IP Library › Granted Patent US 50,996
Granted Patent E1
US 50,996 · App. 17/396,331 · Granted Aug 18, 2026

Serpinc1 iRNA compositions and methods of use thereof

Inventors: Akin Akinc (Needham Heights, MA); Alfica Sehgal (Belmont, MA); Ivanka Toudjarska (Medford, MA); Donald Foster (Attleboro, MA); Stuart Milstein (Arlington, MA); Brian Bettencourt (Groton, MA); Martin A. Maier (Belmont, MA); Klaus Charisse (Acton, MA); Satyanarayana Kuchimanchi (Acton, MA); Kallanthottathil G. Rajeev (Wayland, MA); Muthiah Manoharan (Weston, MA)
Assignee: Genzyme Corporation
C12N15/113A61K31/713C12N2310/14C12N2310/315C12N2310/321C12N2310/322
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Quick Facts
Patent No.
US 50,996
App. No.
17/396,331
Granted
Aug 18, 2026
Kind
E1
Abstract

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.

Claims (82)

1 . A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of Serpinc1, wherein said dsRNA double-stranded ribonucleic acid 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 G, C, or G and U, respectively; Af, Cf Gf, Gf or Cf, and Uf are 2′-fluoro A, G, C or, and U, respectively; and s is a phosphorothioate linkage.

2 . The dsRNA double-stranded ribonucleic acid of claim 1 , further comprising a ligand.

3 . The dsRNA double-stranded ribonucleic acid of claim 2 , wherein the ligand is conjugated to the 3′ end 3′-end of the sense strand of the dsRNA double-stranded ribonucleic acid.

4 . The dsRNA double-stranded ribonucleic acid of claim 2 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.

5 . The dsRNA double-stranded ribonucleic acid of claim 4 , wherein the ligand is

6 . The dsRNA double-stranded ribonucleic acid of claim 4 3 , wherein the dsRNA double-stranded ribonucleic acid is conjugated to the ligand as shown in the following schematic

and, wherein X is O or S.

7 . The dsRNA double-stranded ribonucleic acid of claim 6 , wherein the X is O.

8 . A cell containing the dsRNA double-stranded ribonucleic acid of claim 1 .

9 . A pharmaceutical composition for inhibiting expression of a Serpinc1 gene comprising the dsRNA double-stranded ribonucleic acid of claim 1 .

10 . A method of inhibiting Serpinc1 expression in a cell, the method comprising:

(a) contacting the cell with the dsRNA double-stranded ribonucleic acid 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 prophylactically effective amount of the dsRNA double-stranded ribonucleic acid 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 prophylactically effective amount of the dsRNA double-stranded ribonucleic acid of claim 1 , thereby preventing at least one symptom in the subject having a the 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 double-stranded ribonucleic acid 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 double-stranded ribonucleic acid 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 double-stranded ribonucleic acid.

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 17 , wherein the dsRNA double-stranded ribonucleic acid is administered to the subject once a week.

28 . The method of claim 25 or 26 17 , wherein the dsRNA double-stranded ribonucleic acid 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 prophylactically effective amount of the dsRNA double-stranded ribonucleic acid of claim 1 , thereby inhibiting the expression of Serpinc1 in said subject.

32 . The method of claim 31 , wherein the dsRNA double-stranded ribonucleic acid 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 double-stranded ribonucleic acid.

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 31 , wherein the dsRNA double-stranded ribonucleic acid is administered to the subject once a week.

39 . The method of claim 37 31 , wherein the dsRNA double-stranded ribonucleic acid 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 22 , wherein the dsRNA double-stranded ribonucleic acid is conjugated to the ligand as shown in the following schematic

and, wherein X is O or S.

44 . The dsRNA method 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 16 , wherein the dsRNA double-stranded ribonucleic acid is administered to the subject once a week.

49 . The method of claim 46 or 47 16 , wherein the dsRNA double-stranded ribonucleic acid 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 double-stranded ribonucleic acid 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 double-stranded ribonucleic acid 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 double-stranded ribonucleic acid.

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 double-stranded ribonucleic acid 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 double-stranded ribonucleic acid 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.

63. A double-stranded ribonucleic acid comprising a sense strand, an antisense strand, and a ligand, wherein the nucleotide sequence of the sense strand consists of 5′-GfsgsUfuAfaCfaCfCfAfuUfuAfcUfuCfaAf-3′ (SEQ ID NO:941) and the nucleotide sequence of the antisense strand consists of 5′-usUfsgAfaGfuAfaAfuggUfgUfuAfaCfcsasg-3′ (SEQ ID NO:960), wherein a, g, c, and u are 2′-O-methyl A, G, C, and U, respectively; Af, Gf, Cf, and Uf are 2′-fluoro A, G, C, and U, respectively; and s is a phosphorothioate linkage, wherein the ligand is conjugated to the 3′ end of the sense strand as shown in the schematic

and wherein X is O.

64. A pharmaceutical composition comprising the double-stranded ribonucleic acid of claim 63 and phosphate buffered saline.

65. The pharmaceutical composition of claim 9 , wherein the pharmaceutical composition comprises phosphate buffered saline.

66. A method of treating hemophilia A or hemophilia B prophylactically in a subject in need thereof, comprising administering the double-stranded ribonucleic acid of claim 63 in a prophylactically effective amount to the subject in need thereof.

67. The method of claim 66 , wherein the subject is a hemophilia A or hemophilia B patient with inhibitors.

68. A method of treating hemophilia A or hemophilia B prophylactically in a subject in need thereof, comprising administering the pharmaceutical composition of claim 64 in a prophylactically effective amount to the subject in need thereof.

69. The method of claim 68 , wherein the subject is a hemophilia A or hemophilia B patient with inhibitors.

70. A method of treating hemophilia A or hemophilia B prophylactically in a subject in need thereof, comprising administering the pharmaceutical composition of claim 65 in a prophylactically effective amount to the subject in need thereof.

71. The method of any one of claims 44, 58, 62, 66, 68, or 70 , wherein the subject is a hemophilia A patient with inhibitors.

72. The method of any one of claims 44, 58, 62, 66, 68, and 70 , wherein the subject is a hemophilia B patient with inhibitors.

73. The method of any one of claims 44, 58, 62, 66, 68, and 70 , wherein the subject is a hemophilia A patient without inhibitors.

74. The method of any one of claims 44, 58, 62, 66, 68, and 70 , wherein the subject is a hemophilia B patient without inhibitors.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 29, 2023
From: AKINC, AKIN; SEHGAL, ALFICA; TOUDJARSKA, IVANKA; FOSTER, DONALD; MILSTEIN, STUART; BETTENCOURT, BRIAN; MAIER, MARTIN A.; CHARISSE, KLAUS; KUCHIMANCHI, SATYANARAYANA; MANOHARAN, MUTHIAH; RAJEEV, KALLANTHOTTATHIL G.
To: ALNYLAM PHARMACEUTICALS, INC.
Reel/Frame 064118/0657 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 29, 2023
From: ALNYLAM PHARMACEUTICALS, INC.
To: GENZYME CORPORATION
Reel/Frame 064118/0780 →
Continuity (4)
Provisional Application 61734573 · Dec 7, 2012
Provisional Application 61669249 · Jul 9, 2012
Provisional Application 61638952 · Apr 26, 2012
Reissue 13837129 · Mar 15, 2013
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