Serpinc1 iRNA compositions and methods of use thereof
View Patent ↗The invention relates to iRNA, e.g., double-stranded ribonucleic acid (dsRNA), compositions targeting the Serpinc1 gene, and methods of using such iRNA, e.g., dsRNA, compositions to inhibit expression of Serpinc1 and methods of treating subjects having a bleeding disorder, such as a hemophilia.
1. A double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of Serpinc1, wherein said dsRNA agent comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity which comprises at least 21 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence of 5′ -UUGAAGUAAAUGGUGUUAACCAG-3′ (SEQ ID NO:562),
wherein the antisense strand comprises at least one phosphorothioate internucleoside linkage and a 3′ overhang of at least 1 nucleotide,
wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand are modified nucleotides,
wherein the nucleotide modifications are selected from the group consisting of 2′—O—methyl (2′-OMe) and 2′-fluoro nucleotide modifications, and
wherein a ligand comprising an N-acetylgalactosamine (Ga1NAc) derivative is conjugated to the 3′ end of the sense strand of the dsRNA agent.
2. A cell containing the dsRNA agent of claim 1 .
3. A pharmaceutical composition for inhibiting expression of a Serpinc1 gene comprising the dsRNA agent of claim 1 .
4. A method of inhibiting Serpinc1 expression in a cell, the method comprising:
(a) contacting the cell with the dsRNA agent of claim 1 ; and
(b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a Serpinc1gene, thereby inhibiting expression of the Serpinc1 gene in the cell.
5. A method of treating a subject having a disorder that would benefit from reduction in Serpinc1 expression, comprising administering to the subject a therapeutically effective amount of the dsRNA agent of claim 1 , thereby treating said subject.
6. A method of preventing at least one symptom in a subject having a disorder that would benefit from reduction in Serpinc1 expression, comprising administering to the subject a therapeutically effective amount of the dsRNA agent of claim 2 , thereby preventing at least one symptom in the subject having a disorder that would benefit from reduction in Serpinc1 expression.
7. The method of claim 5 or 6 , wherein the disorder is a bleeding disorder.
8. The method of claim 7 , wherein the bleeding disorder is a hemophilia.
9. A method of inhibiting the expression of Serpinc1 in a subject, the method comprising administering to said subject a therapeutically effective amount of the dsRNA agent of claim 1 , thereby inhibiting the expression of Serpinc1 in said subject.
10. The dsRNA agent of claim 1 , wherein each strand is no more than 30 nucleotides in length.
11. The dsRNA agent of claim 1 , wherein the ligand is
12. The dsRNA agent of claim 1 , wherein the dsRNA agent is conjugated to the ligand as shown in the following schematic
and, wherein X is O or S.
13. The dsRNA agent of claim 12 , wherein the X is O.
14. The dsRNA agent of claim 1 , wherein the region of complementarity consists of the nucleotide sequence of 5′-UUGAAGUAAAUGGUGUUAACCAG-3′ (SEQ ID NO:562).
15. The dsRNA agent of claim 1 , wherein the dsRNA agent comprises a sense strand comprising the nucleotide sequence of 5′-GGUUAACACCAUUUACUUCAA-3′ (SEQ ID NO:294), and an antisense strand comprising the nucleotide sequence of 5′-UUGAAGUAAAUGGUGUUAACCAG-3′ (SEQ ID NO:562).
16. The dsRNA agent of claim 15 , wherein the sense strand comprises 5′-GfgUfuAfaCfaCfCfAfuUfuAfcUfuCfaAf-3′ (SEQ ID NO:956) and the antisense strand comprises 5′-uUfgAfaGfuAfaAfuggUfgUfuAfaCfcsAfsg-3′ (SEQ ID NO:975),
wherein a, c, g, and u are 2′—O—methyl (2′-OMe) A, C, G, and U; Af, Cf, Gf, and Uf are 2′-fluoro A, C, G, and U; and s is a phosphorothioate linkage.
