Double-stranded oligonucleotides for regulating JAK1 expression

Abstract

This invention relates to double-stranded oligonucleotides complementary to JAK1 that result in the regulation of JAK1 expression. Regulation of JAK1 expression is beneficial for a range of medical disorders, including inflammatory bowel disease, organ transplant rejection, graft-versus-host disease, multiple sclerosis, rheumatoid arthritis (RA), juvenile idiopathic arthritis, psoriasis, dermatitis, diabetic nephropathy, systemic lupus erythematosus (SLE), dry eye disease, cancer, myelofibrosis, and asthma. The invention also includes compositions comprising double-stranded oligonucleotides and therapeutic methods using double-stranded oligonucleotides.

Claims

1. A compound comprising double-stranded ribonucleic acid (dsRNA) for reducing the expression of Janus kinase 1 (JAK1), wherein the dsRNA comprises a sense strand and an antisense strand. The sense strand comprises a first continuous nucleotide sequence having a length of at least 15 nucleotides. The antisense strand comprises a second sequence of at least 15 nucleotides in length that is complementary to the JAK1 nucleic acid sequence containing or consisting of SEQ ID NO: 1 or a naturally occurring variant thereof. A compound in which the first and second consecutive nucleotide sequences form complementary double-stranded regions.

2. The compound according to claim 1, wherein the second consecutive nucleotide sequence is complementary to a target sequence in the JAK1 nucleic acid sequence, and the target sequence is one of the sequences of SEQ ID NOs: 385 to 575, preferably one of the sequences of SEQ ID NOs: 385, 386, 405, 447, 456, 479, 498, 512, 517, and 530.

3. The compound according to claim 1 or claim 2, wherein the second continuous nucleotide sequence includes a seed region, and the sequence of the seed region includes or consists of any one of the sequences of sequence numbers 576 to 766.

4. The compound according to any one of claims 1 to 3, wherein the second consecutive nucleotide sequence includes or comprises a sequence that has at least 80% identity with any one of the sequences of sequence numbers 194 to 384, such as at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with any one of the sequences of sequence numbers 194 to 384, and preferably the second consecutive nucleotide sequence includes or comprises any one of the sequences of sequence numbers 194 to 384.

5. The compound according to any one of claims 1 to 4, wherein the antisense chain comprises a uracil nucleotide, such as vinylphosphonate 2'-OMe uracil, located at the 5' end of the antisense chain.

6. The compound according to any one of claims 1 to 5, wherein the first continuous nucleotide sequence comprises or consists of one of the sequences of SEQ ID NOs: 3 to 193, preferably one of the sequences of SEQ ID NOs: 3, 4, 21, 63, 72, 95, 114, 128, 133, and 146.

7. The compound according to any one of claims 1 to 6, wherein the dsRNA comprises at least one modified nucleotide.

8. The compound according to claim 7, wherein the non-bicyclic sugar moiety is independently selected from 2'-O-alkyl-RNA, 2'-O-methyl-RNA (2'OMe modified sugar), 2'-alkoxy-RNA, 2'-O-methoxyethyl-RNA, 2'-amino-DNA, 2'-fluoro-DNA (2'F modified sugar), arabino nucleic acid (ANA), 2'-fluoro-ANA, glycol nucleic acid (GNA), and unlocked nucleic acid (UNA), and preferably the non-bicyclic sugar moiety is independently selected from 2'F modified sugar and 2'OMe modified sugar.

9. The compound according to any one of claims 1 to 8, wherein the dsRNA comprises at least one modified nucleotide bond.

10. The compound according to any one of claims 1 to 9, wherein each nucleotide bond in the dsRNA is either a phosphodiester nucleotide bond or a phosphorothioate nucleotide bond.

11. The compound according to any one of claims 1 to 10, wherein the dsRNA is covalently bound to at least one conjugate region.

