttgtgt tgtgtataac cataaatttt attttgcatc
agattgtcaa 3600tgtattgcat taatttaata aatattttta tttattaaaa
aaaaaaaaaa aaa 36533903691DNAHomo sapiens 390ggcgcaacgc tgagcagctg
gcgcgtcccg cgcggcccca gttctgcgca gcttcccgag 60gctccgcacc agccgcgctt
ctgtccgcct gcagggcatt ccagaaagat gaggatattt 120gctgtcttta
tattcatgac ctactggcat ttgctgaacg catttactgt cacggttccc
180aaggacctat atgtggtaga gtatggtagc aatatgacaa ttgaatgcaa
attcccagta 240gaaaaacaat tagacctggc tgcactaatt gtctattggg
aaatggagga taagaacatt 300attcaatttg tgcatggaga ggaagacctg
aaggttcagc atagtagcta cagacagagg 360gcccggctgt tgaaggacca
gctctccctg ggaaatgctg cacttcagat cacagatgtg 420aaattgcagg
atgcaggggt gtaccgctgc atgatcagct atggtggtgc cgactacaag
480cgaattactg tgaaagtcaa tgccccatac aacaaaatca accaaagaat
tttggttgtg 540gatccagtca cctctgaaca tgaactgaca tgtcaggctg
agggctaccc caaggccgaa 600gtcatctgga caagcagtga ccatcaagtc
ctgagtggta agaccaccac caccaattcc 660aagagagagg agaagctttt
caatgtgacc agcacactga gaatcaacac aacaactaat 720gagattttct
actgcacttt taggagatta gatcctgagg aaaaccatac agctgaattg
780gtcatcccag aactacctct ggcacatcct ccaaatgaaa ggactcactt
ggtaattctg 840ggagccatct tattatgcct tggtgtagca ctgacattca
tcttccgttt aagaaaaggg 900agaatgatgg atgtgaaaaa atgtggcatc
caagatacaa actcaaagaa gcaaagtgat 960acacatttgg aggagacgta
atccagcatt ggaacttctg atcttcaagc agggattctc 1020aacctgtggt
ttaggggttc atcggggctg agcgtgacaa gaggaaggaa tgggcccgtg
1080ggatgcaggc aatgtgggac ttaaaaggcc caagcactga aaatggaacc
tggcgaaagc 1140agaggaggag aatgaagaaa gatggagtca aacagggagc
ctggagggag accttgatac 1200tttcaaatgc ctgaggggct catcgacgcc
tgtgacaggg agaaaggata cttctgaaca 1260aggagcctcc aagcaaatca
tccattgctc atcctaggaa gacgggttga gaatccctaa 1320tttgagggtc
agttcctgca gaagtgccct ttgcctccac tcaatgcctc aatttgtttt
1380ctgcatgact gagagtctca gtgttggaac gggacagtat ttatgtatga
gtttttccta 1440tttattttga gtctgtgagg tcttcttgtc atgtgagtgt
ggttgtgaat gatttctttt 1500gaagatatat tgtagtagat gttacaattt
tgtcgccaaa ctaaacttgc tgcttaatga 1560tttgctcaca tctagtaaaa
catggagtat ttgtaaggtg cttggtctcc tctataacta 1620caagtataca
ttggaagcat aaagatcaaa ccgttggttg cataggatgt cacctttatt
1680taacccatta atactctggt tgacctaatc ttattctcag acctcaagtg
tctgtgcagt 1740atctgttcca tttaaatatc agctttacaa ttatgtggta
gcctacacac ataatctcat 1800ttcatcgctg taaccaccct gttgtgataa
ccactattat tttacccatc gtacagctga 1860ggaagcaaac agattaagta
acttgcccaa accagtaaat agcagacctc agactgccac 1920ccactgtcct
tttataatac aatttacagc tatattttac tttaagcaat tcttttattc
1980aaaaaccatt tattaagtgc ccttgcaata tcaatcgctg tgccaggcat
tgaatctaca 2040gatgtgagca agacaaagta cctgtcctca aggagctcat
agtataatga ggagattaac 2100aagaaaatgt attattacaa tttagtccag
tgtcatagca taaggatgat gcgaggggaa 2160aacccgagca gtgttgccaa
gaggaggaaa taggccaatg tggtctggga cggttggata 2220tacttaaaca
tcttaataat cagagtaatt ttcatttaca aagagaggtc ggtacttaaa
2280ataaccctga aaaataacac tggaattcct tttctagcat tatatttatt
cctgatttgc 2340ctttgccata taatctaatg cttgtttata tagtgtctgg
tattgtttaa cagttctgtc 2400ttttctattt aaatgccact aaattttaaa
ttcatacctt tccatgattc aaaattcaaa 2460agatcccatg ggagatggtt
ggaaaatctc cacttcatcc tccaagccat tcaagtttcc 2520tttccagaag
caactgctac tgcctttcat tcatatgttc ttctaaagat agtctacatt
2580tggaaatgta tgttaaaagc acgtattttt aaaatttttt tcctaaatag
taacacattg 2640tatgtctgct gtgtactttg ctatttttat ttattttagt
gtttcttata tagcagatgg 2700aatgaatttg aagttcccag ggctgaggat
ccatgccttc tttgtttcta agttatcttt 2760cccatagctt ttcattatct
ttcatatgat ccagtatatg ttaaatatgt cctacatata 2820catttagaca
accaccattt gttaagtatt tgctctagga cagagtttgg atttgtttat
2880gtttgctcaa aaggagaccc atgggctctc cagggtgcac tgagtcaatc
tagtcctaaa 2940aagcaatctt attattaact ctgtatgaca gaatcatgtc
tggaactttt gttttctgct 3000ttctgtcaag tataaacttc actttgatgc
tgtacttgca aaatcacatt ttctttctgg 3060aaattccggc agtgtacctt
gactgctagc taccctgtgc cagaaaagcc tcattcgttg 3120tgcttgaacc
cttgaatgcc accagctgtc atcactacac agccctccta agaggcttcc
3180tggaggtttc gagattcaga tgccctggga gatcccagag tttcctttcc
ctcttggcca 3240tattctggtg tcaatgacaa ggagtacctt ggctttgcca
catgtcaagg ctgaagaaac 3300agtgtctcca acagagctcc ttgtgttatc
tgtttgtaca tgtgcatttg tacagtaatt 3360ggtgtgacag tgttctttgt
gtgaattaca ggcaagaatt gtggctgagc aaggcacata 3420gtctactcag
tctattccta agtcctaact cctccttgtg gtgttggatt tgtaaggcac
3480tttatccctt ttgtctcatg tttcatcgta aatggcatag gcagagatga
tacctaattc 3540tgcatttgat tgtcactttt tgtacctgca ttaatttaat
aaaatattct tatttatttt 3600gttacttggt acaccagcat gtccattttc
ttgtttattt tgtgtttaat aaaatgttca 3660gtttaacatc ccagtggaga
aagttaaaaa a 36913911506DNAMus musculus 391ggagtagaca gcaatggcac
tcagtaaaat atctcctaca gaaggttcta gaaggatcct 60tgaagaccac cacatagatg
aagatgtggg ctttgctcta ccacatccac tggtggagct 120gcccgacgca
tacagcccct gggtccttgt ggctagaaat ctgcctgtgc tgattgagaa
180cgggcagctt cgagaagaag ttgaaaagct gcccacactg agcacggacg
gactgagagg 240acacaggtta cagcgcctgg cacacctggc cctggggtac
atcaccatgg cgtatgtgtg 300gaaccgaggg gatgacgatg ttcgaaaggt
gctgccccgc aatattgctg ttccctactg 360cgagctctca gagaagttgg
gcctgcctcc tattctgtct tatgcagact gtgtcctggc 420aaactggaag
aaaaaggacc ccaatgggcc catgacatac gagaacatgg acattctgtt
480ctcatttcct ggtggggact gcgacaaggg cttcttcctc gtctctctat
tggtggaaat 540cgcagcttct cctgcaatca aagcaatccc cactgtatcc
agtgcagtag agcgtcaaga 600cctgaaagca ttggaaaagg cactgcacga
catagctacc agtctggaga aagccaagga 660aatttttaag aggatgcgtg
actttgtgga cccagacacg tttttccacg ttctccgcat 720atatctgtct
ggctggaaat gcagctccaa gctgccagaa ggtctgctgt atgagggggt
780ctgggacacc ccaaaaatgt tttcaggggg cagtgcaggc cagagcagca
tcttccagag 840tcttgatgtc cttctgggaa taaaacacga ggctggcaaa
gaatctcctg cagaattcct 900ccaggaaatg agagagtaca tgcctccagc
ccaccggaac ttccttttct tcttagagtc 960agctccccca gtccgtgagt
ttgtcatttc aagacacaat gaagacttga cgaaagctta 1020taacgagtgt
gtgaatggtc tggtctctgt gagaaagttc cacctcgcaa tagtagatac
1080ttacattatg aaaccttcga agaagaagcc cactgatggc gacaagtcgg
aagagccctc 1140aaatgtggaa agcagaggga ctgggggtac gaatcccatg