17. The dsRNA agent of claim 15 , wherein the sense strand comprises 5′-GfsgsUfuAfaCfaCfCfAfuUfuAfcUfuCfaAf-3′ (SEQ ID NO:941) and the antisense strand comprises 5′-usUfsgAfaGfuAfaAfuggUfgUfuAfaCfcsasg-3′ (SEQ ID NO:960),
wherein a, c, g, and u are 2′—O—methyl (2′-OMe) A, C, G, and U; Af, Cf, Gf, and Uf are 2′-fluoro A, C, G, and U; and s is a phosphorothioate linkage.
18. The method of claim 4 , wherein said cell is within a subject.
19. The method of claim 18 , wherein the subject is a human.
20. The method of claim 19 , wherein the human subject suffers from a bleeding disorder.
21. The method of claim 20 , wherein the bleeding disorder is a hemophilia.
22. The method of claim 4 , wherein the Serpinc1 expression is inhibited by at least about 30%.
23. The method of claim 9 , wherein the subject suffers from a bleeding disorder.
24. The method of claim 23 , wherein the bleeding disorder is a hemophilia.
25. The method of claim 5 or 6 , wherein the administration of the dsRNA agent to the subject causes an increase in blood clotting and/or a decrease in Serpinc1 protein accumulation.
26. The method of claim 5 or 6 , wherein the dsRNA agent is administered at a dose of about 10 mg/kg to about 30 mg/kg.
27. The method of claim 5 or 6 , wherein the dsRNA agent is administered at a dose selected from the group consisting of 0.3 mg/kg 0.5 mg/kg 1mg/kg, 1.5 mg/kg, 3 mg/kg, 10 mg/kg, and 30 mg/kg.
28. The method of claim 5 or 6 , wherein the dsRNA agent is administered to the subject once a week.
29. The method of claim 5 or 6 , wherein the dsRNA agent is administered to the subject twice a month.
30. The method of claim 5 or 6 , wherein the dsRNA agent is administered to the subject subcutaneously at a cumulative weekly dose of about 0.5 mg/kg to about 5 mg/kg.
31. The method of claim 5 or 6 , further comprising measuring thrombin levels in said subject.
32. The method of claim 9 , wherein the dsRNA agent is administered at a dose of about 10 mg/kg to about 30 mg/kg.
33. The method of claim 9 , wherein the dsRNA agent is administered at a dose selected from the group consisting of 0.3 mg/kg 0.5 mg/kg 1 mg/kg, 1.5mg/kg, 3 mg/kg, 10 mg/kg, and 30 mg/kg.
34. The method of claim 9 , wherein the dsRNA agent is administered to the subject once a week.
35. The method of claim 9 , wherein the dsRNA agent is administered to the subject twice a month.
36. The method of claim 9 , wherein the dsRNA agent is administered to the subject subcutaneously at a cumulative weekly dose of about 0.5 mg/kg to about 5 mg/kg.
37. The method of claim 9 , further comprising measuring thrombin levels in said subject.
38. The method of claim 8 wherein the subject suffers from hemophilia A.
39. The method of claim 8 wherein the subject suffers from hemophilia B.
40. The method of claim 8 wherein the subject suffers from hemophilia C.
41. The method of claim 8 wherein the subject suffers from hemophilia A and is an inhibitor subject.
42. The method of claim 8 wherein the subject suffers from hemophilia B and is an inhibitor subject.
43. The method of claim 8 wherein the subject suffers from hemophilia C and is an inhibitor subject.
44. The method of claim 21 , wherein the subject suffers from hemophilia A.
45. The method of claim 21 , wherein the subject suffers from hemophilia B.
46. The method of claim 21 , wherein the subject suffers from hemophilia C.
47. The method of claim 21 , wherein the subject suffers from hemophilia A and is an inhibitor subject.
48. The method of claim 21 , wherein the subject suffers from hemophilia B and is an inhibitor subject.
49. The method of claim 21 , wherein the subject suffers from hemophilia C and is an inhibitor subject.
50. The method of claim 24 , wherein the subject suffers from hemophilia A.
51. The method of claim 24 , wherein the subject suffers from hemophilia B.
52. The method of claim 24 , wherein the subject suffers from hemophilia C.
53. The method of claim 24 , wherein the subject suffers from hemophilia A and is an inhibitor subject.
54. The method of claim 24 , wherein the subject suffers from hemophilia B and is an inhibitor subject.
55. The method of claim 24 , wherein the subject suffers from hemophilia C and is an inhibitor subject.