12. The compound according to claim 11, wherein the dsRNA is covalently bonded to the conjugate portion via a linker.

13. The compounds shown in Table 3 are 614, 673, 724, 728, 753, 756, 818, 874, 875, 876, 877, 878, 883, 884, 1069, 1075, 1085, 1107, 1108, 1138, 1182, 1189, 1190, 1304, 1306, 1311, 1367, 1368, 1372, 1412, 1413, 1432, 1579, 1580, 1581, 1583, 1584, 1586, 1587, 1588, 1595, 1596, 1601, 1602, 1603, 1608, 1609, 1611, 1640, 1642, and 167 1, 1672, 1673, 1674, 1677, 1678, 1690, 1692, 1698, 1699, 1723, 1769, 1770, 1780, 1798, 1876, 1927, 1928, 1929, 1936, 1952, 1954, 1956, 1958, 1978, 206 6, 2068, 2102, 2111, 2138, 2146, 2148, 2205, 2206, 2218, 2229, 2230, 2237, 2238, 2239, 2269, 2308, 2317, 2318, 2319, 2320, 2321, 2322, 2323, 2520, 252 7, 2647, 2761, 2762, 2763, 2764, 2811, 2962, 2975, 2977, 3028, 3032, 3081, 3131, 3134, 3141, 3144, 3146, 3147, 3159, 3160, 3229, 3247, 3250, 3251, 32 52, 3254, 3255, 3258, 3259, 3260, 3261, 3265, 3268, 3272, 3275, 3276, 3278, 3279, 3281, 3282, 3283, 3284, 3285, 3286, 3313, 3314, 3323, 3353, 3365, 33 Compounds selected from 67, 3368, 3371, 3372, 3376, 3409, 3505, 3556, 3557, 3558, 3559, 3654, 3662, 3663, 3683, 3689, 3694, 3695, 3698, 3702, 3719, 3781, 3894, 4099, 4169, 4239, 4305, 4374, 4411, 4475, 4612, 4671, 4672, 4679, 4682, 4683, 4684, 4690, 4794, 4803, and 4807, preferably compounds 614, 673, 1182, 1770 shown in Table 3.Compounds selected from 1954, 2319, 3131, 3255, 3265, and 3313.

14. Compounds selected from compounds 614, 673, 1182, 1770, 1954, 2319, 3131, 3255, 3265, 3313, 614_C16, 673_C16, 1182_C16, 1770_C16, 1954_C16, 2319_C16, 3131_C16, 3255_C16, 3265_C16, 3313_C16, 614_C22, 673_C22, 1182_C22, 1770_C22, 1954_C22, 2319_C22, 3131_C22, 3255_C22, 3265_C22, and 3313_C22.

15. The compound according to any one of claims 1 to 14, wherein the compound is in the form of a pharmaceutically acceptable salt, preferably a sodium salt or a potassium salt.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15, and a pharmaceutically acceptable diluent, solvent, carrier, salt and / or adjuvant, preferably an aqueous diluent or solvent; more preferably phosphate-buffered saline.

17. An in vivo or in vitro method for suppressing JAK1 expression in target cells, comprising administering an effective amount of a compound according to any one of claims 1 to 15 or a pharmaceutical composition according to claim 16 to the cells.

18. A compound according to any one of claims 1 to 15 or a pharmaceutical composition according to claim 16, for use in a method for treating or preventing a disease.

19. The compound or pharmaceutical composition for use according to claim 18, wherein the disease is selected from the group consisting of inflammatory bowel disease, organ transplant rejection, graft-versus-host disease, multiple sclerosis, rheumatoid arthritis (RA), juvenile idiopathic arthritis, psoriasis, dermatitis, diabetic nephropathy, systemic lupus erythematosus (SLE), dry eye disease, cancer, myelofibrosis, and asthma, and is preferably dry eye disease.

20. A kit comprising the compound described in any one of claims 1 to 15 and instructions for use.

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