actttcctaa ggagtgtgaa 1200agatacaacc gagaaagctc ttctgagttg
gccttagtgt agcaagctcc acttctatca 1260gggcacagaa aacaccttca
tcctgtcata gctcattaaa tcagatccac caagtaagac 1320tatagaataa
tttgcctgtt gtatattatg tagatttcaa aaatcatctg tgcattccct
1380gtaggaaaat aatcaagctg aactatttaa tgatattaaa atgatataag
aaataatata 1440aaatatattt atgattgaaa tacaacaatg agacccagta
aataaaagtt attgtgaagt 1500tgacta 15063921944DNAHomo sapiens
392aatttctcac tgcccctgtg ataaactgtg gtcactggct gtggcagcaa
ctattataag 60atgctctgaa aactcttcag acactgaggg gcaccagagg agcagactac
aagaatggca 120cacgctatgg aaaactcctg gacaatcagt aaagagtacc
atattgatga agaagtgggc 180tttgctctgc caaatccaca ggaaaatcta
cctgattttt ataatgactg gatgttcatt 240gctaaacatc tgcctgatct
catagagtct ggccagcttc gagaaagagt tgagaagtta 300aacatgctca
gcattgatca tctcacagac cacaagtcac agcgccttgc acgtctagtt
360ctgggatgca tcaccatggc atatgtgtgg ggcaaaggtc atggagatgt
ccgtaaggtc 420ttgccaagaa atattgctgt tccttactgc caactctcca
agaaactgga actgcctcct 480attttggttt atgcagactg tgtcttggca
aactggaaga aaaaggatcc taataagccc 540ctgacttatg agaacatgga
cgttttgttc tcatttcgtg atggagactg cagtaaagga 600ttcttcctgg
tctctctatt ggtggaaata gcagctgctt ctgcaatcaa agtaattcct
660actgtattca aggcaatgca aatgcaagaa cgggacactt tgctaaaggc
gctgttggaa 720atagcttctt gcttggagaa agcccttcaa gtgtttcacc
aaatccacga tcatgtgaac 780ccaaaagcat ttttcagtgt tcttcgcata
tatttgtctg gctggaaagg caacccccag 840ctatcagacg gtctggtgta
tgaagggttc tgggaagacc caaaggagtt tgcagggggc 900agtgcaggcc
aaagcagcgt ctttcagtgc tttgacgtcc tgctgggcat ccagcagact
960gctggtggag gacatgctgc tcagttcctc caggacatga gaagatatat
gccaccagct 1020cacaggaact tcctgtgctc attagagtca aatccctcag
tccgtgagtt tgtcctttca 1080aaaggtgatg ctggcctgcg ggaagcttat
gacgcctgtg tgaaagctct ggtctccctg 1140aggagctacc atctgcaaat
cgtgactaag tacatcctga ttcctgcaag ccagcagcca 1200aaggagaata
agacctctga agacccttca aaactggaag ccaaaggaac tggaggcact
1260gatttaatga atttcctgaa gactgtaaga agtacaactg agaaatccct
tttgaaggaa 1320ggttaatgta acccaacaag agcacatttt atcatagcag
agacatctgt atgcattcct 1380gtcattaccc attgtaacag agccacaaac
taatactatg caatgtttta ccaataatgc 1440aatacaaaag acctcaaaat
acctgtgcat ttcttgtagg aaaacaacaa aaggtaatta 1500tgtgtaatta
tactagaagt tttgtaatct gtatcttatc attggaataa aatgacattc
1560aataaataaa aatgcataag atatattctg tcggctgggc gcggtggctc
acgcctgtaa 1620tcccagcact ttgggaggcc gaggcgggcg gatcacaagg
tcaggagatc gagaccatct 1680tggctaacac ggtgaaaccc cgtctctact
aaaaatacaa aaaattagcc gggcgcggtg 1740gcgggcacct gtagtcccag
ctactcggga ggctgaggca ggagaatggc gtgaacctgg 1800gaggcggagc
ttgcagtgag ccaagattgt gccactgcaa tccggcctgg gctaaagagc
1860gggactccgt ctcaaaaaaa aaaaaaaaaa gatatattct gtcataataa
ataaaaatgc 1920ataagatata aaaaaaaaaa aaaa 19443932020DNAMus
musculus 393gggcagtggg gaggagaagc agaaggactg ggtctggagg agcagctcaa
gttctagcta 60gctgcagtgg gtttgcctgc actctgctct gggtcccagc ccgggcctct
gatcattatc 120catcctgctg tctccagtcc ccactcctgg ggcgtcctct
tcaccctaca ttctttccct 180ccgcctcacc tcctccttgt agaacttctc
tctctctctc tctctctctc tctctctctc 240tctctctctc tctgtgtgtg
tgtgtgtgtc tgtctgtctg tctgtctctc tctcctccca 300ggaccttttt
ctaacctccc ttggagggct ggggaggccc gggccataga ggagatgagg
360gaggacctgc tccttggctt tttgcttctg ggactgcttt gggaagctcc
agttgtgtct 420tcagggcctg ggaaagagct ccccgtggtg tgggcccagg
agggagctcc cgtccatctt 480ccctgcagcc tcaaatcccc caacctggat
cctaactttc tacgaagagg aggggttatc 540tggcaacatc aaccagacag
tggccaaccc actcccatcc cggcccttga ccttcaccag 600gggatgccct
cgcctagaca acccgcaccc ggtcgctaca cggtgctgag cgtggctcca
660ggaggcctgc gcagcgggag gcagcccctg catccccacg tgcagctgga
ggagcgcggc 720ctccagcgcg gggacttctc tctgtggttg cgcccagctc
tgcgcaccga tgcgggcgag 780taccacgcca ccgtgcgcct cccgaaccgc
gccctctcct gcagtctccg cctgcgcgtc 840ggccaggcct cgatgattgc
tagtccctca ggagtcctca agctgtctga ttgggtcctt 900ttgaactgct
ccttcagccg tcctgaccgc ccagtctctg tgcactggtt ccagggccag
960aaccgagtgc ctgtctacaa ctcaccgcgt cattttttag ctgaaacttt
cctgttactg 1020ccccaagtca gccccctgga ctctgggacc tggggctgtg
tcctcaccta cagagatggc 1080ttcaatgtct ccatcacgta caacctcaag
gttctgggtc tggagcccgt agcccctctg 1140acagtgtacg ctgctgaagg
ttctagggtg gagctgccct gtcatttgcc cccaggagtg 1200gggacccctt
ctttgctcat tgccaagtgg actcctcctg gaggaggtcc tgagctcccc
1260gtggctggaa agagtggcaa ttttaccctt caccttgagg ctgtgggtct
ggcacaggct 1320gggacctaca cctgtagcat ccatctgcag ggacagcagc
tcaatgccac tgtcacgttg 1380gcggtcatca cagtgactcc caaatccttc
gggttacctg gctcccgggg gaagctgttg 1440tgtgaggtaa ccccggcatc
tggaaaggaa agatttgtgt ggcgtcccct gaacaatctg 1500tccaggagtt
gcccgggccc tgtgctggag attcaggagg ccaggctcct tgctgagcga
1560tggcagtgtc agctgtacga gggccagagg cttcttggag cgacagtgta
cgccgcagag 1620tctagctcag gcgcccacag tgctaggaga atctcaggtg
accttaaagg aggccatctc 1680gttctcgttc tcatccttgg tgccctctcc
ctgttccttt tggtggccgg ggcctttggc 1740tttcactggt ggagaaaaca
gttgctactg agaagatttt ctgccttaga acatgggatt 1800cagccatttc
cggctcagag gaagatagag gagctggagc gagaactgga gacggagatg
1860ggacaggagc cggagcccga gccggagcca cagctggagc cagagcccag
gcagctctga 1920cctggagccg aggcagccag caggtctcag cagctccgcc
cgcccgcccg cccgcccgaa 1980taaactccct gtcagcagca tcaaaaaaaa
aaaaaaaaaa 20203941995DNAHomo sapiens 394acaggggtga aggcccagag
accagcagaa cggcatccca gccacgacgg ccactttgct 60ctgtctgctc tccgccacgg
ccctgctctg ttccctggga cacccccgcc cccacctcct 120caggctgcct
gatctgccca gctttccagc tttcctctgg attccggcct ctggtcatcc
180ctccccaccc tctctccaag gccctctcct ggtctccctt cttctagaac
cccttcctcc 240acctccctct ctgcagaact tctcctttac cccccacccc
ccaccactgc cccctttcct 300tttctgacct ccttttggag ggctcagcgc
tgcccagacc ataggagaga tgtgggaggc 360tcagttcctg ggcttgctgt
ttctgcagcc gctttgggtg gctccagtga agcctctcca 420gccaggggct
gaggtcccgg tggtgtgggc ccaggagggg gctcctgccc agctcccctg
480cagccccaca atccccctcc aggatctcag ccttctgcga agagcagggg
tcacttggca 540gcatcagcca gacagtggcc cgcccgctgc cgcccccggc
catcccctgg cccccggccc 600tcacccggcg gcgccctcct cctgggggcc
caggccccgc cgctacacgg tgctgagcgt 660gggtcccgga ggcctgcgca
