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) for inhibiting expression of Serpinc1, wherein said dsRNA comprises a sense strand and an antisense strand,
wherein the sense strand comprises the nucleotide sequence of 5′-GfsgsUfuAfaCfaCfCfAfuUfuAfcUfuCfaAf-3′ (SEQ ID NO:941) and the antisense strand comprises the nucleotide sequence of 5′-usUfsgAfaGfuAfaAfuggUfgUfuAfaCfcsasg-3′ (SEQ ID NO:960),
wherein a, g, c and u are 2′-O-methyl(2′-OMe) A, U, C, or G; Af, Cf, Gf or Uf are 2′-fluoro A, G, C or U; and s is a phosphorothioate linkage.
2. The dsRNA of claim 1 , further comprising a ligand.
3. The dsRNA of claim 2 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA.
4. The dsRNA of claim 2 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.
5. The dsRNA of claim 4 , wherein the ligand is
6. The dsRNA of claim 4 , wherein the dsRNA is conjugated to the ligand as shown in the following schematic
and, wherein X is O or S.
7. The dsRNA of claim 6 , wherein the X is O.
8. A cell containing the dsRNA of claim 1 .
9. A pharmaceutical composition for inhibiting expression of a Serpinc1 gene comprising the dsRNA of claim 1 .
10. A method of inhibiting Serpinc1 expression in a cell, the method comprising:
(a) contacting the cell with the dsRNA of claim 1 ; and
(b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a Serpinc1 gene, thereby inhibiting expression of the Serpinc1 gene in the cell.
11. The method of claim 10 , wherein said cell is within a subject.
12. The method of claim 11 , wherein the subject is a human.
13. The method of claim 12 , wherein the human subject suffers from a bleeding disorder.
14. The method of claim 13 , wherein the bleeding disorder is a hemophilia.
15. The method of any one of claims 10 - 14 , wherein the Serpinc1 expression is inhibited by at least about 30%.
16. 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 of claim 1 , thereby treating said subject.
17. 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 of claim 1 , thereby preventing at least one symptom in the subject having a disorder that would benefit from reduction in Serpinc1 expression.
18. The method of claim 16 , wherein the disorder is a bleeding disorder.
19. The method of claim 18 , wherein the bleeding disorder is a hemophilia.
20. The method of claim 16 , wherein the administration of the dsRNA to the subject causes an increase in blood clotting and/or a decrease in Serpinc1 protein accumulation.
21. The method of claim 16 , wherein the dsRNA is conjugated to a ligand.
22. The method of claim 21 , wherein the ligand is conjugated to the 3′-end of the sense strand of the dsRNA.
23. The method of claim 22 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.
24. The method of claim 17 , wherein the dsRNA is administered at a dose of about 0.01 mg/kg to about 50 mg/kg.
25. The method of claim 24 , wherein the dsRNA is administered at a dose of about 10 mg/kg to about 30 mg/kg.
26. The method of claim 24 , wherein the dsRNA is administered at a dose selected from the group consisting of 0.3 mg/kg 0.5 mg/kg 1 mg/kg, 1.5 mg/kg, 3 mg/kg, 10 mg/kg, and 30 mg/kg.
27. The method of claim 25 or 26 , wherein the dsRNA is administered to the subject once a week.
28. The method of claim 25 or 26 , wherein the dsRNA is administered to the subject twice a month.
29. The method of claim 16 , further comprising measuring thrombin levels in said subject.
30. The method of claim 17 , wherein the dsRNA is administered to the subject subcutaneously at a cumulative weekly dose of about 0.5 mg/kg to about 5 mg/kg.
31. 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 of claim 1 , thereby inhibiting the expression of Serpinc1 in said subject.
32. The method of claim 31 , wherein the dsRNA is conjugated to a ligand.
33. The method of claim 32 , wherein the ligand is conjugated to the 3′-end of the sense strand of the dsRNA.
34. The method of claim 33 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.
35. The method of claim 31 , wherein the dsRNA is administered at a dose of about 0.01 mg/kg to about 50 mg/kg.
36. The method of claim 35 , wherein the dsRNA is administered at a dose of about 10 mg/kg to about 30 mg/kg.
37. The method of claim 35 , wherein the dsRNA is administered at a dose selected from the group consisting of 1 mg/kg, 3 mg/kg, 10 mg/kg, and 30 mg/kg.
38. The method of claim 37 , wherein the dsRNA is administered to the subject once a week.
39. The method of claim 37 , wherein the dsRNA is administered to the subject twice a month.
40. The method of claim 31 , wherein the dsRNA is administered to the subject subcutaneously at a cumulative weekly dose of about 0.5 mg/kg to about 5 mg/kg.
41. The method of claim 31 , further comprising measuring thrombin levels in said subject.
42. The method of claim 21 , wherein the ligand is
43. The method of claim 21 , wherein the dsRNA is conjugated to the ligand as shown in the following schematic
and, wherein X is O or S.
44. The dsRNA of claim 43 , wherein the X is O.
45. The method of claim 16 , wherein the dsRNA is administered at a dose of about 0.01 mg/kg to about 50 mg/kg.
46. The method of claim 45 , wherein the dsRNA is administered at a dose of about 10 mg/kg to about 30 mg/kg.
47. The method of claim 45 , wherein the dsRNA is administered at a dose selected from the group consisting of 0.3 mg/kg 0.5 mg/kg 1 mg/kg, 1.5 mg/kg, 3 mg/kg, 10 mg/kg, and 30 mg/kg.
48. The method of claim 46 or 47 , wherein the dsRNA is administered to the subject once a week.
49. The method of claim 46 or 47 , wherein the dsRNA is administered to the subject twice a month.
50. The method of claim 17 , wherein the disorder is a bleeding disorder.
51. The method of claim 50 , wherein the bleeding disorder is a hemophilia.
52. The method of claim 17 , wherein the administration of the dsRNA to the subject causes an increase in blood clotting and/or a decrease in Serpinc1 protein accumulation.
53. The method of claim 17 , wherein the dsRNA is conjugated to a ligand.
54. The method of claim 53 , wherein the ligand is conjugated to the 3′-end of the sense strand of the dsRNA.
55. The method of claim 54 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.
56. The method of claim 55 , wherein the ligand is
57. The method of claim 55 , wherein the dsRNA is conjugated to the ligand as shown in the following schematic
and, wherein X is O or S.
58. The method of claim 57 , wherein the X is O.
59. The method of claim 17 , further comprising measuring thrombin levels in said subject.
60. The method of claim 34 , wherein the ligand is
61. The method of claim 34 , wherein the dsRNA is conjugated to the ligand as shown in the following schematic
and, wherein X is O or S.
62. The method of claim 61 , wherein the X is O.