gcgggaggct gcccctgcag ccccgcgtcc agctggatga 720gcgcggccgg
cagcgcgggg acttctcgct atggctgcgc ccagcccggc gcgcggacgc
780cggcgagtac cgcgccgcgg tgcacctcag ggaccgcgcc ctctcctgcc
gcctccgtct 840gcgcctgggc caggcctcga tgactgccag ccccccagga
tctctcagag cctccgactg 900ggtcattttg aactgctcct tcagccgccc
tgaccgccca gcctctgtgc attggttccg 960gaaccggggc cagggccgag
tccctgtccg ggagtccccc catcaccact tagcggaaag 1020cttcctcttc
ctgccccaag tcagccccat ggactctggg ccctggggct gcatcctcac
1080ctacagagat ggcttcaacg tctccatcat gtataacctc
actgttctgg gtctggagcc 1140cccaactccc ttgacagtgt acgctggagc
aggttccagg gtggggctgc cctgccgcct 1200gcctgctggt gtggggaccc
ggtctttcct cactgccaag tggactcctc ctgggggagg 1260ccctgacctc
ctggtgactg gagacaatgg cgactttacc cttcgactag aggatgtgag
1320ccaggcccag gctgggacct acacctgcca tatccatctg caggaacagc
agctcaatgc 1380cactgtcaca ttggcaatca tcacagtgac tcccaaatcc
tttgggtcac ctggatccct 1440ggggaagctg ctttgtgagg tgactccagt
atctggacaa gaacgctttg tgtggagctc 1500tctggacacc ccatcccaga
ggagtttctc aggaccttgg ctggaggcac aggaggccca 1560gctcctttcc
cagccttggc aatgccagct gtaccagggg gagaggcttc ttggagcagc
1620agtgtacttc acagagctgt ctagcccagg tgcccaacgc tctgggagag
ccccaggtgc 1680cctcccagca ggccacctcc tgctgtttct catccttggt
gtcctttctc tgctcctttt 1740ggtgactgga gcctttggct ttcacctttg
gagaagacag tggcgaccaa gacgattttc 1800tgccttagag caagggattc
accctccgca ggctcagagc aagatagagg agctggagca 1860agaaccggag
ccggagccgg agccggaacc ggagcccgag cccgagcccg agccggagca
1920gctctgacct ggagctgagg cagccagcag atctcagcag cccagtccaa
ataaactccc 1980tgtcagcagc aaaaa 19953952725DNAMus musculus
395accattttaa ccgaggagct aaagctatcc ctacacagag ctgtccttgg
atttcccctg 60ccaagtactc atgttttcag gtcttaccct caactgtgtc ctgctgctgc
tgcaactact 120acttgcaagg tcattggaaa atgcttatgt gtttgaggtt
ggtaagaatg cctatctgcc 180ctgcagttac actctatcta cacctggggc
acttgtgcct atgtgctggg gcaagggatt 240ctgtccttgg tcacagtgta
ccaacgagtt gctcagaact gatgaaagaa atgtgacata 300tcagaaatcc
agcagatacc agctaaaggg cgatctcaac aaaggagacg tgtctctgat
360cataaagaat gtgactctgg atgaccatgg gacctactgc tgcaggatac
agttccctgg 420tcttatgaat gataaaaaat tagaactgaa attagacatc
aaagcagcca aggtcactcc 480agctcagact gcccatgggg actctactac
agcttctcca agaaccctaa ccacggagag 540aaatggttca gagacacaga
cactggtgac cctccataat aacaatggaa caaaaatttc 600cacatgggct
gatgaaatta aggactctgg agaaacgatc agaactgcta tccacattgg
660agtgggagtc tctgctgggt tgaccctggc acttatcatt ggtgtcttaa
tccttaaatg 720gtattcctgt aagaaaaaga agttatcgag tttgagcctt
attacactgg ccaacttgcc 780tccaggaggg ttggcaaatg caggagcagt
caggattcgc tctgaggaaa atatctacac 840catcgaggag aacgtatatg
aagtggagaa ttcaaatgag tactactgct acgtcaacag 900ccagcagcca
tcctgaccgc ctctggactg ccacttttaa aggctcgcct tcatttctga
960ctttggtatt tccctttttg aaaactatgt gatatgtcac ttggcaacct
cattggaggt 1020tctgaccaca gccactgaga aaagagttcc agttttctgg
ggataattaa ctcacaaggg 1080gattcgactg taactcatgc tacattgaaa
tgctccattt tatccctgag tttcagggat 1140cggatctccc actccagaga
cttcaatcat gcgtgttgaa gctcactcgt gctttcatac 1200attaggaatg
gttagtgtga tgtctttgag acatagaggt ttgtggtata tctgcaaagc
1260tcctgaacag gtagggggaa taaagggcta agataggaag gtgaggttct
ttgttgatgt 1320tgaaaatcta aagaagttgg tagcttttct agagatttct
gaccttgaaa gattaagaaa 1380aagccaggtg gcatatgctt aacactatat
aacttgggaa ccttaggcag gagggtgata 1440agttcaaggt cagccagggc
tatgctggta agactgtctc aaaatccaaa gacgaaaata 1500aacatagaga
cagcaggagg ctggagatga ggctcggaca gtgaggtgca ttttgtacaa
1560gcacgaggaa tctatatttg atcgtagacc ccacatgaaa aagctaggcc
tggtagagca 1620tgcttgtaga ctcaagagat ggagaggtaa aggcacaaca
gatccccggg gcttgcgtgc 1680agtcagctta gcctaggtgc tgagttccaa
gtccacaaga gtccctgtct caaagtaaga 1740tggactgagt atctggcgaa
tgtccatggg ggttgtcctc tgctctcaga agagacatgc 1800acatgaacct
gcacacacac acacacacac acacacacac acacacacac acacacacac
1860acacacatga aatgaaggtt ctctctgtgc ctgctacctc tctataacat
gtatctctac 1920aggactctcc tctgcctctg ttaagacatg agtgggagca
tggcagagca gtccagtaat 1980taattccagc actcagaagg ctggagcaga
agcgtggaga gttcaggagc actgtgccca 2040acactgccag actcttctta
cagaagaaaa aggttacccg caagcagcct gctgtctgta 2100aaaggaaacc
ctgcgaaagg caaactttga ctgttgtgtg ctcaagggga actgactcag
2160acaacttctc cattcctgga ggaaactgga gctgtttctg acagaagaac
aaccggtgac 2220tgggacatac gaaggcagag ctcttgcagc aatctatata
gtcagcaaaa tattctttgg 2280gaggacagtc gtcaccaaat tgatttccaa
gccggtggac ctcagtttca tctggcttac 2340agctgcctgc ccagtgccct
tgatctgtgc tggctcccat ctataacaga atcaaattaa 2400atagaccccg
agtgaaaata ttaagtgagc agaaaggtag ctttgttcaa agattttttt
2460gcattgggga gcaactgtgt acatcagagg acatctgtta gtgaggacac
caaaacctgt 2520ggtaccgttt tttcatgtat gaattttgtt gtttaggttg
cttctagcta gctgtggagg 2580tcctggcttt cttaggtggg tatggaaggg
agaccatcta acaaaatcca ttagagataa 2640cagctctcat gcagaaggga
aaactaatct caaatgtttt aaagtaataa aactgtactg 2700gcaaagtact
ttgagcatat ttaaa 27253962448DNAHomo sapiens 396agaacactta
caggatgtgt gtagtgtggc atgacagaga actttggttt cctttaatgt 60gactgtagac
ctggcagtgt tactataaga atcactggca atcagacacc cgggtgtgct
120gagctagcac tcagtggggg cggctactgc tcatgtgatt gtggagtaga
cagttggaag 180aagtacccag tccatttgga gagttaaaac tgtgcctaac
agaggtgtcc tctgactttt 240cttctgcaag ctccatgttt tcacatcttc
cctttgactg tgtcctgctg ctgctgctgc 300tactacttac aaggtcctca
gaagtggaat acagagcgga ggtcggtcag aatgcctatc 360tgccctgctt
ctacacccca gccgccccag ggaacctcgt gcccgtctgc tggggcaaag
420gagcctgtcc tgtgtttgaa tgtggcaacg tggtgctcag gactgatgaa
agggatgtga 480attattggac atccagatac tggctaaatg gggatttccg
caaaggagat gtgtccctga 540ccatagagaa tgtgactcta gcagacagtg
ggatctactg ctgccggatc caaatcccag 600gcataatgaa tgatgaaaaa
tttaacctga agttggtcat caaaccagcc aaggtcaccc 660ctgcaccgac
tcggcagaga gacttcactg cagcctttcc aaggatgctt accaccaggg
720gacatggccc agcagagaca cagacactgg ggagcctccc tgatataaat
ctaacacaaa 780tatccacatt ggccaatgag ttacgggact ctagattggc
caatgactta cgggactctg 840gagcaaccat cagaataggc atctacatcg
gagcagggat ctgtgctggg ctggctctgg 900ctcttatctt cggcgcttta
attttcaaat ggtattctca tagcaaagag aagatacaga 960atttaagcct
catctctttg gccaacctcc ctccctcagg attggcaaat gcagtagcag
1020agggaattcg ctcagaagaa aacatctata ccattgaaga gaacgtatat
gaagtggagg 1080agcccaatga gtattattgc tatgtcagca gcaggcagca
accctcacaa cctttgggtt 1140gtcgctttgc aatgccatag atccaaccac
cttatttttg agcttggtgt tttgtctttt 1200tcagaaacta tgagctgtgt
cacctgactg gttttggagg ttctgtccac tgctatggag 1260cagagttttc
ccattttcag aagataatga ctcacatggg aattgaactg ggacctgcac
1320tgaacttaaa caggcatgtc attgcctctg tatttaagcc aacagagtta
cccaacccag 1380agactgttaa tcatggatgt tagagctcaa acgggctttt
atatacacta ggaattcttg 1440acgtggggtc tctggagctc caggaaattc
gggcacatca tatgtccatg aaacttcaga 1500taaactaggg aaaactgggt
gctgaggtga aagcataact tttttggcac agaaagtcta 1560aaggggccac
tgattttcaa agagatctgt gatccctttt tgttttttgt ttttgagatg
1620gagtcttgct ctgttgccca ggctggagtg caatggcaca atctcggctc
actgcaagct 1680ccgcctcctg ggttcaagcg attctcctgc ctcagcctcc
tgagtggctg ggattacagg 1740catgcaccac catgcccagc taatttgttg
tatttttagt agagacaggg tttcaccatg 1800ttggccagtg tggtctcaaa
ctcctgacct catgatttgc ctgcctcggc ctcccaaagc 1860actgggatta
caggcgtgag ccaccacatc cagccagtga tccttaaaag attaagagat
1920gactggacca ggtctacctt gatcttgaag attcccttgg aatgttgaga
tttaggctta 1980tttgagcact gcctgcccaa ctgtcagtgc cagtgcatag
cccttctttt gtctccctta 2040tgaagactgc cctgcagggc tgagatgtgg
caggagctcc cagggaaaaa cgaagtgcat 2100ttgattggtg tgtattggcc
aagttttgct tgttgtgtgc ttgaaagaaa atatctctga 2160ccaacttctg
tattcgtgga ccaaactgaa gctatatttt tcacagaaga agaagcagtg
2220acggggacac aaattctgtt gcctggtgga aagaaggcaa aggccttcag
caatctatat 2280taccagcgct ggatcctttg acagagagtg gtccctaaac
ttaaatttca agacggtata 2340ggcttgatct gtcttgctta ttgttgcccc
ctgcgcctag cacaattctg acacacaatt 2400ggaacttact aaaaattttt
ttttactgtt aaaaaaaaaa aaaaaaaa 24483971933DNAMus musculus
397ctacacatat gtagcacgta ccttggatca aagctgtcta tataaagtcc
ccgagtctgt 60gtgggttcaa acacatctca aggcttctgg atcctgttgg gttttactct
gctccctgag 120gacctcagca catttgcccc ccagccatgg cttgtcttgg
actccggagg tacaaagctc 180aactgcagct gccttctagg acttggcctt
ttgtagccct gctcactctt cttttcatcc 240cagtcttctc tgaagccata
caggtgaccc aaccttcagt ggtgttggct agcagccatg 300gtgtcgccag
ctttccatgt gaatattcac catcacacaa cactgatgag gtccgggtga
360ctgtgctgcg gcagacaaat gaccaaatga ctgaggtctg tgccacgaca
ttcacagaga 420agaatacagt gggcttccta gattacccct tctgcagtgg
tacctttaat gaaagcagag 480tgaacctcac catccaagga ctgagagctg
ttgacacggg actgtacctc tgcaaggtgg 540aactcatgta cccaccgcca
tactttgtgg gcatgggcaa cgggacgcag atttatgtca 600ttgatccaga
accatgcccg gattctgact tcctcctttg gatccttgtc gcagttagct
660tggggttgtt tttttacagt ttcctggtca ctgctgtttc tttgagcaag
atgctaaaga 720aaagaagtcc tcttacaaca ggggtctatg tgaaaatgcc
cccaacagag ccagaatgtg 780aaaagcaatt tcagccttat tttattccca
tcaactgaaa ggccgtttat gaagaagaag 840gagcatactt cagtctctaa
aagctgaggc aatttcaact ttccttttct ctccagctat 900ttttacctgt
ttgtatattt taaggagagt atgcctctct ttaatagaaa gctggatgca
960aaattccaat taagcatact acaatttaaa gctaaggagc atgaacagag
agctgggata 1020tttctgttgt gtcagaacca ttttactaaa agcatcactt
ggaagcagca taaggatata 1080gcattatggt gtggggtcaa gggaacatta
gggaatggca cagcccaaag aaaggaaggg 1140ggtgaaggaa gagattatat
tgtacacatc ttgtatttac ctgagagatg tttatgactt 1200aaataatttt
taaatttttc atgctgttat tttctttaac aatgtataat tacacgaagg
1260tttaaacatt tattcacaga gctatgtgac atagccagtg gttccaaagg
ttgtagtgtt 1320ccaagatgta tttttaagta atattgtaca tgggtgtttc
atgtgctgtt gtgtatttgc 1380tggtggtttg aatataaaca ctatgtatca
gtgtcgtccc acagtgggtc ctggggaggt 1440ttggctgggg agcttaggac
actaatccat caggttggac tcgaggtcct gcaccaactg 1500gcttggaaac
tagatgaggc tgtcacaggg ctcagttgca taaaccgatg gtgatggagt
1560gtaaactggg tctttacact cattttattt tttgtttctg cttttgtttt
cttcaatgat 1620ttgcaaggaa accaaaagct ggcagtgttt gtatgaacct
gacagaacac tgtcttcaag 1680gaaatgcctc attcctgaga ccagtaggtt
tgttttttta ggaagttcca atactaggac 1740cccctacaag tactatggct
cctcgaaaac acaaagttaa tgccacagga agcagcagat 1800ggtaggatgg
gatgcacaag agttcctgaa aactaacact gttagtgttt tttttttaac
1860tcaatatttt ccatgaaaat gcaaccacat gtataatatt tttaattaaa
taaaagtttc 1920ttgtgattgt ttt 19333982033DNAHomo sapiens
398cttctgtgtg tgcacatgtg taatacatat ctgggatcaa agctatctat
ataaagtcct 60tgattctgtg tgggttcaaa cacatttcaa agcttcagga tcctgaaagg
ttttgctcta 120cttcctgaag acctgaacac cgctcccata aagccatggc
ttgccttgga tttcagcggc 180acaaggctca gctgaacctg gctaccagga
cctggccctg cactctcctg ttttttcttc 240tcttcatccc tgtcttctgc
aaagcaatgc acgtggccca gcctgctgtg gtactggcca 300gcagccgagg
catcgccagc tttgtgtgtg agtatgcatc tccaggcaaa gccactgagg
360tccgggtgac agtgcttcgg caggctgaca gccaggtgac tgaagtctgt
gcggcaacct 420acatgatggg gaatgagttg accttcctag atgattccat
ctgcacgggc acctccagtg 480gaaatcaagt gaacctcact atccaaggac
tgagggccat ggacacggga ctctacatct 540gcaaggtgga gctcatgtac
ccaccgccat actacctggg cataggcaac ggaacccaga 600tttatgtaat
tgatccagaa ccgtgcccag attctgactt cctcctctgg atccttgcag
660cagttagttc ggggttgttt ttttatagct ttctcctcac agctgtttct
ttgagcaaaa 720tgctaaagaa aagaagccct cttacaacag gggtctatgt
gaaaatgccc ccaacagagc 780cagaatgtga aaagcaattt cagccttatt
ttattcccat caattgagaa accattatga 840agaagagagt ccatatttca
atttccaaga gctgaggcaa ttctaacttt tttgctatcc 900agctattttt
atttgtttgt gcatttgggg ggaattcatc tctctttaat ataaagttgg
960atgcggaacc caaattacgt gtactacaat ttaaagcaaa ggagtagaaa
gacagagctg 1020ggatgtttct gtcacatcag ctccactttc agtgaaagca
tcacttggga ttaatatggg 1080gatgcagcat tatgatgtgg gtcaaggaat
taagttaggg aatggcacag cccaaagaag 1140gaaaaggcag ggagcgaggg
agaagactat attgtacaca ccttatattt acgtatgaga 1200cgtttatagc
cgaaatgatc ttttcaagtt aaattttatg ccttttattt cttaaacaaa
1260tgtatgatta catcaaggct tcaaaaatac tcacatggct atgttttagc
cagtgatgct 1320aaaggttgta ttgcatatat acatatatat atatatatat
atatatatat atatatatat 1380atatatatat atatatattt taatttgata
gtattgtgca tagagccacg tatgtttttg 1440tgtatttgtt aatggtttga
atataaacac tatatggcag tgtctttcca ccttgggtcc 1500cagggaagtt
ttgtggagga gctcaggaca ctaatacacc aggtagaaca caaggtcatt
1560tgctaactag cttggaaact ggatgaggtc atagcagtgc ttgattgcgt
ggaattgtgc 1620tgagttggtg ttgacatgtg ctttggggct tttacaccag
ttcctttcaa tggtttgcaa 1680ggaagccaca gctggtggta tctgagttga
cttgacagaa cactgtcttg aagacaatgg 1740cttactccag gagacccaca
ggtatgacct tctaggaagc tccagttcga tgggcccaat 1800tcttacaaac
atgtggttaa tgccatggac agaagaaggc agcaggtggc agaatggggt
1860gcatgaaggt ttctgaaaat taacactgct tgtgttttta actcaatatt
ttccatgaaa 1920atgcaacaac atgtataata tttttaatta aataaaaatc
tgtggtggtc gttttaaaaa 1980aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa
aaaaaaaaaa aaaaaaaaaa aaa 20333993014DNAMus musculus 399cgcacaagta
caaccacaca gaagacacag ctggaaagct ccctggcctg ggcattcctc 60tggggcagag
acctcacgcg aaaatatgga gcctcaaagt cagagcatga cgctggaggt
120gccgttgtcc ttggggagat accacatttc tgaggaatat ggctttctcc
ttccaaatcc 180tctggaagca cttccagatc attacaagcc ttggatggaa
attgccctca gacttcctca 240cttaatcgag aaccgccagc tccgagctca
cgtgtacagg atgcctctcc tggactgcag 300attcctaaag agttaccgtg
agcagcgcct ggcacacatg gcgctggccg ctatcaccat 360gggattcgtc
tggcaggagg gggaaggcca accccaaaag gtgctgccaa gatctcttgc
420cattcctttt gttgaggtat ccaggaactt gggactcccg cctatcctgg
tccactctga 480cctggtgctg acaaactgga ccaaaaggaa cccagaagga
ccgttggaaa tcagtaacct 540ggaaaccatc atctcatttc cggggggaga
gagcctgcgg ggcttcatcc tagtgacagt 600cttggtggag aaggcagcag
tgcccggcct taaggccctg gttcagggaa tggaggccat 660tcggcaacac
agtcaggaca ccctgctaga agccctgcag cagctgagac tctccatcca
720ggatatcacc agagccttgg cccaaatgca tgattatgtg gacccagaca
tattttactc 780ggtcatccgg atcttcctct ctgggtggaa ggacaatcca
gccatgcctg tggggctggt 840ctatgaaggt gttgccacag agcctctgaa
gtactctgga ggaagtgcag cccagagctc 900cgtgcttcat gccttcgatg
agttcctggg cattgagcat tgcaaggaaa gtgttggctt 960tctacacaga
atgagggact acatgccgcc ttcccataag gctttcctgg aagatctcca
1020cgtagctcct tctctgagag actacatact ggcctctggt cctggggact
gcctgatggc 1080ctataaccag tgtgtggagg ccctgggaga gctgcgcagt
taccacatca atgtcgtggc 1140cagatacatt atctccgctg ccaccagggc
caggagcagg gggctaacta atccctcacc 1200ccatgccttg gaagacaggg
gcactggggg tactgccatg ctgagcttct tgaagagtgt 1260cagggagaag
accatggagg ccctcctgtg tcctggtgct tagcagtcat gtcctgcacc
1320ctaacactta gatgttctca tcctgcatcc cagcgttaga ggttcacatc
ctgcatccta 1380gtgcttagct gttcttgtgc tatatcccag cgcttagcag
tcatgtcctg catcctagtg 1440cttagcattt tatatccagc atcttagtgc
ttagagattc acatcctgca tcctagagct 1500tagcatttta tatccagcat
ccttgtgcgt atcagctatg ttttgtatcc tgcttagcag 1560ttaacatcct
gcatcctagt acttatctgt tctcatcctg catcctagag cttagcagtc
1620aggtcccgtg ggagcaagaa ccagggtctg agctctgtct gagcccaagc
atggctttac 1680tgctttgtta attgtggctc ccacctccac cccaccccag
ccagtttgct tgctagaagc 1740ctttctgcac tgcctaatcc ccctgcctca
cagcagagag ctgcagccat gacctcctca 1800ttcagtatta ggtggacaag
tcggagatac ccaaactcaa ttttaaaaga atcaagttgc 1860ttttggggca
tgttacttca tcttttctta ccctgggcct cttcccttct tccctacctc
1920cctcgtccct tagtctttca cccctctctc tttctccttt tgtcaccctc
cccctcccct 1980gcttactctc ttttcccttc ccccctctcc tcatccctcc
ttcctttctt ccttcccttt 2040ttgtctgtga agcaccaggt ctgatgggcc
tcaaactgtg atcttcctgt ctcacccttc 2100aaaggttatg tgtatgtgac
gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt 2160tcgtttcttt
tgtttttccc tagtggagat gacacccaaa gatttgcaca taccaggcaa
2220ttgctccacc acctgactac agtcccagct ctctgtattc ctgaaggaaa
gtcttgatga 2280gttgcctagg ctggtattga gctctttagc ccaggcaggc
cttagtctga gtagctggga 2340tgtacaggga tgagccactg agccatgctg
ctgctgctaa cgatgatgac gatgatgatg 2400atgaagatta tgataactac
agtcactgca ataatgacgg caaagataat gatggctgtc 2460tcttcccttt
tttgttattt tattttttat tttaatttac tttaagacag tatcctacta
2520tgctttagtc caggttgcct tgaactacct cagcctcccc agtgcttaga
ttatactcat 2580gaaccaccaa ggctggctct agattctttc aattcactaa
gccctactgt gctcttgtct 2640gtgacctggg acagccttcc cctccatgcc
caggctgaat tcagcactgg gggtgggggt 2700ggggttagat gctgagtgga
gatttgtggg gttaaagatg ctgtccatgc agacctggaa 2760gtcaccagca
cgggagctat cagctactga ctaggaaccc gatgcgactc ccccacagag
2820ggtagacatt gtcggttcta ttttaactct ctctgttcta tttttaggac
cgtgtttttc 2880tttctcctag tgacactgga aatttgtatg tgaaaaatgc
tttaactgac cccttgaaag 2940ccagtaagcc aaaataagaa taaatagtaa
gtccacatgt ttaggataaa aataaatatg 3000gcttttatat ccga
30144002294DNAHomo sapiens 400agtccagatg atagttaaga aagcagtaag
aatacagaga gtccacaatg agatgaaaat 60gcactgccag ttgaaacatc ctcctacact
ggagctttat aaatatttta aagacaagga 120ttggattaga tttgacatta
gaaatgtacc ataatacaga aggcaatgga cacctaaaga 180acagaatgaa
aaccttctta ggaaatgaag cttgacactt cacccaccag gccaccacaa
240gaatgttgca ttttcattat tatgatactt caaacaaaat aatggagccc
cacagaccga 300atgtgaagac agcagtgcca ttgtctttgg aaagctatca
catatctgaa gagtatggct 360ttcttcttcc agattctctg aaagaacttc
cagatcatta taggccttgg atggaaattg 420ccaacaaact tcctcaattg
attgatgctc accagcttca agctcatgtg gacaagatgc 480ccctgctgag
ctgccagttc ctgaagggtc accgggagca gcgcctggcc cacctggtcc
540tgagcttcct caccatgggt tatgtctggc aggaaggaga ggcgcagcct
gcagaggtcc 600tgccaaggaa tcttgccctt ccatttgtcg aagtctccag
gaacttgggg ctccctccta 660tcctggtcca ctcagacttg gtgctgacga
actggaccaa aaaagatcca gacggattcc 720tggaaattgg gaacctggag
accatcatct catttcctgg gggagagagc ctgcatggtt 780ttatactggt
gactgctttg gtagagaaag aagcagtgcc tgggataaag gctcttgttc
840aggccacgaa tgctatcttg cagcccaacc aggaggccct gctccaagcc
ctgcagcgac 900tgagactgtc tattcaggac atcaccaaaa ccttaggaca
gatgcatgat tatgtagatc 960cagacatatt ttatgcaggc atccggatct
ttctctctgg atggaaagac aacccagcaa 1020tgcctgcagg gctgatgtat
gaaggagttt cccaagagcc cctgaaatac tccggcggga 1080gtgcagctca
gagcacagtg cttcatgcct ttgatgagtt cttaggcatt cgtcatagca
1140aggaaagtgg tgactttctg tacagaatga gggattacat gcctccttcc
cataaggcct 1200tcatagaaga catccactca gcaccttccc tgagggacta
catcctgtca tctggacagg 1260accacttgct gacagcttat aaccagtgtg
tgcaggccct ggcagagctg cggagctatc 1320acatcaccat ggtcaccaaa
tacctcatca cagctgcagc caaggcaaag catgggaagc 1380caaaccatct
cccagggcct cctcaggctt taaaagacag gggcacaggt ggaaccgcag
1440ttatgagctt tcttaagagt gtcagggata agaccttgga gtcaatcctt
cacccacgtg 1500gttaggaggc tgccctctcc ccagcaatgc agagccccca
tggagggcag gtgggcctgg 1560agaatgaggg tcagggttct gcctgggatc
atccaggaag gatctcagcc ctattcatgt 1620ttctgctcta cagagcacta
tattctcctt gttgagagct gttggcttca caaaggagag 1680ttgatgtggc
caagcctttc cctccctacc tgatcactgc
ttaacggcat gtataatgga 1740tacttcctca tgcagaaccc ccagaggagt
gactgtatgc cattctcttt gccaagtaat 1800agaaaaccaa tctaaatgtc
aaaaatcaga taaaattgcc tggggataca ttacttgttg 1860attttcttaa
aaaacaaatt cacttaacaa ttcattaagt tcatactgag cactgcctcc
1920aagattaaaa ccaggatttc tgtggtccca gaccagccct cttctccctg
aatgtgttga 1980gttggtggca ggaggttgga aatgctccag tggagatggg
aagatagagg atgctgacaa 2040taaggacttg gaagtcacta gtgtgaaaat
gagcagttaa tgatatggga acggatgaga 2100ctttccacgt ggtacctaga
tttgcaaatt ctattgtaat gcctttattt ttagaagaat 2160tattctctct
tcttactctg aaaatctgta tttgtaaaat gaatgaatgg atcctatata
2220agtaaataag aaaactggga ataagtagta aatcaatgtg tttagtgtgc
aaataaatgt 2280aaatgctttt attg 22944013143DNAMus musculus
401aaagctcctt taagaaaagc agggcagata tcagggcagc ctggcttagc
agtagtgttg 60gagaagaagc tagcaggcag gcagcagaga catggagctg gcctcagcac
atctccacaa 120agggcaggtt ccctggggag gactactgct cacagcctca
cttttagcct cctggagccc 180tgccaccact gctgaagtca ccattgaggc
tgtgccgccc caggttgctg aagacaacaa 240tgttcttcta cttgttcaca
atctgcccct ggcgcttgga gcctttgcct ggtacaaggg 300aaacactacg
gctatagaca aagaaattgc acgatttgta ccaaatagta atatgaattt
360cacggggcaa gcatacagcg gcagagagat aatatacagc aatggatccc
tgctcttcca 420aatgatcacc atgaaggata tgggagtcta cacactagat
atgacagatg aaaactatcg 480tcgtactcag gcgactgtgc gatttcatgt
acaccagcca gtgactcagc ccttcctcca 540agtcaccaac accacagtca
aagaactaga ctctgtgacc ctgacctgct tgtcgaatga 600cattggagcc
aacatccagt ggctcttcaa tagccagagt cttcagctca cagagagaat
660gacactctcc cagaacaaca gcatcctcag aatagaccct attaagaggg
aagatgccgg 720cgagtatcag tgtgaaatct cgaatccagt cagcgtcagg
aggagcaact caatcaagct 780ggacataata tttgacccaa cacaaggagg
cctctcagat ggcgccattg ctggcatcgt 840gattggagtt gtggctgggg
tggctctaat agcagggctg gcatatttcc tctattccag 900gaagtctggc
ggatctggct ccttctgaca actctcctaa caaggtggat gacgtcgcat
960acactgtcct gaacttcaat tcccagcaac ccaaccggcc aacttcagcc
ccttcttctc 1020caagagccac agaaacagtt tattcagaag taaaaaagaa
gtgagcataa tctgtccgtc 1080tgtcctgctg gctgcaccag tgatgcattc
ccggattctg ttcctcactg gagggtctca 1140gcacacacac acacgtacac
atgcgcgcgc gcacacacac acacacacac acacacacac 1200acttacacac
acactcatgc attcactcta ttgactcctt cagtgtctat agaagaaaag
1260gtggatcctg gagcctacag aaaactcaac ccttctaggc tttcaaattt
ggctgagagt 1320gaggtatcaa aatttctcac cctttcactt tcctgaccca
gattgttgaa aattgaccta 1380ttcagagcac cttcattccc ctcccaactc
caagtcctgc cctatcagag tctgacttga 1440atttccataa accttggagg
tcacctaagt gcttacgcca aacaaaacaa aacaaaacaa 1500aacaaaacaa
aacaaaacaa aacaaaacaa accagaagca ggaaatggcc agtcccatat
1560ctttaaaggc tgattggaag ccaccataca tgagaagatc aaacctccat
gggcaatcta 1620cacacccgac aactgtcatg cttacccatc tgggacattc
gagtctctga accttgtgcc 1680ctcacgcctg agcccttctc tgagcctttc
tccagaaaat ccactcacag caactagaga 1740ggctctttgt cagcaactcc
aagcaaactg ctaggcagga ttcagaagaa aagacagcat 1800ctctaacatc
caccaggaag gtgcccagaa aagcagagct ggtgactttg gactgacaga
1860catctggagt gtgaaaaagc agcacagagc taaccttcgg agagtgttga
aattatttga 1920aaagaagcca tatttggagg tattggagtt ttcctctttc
tgagacaatc cactatttga 1980aaattgtagc tactgaattg cctctcagta
tgcgagctga tcactttgcc ttagggccac 2040tagatttctg tctcccttag
cccctcaagc ccttttgatc atgagttcca aaccaaaaat 2100aaataaatga
acagtgaggc agtcccttgc agtaccactg tcatgggtca ggctaagcct
2160cctgcttttc tgaattagtc aagaaaagcc ttggtttccc tttttccatc
tctttatctt 2220gtctttcaga tactggccag agcctggaca ctcttcctct
gagatctcca gcttctctgc 2280cttcttgtgt ttcttttaaa ctctaacaaa
aactgttctc accttcaaaa aataaaataa 2340taacaagctt tccacatccc
caccaaagag ggacccagct aggtttctgg aaacccagca 2400ccagcctcca
gctgcccttc tgcagtgttt ctgcctctgt ttccctttcg ttttgacttt
2460tttccttctt ttgagacaga gttccagcat ggagcctgtg caggtttcaa
tcccacagta 2520acaccttctg cagcacccca cctgctcaga ctgcagccct
ggccaccagg cctggctacc 2580tggacattct gtctgccctg cactctcagg
aaaccttggc ctctgctact gtctgtttgg 2640ctcattcaaa gtgtgtcctt
aaaggaatgc agtcacccat gccagaggca gtgtttacag 2700cctggaatgc
tctgcacttc cagtggacca gtgctccacc ggaagtgggc tgttagcagg
2760gtcctctcac ctggccctgg cctttctgta gccttgaatc ctgccttccc
caccagggca 2820ccagggatga gtgcagcagc aggaggagag gcaaacagtc
acctcaggaa ccttctgagc 2880taaggcacac cctctgtgcc tgtcaagcaa
aggttgtatt ggatatcaag tgtttggtct 2940cacgccaagc caacaggctt
tggagagaat taattagttc tcctactcag ggatttcttt 3000cagtcctaac
acagcctgtg tatattttgc ttcacccacg caatgctgga ttatttaatt
3060ttgcccggct taagacaaat ctgagttact tgtaaatttg ctctatgttc
ataataaaaa 3120tgtattatat atcactgata gca 31434023470DNAHomo sapiens
402aaagctctgg gccccaggga ggaggctcag cacagagagt ggaaaacagc
agaggtgaca 60gagcagccgt gctcgaagcg ttcctggagc ccaagctctc ctccacaggt
gaagacaggg 120ccagcaggag acaccatggg gcacctctca gccccacttc
acagagtgcg tgtaccctgg 180caggggcttc tgctcacagc ctcacttcta
accttctgga acccgcccac cactgcccag 240ctcactactg aatccatgcc
attcaatgtt gcagagggga aggaggttct tctccttgtc 300cacaatctgc
cccagcaact ttttggctac agctggtaca aaggggaaag agtggatggc
360aaccgtcaaa ttgtaggata tgcaatagga actcaacaag ctaccccagg
gcccgcaaac 420agcggtcgag agacaatata ccccaatgca tccctgctga
tccagaacgt cacccagaat 480gacacaggat tctacaccct acaagtcata
aagtcagatc ttgtgaatga agaagcaact 540ggacagttcc atgtataccc
ggagctgccc aagccctcca tctccagcaa caactccaac 600cctgtggagg
acaaggatgc tgtggccttc acctgtgaac ctgagactca ggacacaacc
660tacctgtggt ggataaacaa tcagagcctc ccggtcagtc ccaggctgca
gctgtccaat 720ggcaacagga ccctcactct actcagtgtc acaaggaatg
acacaggacc ctatgagtgt 780gaaatacaga acccagtgag tgcgaaccgc
agtgacccag tcaccttgaa tgtcacctat 840ggcccggaca cccccaccat
ttccccttca gacacctatt accgtccagg ggcaaacctc 900agcctctcct
gctatgcagc ctctaaccca cctgcacagt actcctggct tatcaatgga
960acattccagc aaagcacaca agagctcttt atccctaaca tcactgtgaa
taatagtgga 1020tcctatacct gccacgccaa taactcagtc actggctgca
acaggaccac agtcaagacg 1080atcatagtca ctgagctaag tccagtagta
gcaaagcccc aaatcaaagc cagcaagacc 1140acagtcacag gagataagga
ctctgtgaac ctgacctgct ccacaaatga cactggaatc 1200tccatccgtt
ggttcttcaa aaaccagagt ctcccgtcct cggagaggat gaagctgtcc
1260cagggcaaca ccaccctcag cataaaccct gtcaagaggg aggatgctgg
gacgtattgg 1320tgtgaggtct tcaacccaat cagtaagaac caaagcgacc
ccatcatgct gaacgtaaac 1380tataatgctc taccacaaga aaatggcctc
tcacctgggg ccattgctgg cattgtgatt 1440ggagtagtgg ccctggttgc
tctgatagca gtagccctgg catgttttct gcatttcggg 1500aagaccggca
ggaccactcc aatgacccac ctaacaagat gaatgaagtt acttattcta
1560ccctgaactt tgaagcccag caacccacac aaccaacttc agcctcccca
tccctaacag 1620ccacagaaat aatttattca gaagtaaaaa agcagtaatg
aaacctgtcc tgctcactgc 1680agtgctgatg tatttcaagt ctctcaccct
catcactagg agattccttt cccctgtagg 1740ggtagagggg tggggacaga
aacaactttc tcctactctt ccttcctaat aggcatctcc 1800aggctgcctg
gtcactgccc ctctctcagt gtcaatagat gaaagtacat tgggagtctg
1860taggaaaccc aaccttcttg tcattgaaat ttggcaaagc tgactttggg
aaagagggac 1920cagaacttcc cctcccttcc ccttttccca acctggactt
gttttaaact tgcctgttca 1980gagcactcat tccttcccac ccccagtcct
gtcctatcac tctaattcgg atttgccata 2040gccttgaggt tatgtccttt
tccattaagt acatgtgcca ggaaacaaga gagagagaaa 2100gtaaaggcag
taatgccttc tcctatttct ccaaagcctt gtgtgaactc accaaacaca
2160agaaaatcaa atatataacc aatagtgaaa tgccacacct ttgtccactg
tcagggttgt 2220ctacctgtag gatcagggtc taagcacctt ggtgcttagc
tagaatacca cctaatcctt 2280ctggcaagcc tgtcttcaga gaacccacta
gaagcaacta ggaaaatcac ttgccaaaat 2340ccaaggcaat tcctgatgga
aaatgcaaaa gcacatatat gttttaatat ctttatgggc 2400tctgttcaag
gcagtgctga gagggagggg ttatagcttc aggagggaac cagcttctga
2460taaacacaat ctgctaggaa cttgggaaag gaatcagaga gctgcccttc
agcgattatt 2520taaattattg ttaaagaata cacaatttgg ggtattggga
tttttctcct tttctctgag 2580acattccacc attttaattt ttgtaactgc
ttatttatgt gaaaagggtt atttttactt 2640agcttagcta tgtcagccaa
tccgattgcc ttaggtgaaa gaaaccaccg aaatccctca 2700ggtcccttgg
tcaggagcct ctcaagattt tttttgtcag aggctccaaa tagaaaataa
2760gaaaaggttt tcttcattca tggctagagc tagatttaac tcagtttcta
ggcacctcag 2820accaatcatc aactaccatt ctattccatg tttgcacctg
tgcattttct gtttgccccc 2880attcactttg tcaggaaacc ttggcctctg
ctaaggtgta tttggtcctt gagaagtggg 2940agcaccctac agggacacta
tcactcatgc tggtggcatt gtttacagct agaaagctgc 3000actggtgcta
atgccccttg gggaaatggg gctgtgagga ggaggattat aacttaggcc
3060tagcctcttt taacagcctc tgaaatttat cttttcttct atggggtcta
taaatgtatc 3120ttataataaa aaggaaggac aggaggaaga caggcaaatg
tacttctcac ccagtcttct 3180acacagatgg aatctctttg gggctaagag
aaaggtttta ttctatattg cttacctgat 3240ctcatgttag gcctaagagg
ctttctccag gaggattagc ttggagttct ctatactcag 3300gtacctcttt
cagggttttc taaccctgac acggactgtg catactttcc ctcatccatg
3360ctgtgctgtg ttatttaatt tttcctggct aagatcatgt ctgaattatg
tatgaaaatt 3420attctatgtt tttataataa aaataatata tcagacatcg
aaaaaaaaaa 34704031155DNAMus musculus 403ccaaagcact tcttagctta
tcatgggact ctgcatacgc ctgtgccaaa tacacaggaa 60cacgttcaca taccttcttg
cctgtccgcc tactcttctt gccccacctc catagttctt 120atagccacac
cctgcaagga aaaaccccag actcctgtga aggcagaaag cagacaagga
180tgtatgtgtg ggttcagcag cccacagccc ttctgctgct gggactcaca
cttggagtta 240cagcaaggcg gctcaactgt gttaaacata cctaccccag
tggtcacaag tgctgtcgtg 300agtgccagcc aggccatggt atggtgagcc
gctgtgatca taccagggat actctatgtc 360atccgtgtga gactggcttc
tacaatgaag ctgtcaatta tgatacctgc aagcagtgta 420cacagtgcaa
ccatcgaagt ggaagtgaac tcaagcagaa ttgcacacct actcaggata
480ctgtctgcag atgtagacca ggcacccaac ctcggcagga cagcggctac
aagcttggag 540ttgactgtgt tccctgccct cctggccact tttctccagg
caacaaccag gcctgcaagc 600cctggaccaa ttgtacctta tctggaaagc
agacccgcca cccagccagt gacagcttgg 660acgcagtctg tgaggacaga
agcctcctgg ccacactgct ctgggagacc cagcgcccta 720cattcaggcc
aaccactgtc caatccacca cagtctggcc caggacttct gagttgccct
780ctccacccac cttggtgact cctgagggcc ctgcatttgc tgttctccta
ggcctgggcc 840tgggcctgct ggctcccttg actgtcctgc tggccttgta
cctgctccgg aaggcttgga 900gattgcctaa cactcccaaa ccttgttggg
gaaacagctt caggaccccg atccaggagg 960aacacacaga cgcacacttt
actctggcca agatctgagc attactacag gagtggattt 1020tatggggcac
ggacaaccca tatcctgatg cctgccagta ccctccacac cgttctaggt
1080gctgggctgg ctctgggctt tcctatgtat gctatgcata ctacctgcct
ggtggtgctc 1140ctaataaaca tgcta 11554041120DNAHomo sapiens
404ccgcaaggaa aacccagact ctggcgacag cagagacgag gatgtgcgtg
ggggctcggc 60ggctgggccg cgggccgtgt gcggctctgc tcctcctggg cctggggctg
agcaccgtga 120cggggctcca ctgtgtcggg gacacctacc ccagcaacga
ccggtgctgc cacgagtgca 180ggccaggcaa cgggatggtg agccgctgca
gccgctccca gaacacggtg tgccgtccgt 240gcgggccggg cttctacaac
gacgtggtca gctccaagcc gtgcaagccc tgcacgtggt 300gtaacctcag
aagtgggagt gagcggaagc agctgtgcac ggccacacag gacacagtct
360gccgctgccg ggcgggcacc cagcccctgg acagctacaa gcctggagtt
gactgtgccc 420cctgccctcc agggcacttc tccccaggcg acaaccaggc
ctgcaagccc tggaccaact 480gcaccttggc tgggaagcac accctgcagc
cggccagcaa tagctcggac gcaatctgtg 540aggacaggga ccccccagcc
acgcagcccc aggagaccca gggccccccg gccaggccca 600tcactgtcca
gcccactgaa gcctggccca gaacctcaca gggaccctcc acccggcccg
660tggaggtccc cgggggccgt gcggttgccg ccatcctggg cctgggcctg
gtgctggggc 720tgctgggccc cctggccatc ctgctggccc tgtacctgct
ccggagggac cagaggctgc 780cccccgatgc ccacaagccc cctgggggag
gcagtttccg gacccccatc caagaggagc 840aggccgacgc ccactccacc
ctggccaaga tctgacctgg gcccaccaag gtggacgctg 900ggccccgcca
ggctggagcc cggagggtct gctgggcgag cagggcaggt gcaggccgcc
960tgccccgcca cgctcctggg ccaactctgc accgttctag gtgccgatgg
ctgcctccgg 1020ctctctgctt acgtatgcca tgcatacctc ctgccccgcg
ggaccacaat aaaaaccttg 1080gcagacggga gtctccgacc ggcaaaaaaa
aaaaaaaaaa 11204051609DNAMus musculus 405attgcttttt gtctcctgtt
ctgggacctt tatcttctga cccgcaggct tgactttgcc 60cttattggct cctttgtggt
gaagagcagt cttcccccag gttccccgcc acagctgtat 120ctcctctgca
ccccgactgc agagatggaa ggggaagggg ttcaacccct ggatgagaat
180ctggaaaacg gatcaaggcc aagattcaag tggaagaaga cgctaaggct
ggtggtctct 240gggatcaagg gagcagggat gcttctgtgc ttcatctatg
tctgcctgca actctcttcc 300tctccggcaa aggaccctcc aatccaaaga
ctcagaggag cagttaccag atgtgaggat 360gggcaactat tcatcagctc
atacaagaat gagtatcaaa ctatggaggt gcagaacaat 420tcggttgtca
tcaagtgcga tgggctttat atcatctacc tgaagggctc ctttttccag
480gaggtcaaga ttgaccttca tttccgggag gatcataatc ccatctctat
tccaatgctg 540aacgatggtc gaaggattgt cttcactgtg gtggcctctt
tggctttcaa agataaagtt 600tacctgactg taaatgctcc tgatactctc
tgcgaacacc tccagataaa tgatggggag 660ctgattgttg tccagctaac
gcctggatac tgtgctcctg aaggatctta ccacagcact 720gtgaaccaag
taccactgtg aattccactc tgagggtgga cgggacacag gttctttctc
780gagagagatg agtgcatcct gctcatgaga tgtgactgaa tgcagagcct
accctacttc 840ctcactcagg gatatttaaa tcatgtctta cataacagtt
gacctctcat tcccaggatt 900gccttgagcc tgctaagagc tgttctggga
atgaaaaaaa aaataaatgt ctcttcaaga 960cacattgctt ctgtcggtca
gaagctcatc gtaataaaca tctgccactg aaaatggcgc 1020ttgattgcta
tcttctagaa ttttgatgtt gtcaaaagaa agcaaaacat ggaaagggtg
1080gtgtccaccg gccagtagga gctggagtgc tctcttcaag gttaaggtga
tagaagttta 1140catgttgcct aaaactgtct ctcatctcat ggggggcttg
gaaagaagat taccccgtgg 1200aaagcaggac ttgaagatga ctgtttaagc
aacaaggtgc actcttttcc tggcccctga 1260atacacataa aagacaactt
ccttcaaaga actacctagg gactatgata cccaccaaag 1320aaccacgtca
gcgatgcaaa gaaaaccagg agagctttgt ttattttgca gagtatacga
1380gagattttac cctgagggct atttttatta tacaggatga gagtgaactg
gatgtctcag 1440gataaaggcc aagaaggatt tttcacagtc tgagcaagac
tgtttttgta ggttctctct 1500ccaaaacttt taggtaaatt tttgataatt
ttaaaatttt tagttatatt tttggaccat 1560tttcaataga agattgaaac
atttccagat ggtttcatat ccccacaag 16094063484DNAHomo sapiens
406ggccctggga cctttgccta ttttctgatt gataggcttt gttttgtctt
tacctccttc 60tttctgggga aaacttcagt tttatcgcac gttccccttt tccatatctt
catcttccct 120ctacccagat tgtgaagatg gaaagggtcc aacccctgga
agagaatgtg ggaaatgcag 180ccaggccaag attcgagagg aacaagctat
tgctggtggc ctctgtaatt cagggactgg 240ggctgctcct gtgcttcacc
tacatctgcc tgcacttctc tgctcttcag gtatcacatc 300ggtatcctcg
aattcaaagt atcaaagtac aatttaccga atataagaag gagaaaggtt
360tcatcctcac ttcccaaaag gaggatgaaa tcatgaaggt gcagaacaac
tcagtcatca 420tcaactgtga tgggttttat ctcatctccc tgaagggcta
cttctcccag gaagtcaaca 480ttagccttca ttaccagaag gatgaggagc
ccctcttcca actgaagaag gtcaggtctg 540tcaactcctt gatggtggcc
tctctgactt acaaagacaa agtctacttg aatgtgacca 600ctgacaatac
ctccctggat gacttccatg tgaatggcgg agaactgatt cttatccatc
660aaaatcctgg tgaattctgt gtcctttgag gggctgatgg caatatctaa
aaccaggcac 720cagcatgaac accaagctgg gggtggacag ggcatggatt
cttcattgca agtgaaggag 780cctcccagct cagccacgtg ggatgtgaca
agaagcagat cctggccctc ccgcccccac 840ccctcaggga tatttaaaac
ttattttata taccagttaa tcttatttat ccttatattt 900tctaaattgc
ctagccgtca caccccaaga ttgccttgag cctactaggc acctttgtga
960gaaagaaaaa atagatgcct cttcttcaag atgcattgtt tctattggtc
aggcaattgt 1020cataataaac ttatgtcatt gaaaacggta cctgactacc
atttgctgga aatttgacat 1080gtgtgtggca ttatcaaaat gaagaggagc
aaggagtgaa ggagtggggt tatgaatctg 1140ccaaaggtgg tatgaaccaa
cccctggaag ccaaagcggc ctctccaagg ttaaattgat 1200tgcagtttgc
atattgccta aatttaaact ttctcatttg gtgggggttc aaaagaagaa
1260tcagcttgtg aaaaatcagg acttgaagag agccgtctaa gaaataccac
gtgctttttt 1320tctttaccat tttgctttcc cagcctccaa acatagttaa
tagaaatttc ccttcaaaga 1380actgtctggg gatgtgatgc tttgaaaaat
ctaatcagtg acttaagaga gattttcttg 1440tatacaggga gagtgagata
acttattgtg aagggttagc tttactgtac aggatagcag 1500ggaactggac
atctcagggt aaaagtcagt acggatttta atagcctggg gaggaaaaca
1560cattctttgc cacagacagg caaagcaaca catgctcatc ctcctgccta
tgctgagata 1620cgcactcagc tccatgtctt gtacacacag aaacattgct
ggtttcaaga aatgaggtga 1680tcctattatc aaattcaatc tgatgtcaaa
tagcactaag aagttattgt gccttatgaa 1740aaataatgat ctctgtctag
aaataccata gaccatatat agtctcacat tgataattga 1800aactagaagg
gtctataatc agcctatgcc agggcttcaa tggaatagta tccccttatg
1860tttagttgaa atgtcccctt aacttgatat aatgtgttat gcttatggcg
ctgtggacaa 1920tctgattttt catgtcaact ttccagatga tttgtaactt
ctctgtgcca aaccttttat 1980aaacataaat ttttgagata tgtattttaa
aattgtagca catgtttccc tgacattttc 2040aatagaggat acaacatcac
agaatctttc tggatgattc tgtgttatca aggaattgta 2100ctgtgctaca
attatctcta gaatctccag aaaggtggag ggctgttcgc ccttacacta
2160aatggtctca gttggatttt tttttcctgt tttctatttc ctcttaagta
caccttcaac 2220tatattccca tccctctatt ttaatctgtt atgaaggaag
gtaaataaaa atgctaaata 2280gaagaaattg taggtaaggt aagaggaatc
aagttctgag tggctgccaa ggcactcaca 2340gaatcataat catggctaaa
tatttatgga gggcctactg tggaccaggc actgggctaa 2400atacttacat
ttacaagaat cattctgaga cagatattca atgatatctg gcttcactac
2460tcagaagatt gtgtgtgtgt ttgtgtgtgt gtgtgtgtgt gtatttcact
ttttgttatt 2520gaccatgttc tgcaaaattg cagttactca gtgagtgata
tccgaaaaag taaacgttta 2580tgactatagg taatatttaa gaaaatgcat
ggttcatttt taagtttgga atttttatct 2640atatttctca cagatgtgca
gtgcacatgc aggcctaagt atatgttgtg tgtgttgttt 2700gtctttgatg
tcatggtccc ctctcttagg tgctcactcg ctttgggtgc acctggcctg
2760ctcttcccat gttggcctct gcaaccacac agggatattt ctgctatgca
ccagcctcac 2820tccaccttcc ttccatcaaa aatatgtgtg tgtgtctcag
tccctgtaag tcatgtcctt 2880cacagggaga attaaccctt cgatatacat
ggcagagttt tgtgggaaaa gaattgaatg 2940aaaagtcagg agatcagaat
tttaaatttg acttagccac taactagcca tgtaaccttg 3000ggaaagtcat
ttcccatttc tgggtcttgc ttttctttct gttaaatgag aggaatgtta
3060aatatctaac agtttagaat cttatgctta cagtgttatc tgtgaatgca
catattaaat 3120gtctatgttc ttgttgctat gagtcaagga gtgtaacctt
ctcctttact atgttgaatg 3180tatttttttc tggacaagct tacatcttcc
tcagccatct ttgtgagtcc ttcaagagca 3240gttatcaatt gttagttaga
tattttctat ttagagaatg cttaagggat tccaatcccg 3300atccaaatca
taatttgttc ttaagtatac tgggcaggtc ccctatttta agtcataatt
3360ttgtatttag tgctttcctg gctctcagag agtattaata ttgatattaa
taatatagtt 3420aatagtaata ttgctattta catggaaaca aataaaagat
ctcagaattc actaaaaaaa 3480aaaa 3484
* * * * *