Transthyretin (TTR) iRNA compositions and methods of use thereof for treating or preventing TTR-associated diseases
The present invention provides iRNA agents, e.g., double stranded iRNA agents, that target the transthyretin (TTR) gene and methods of using such iRNA agents for treating or preventing TTR-associated diseases.
1. A salt of a double stranded ribonucleic acid (RNAi) agent for inhibiting expression of transthyretin (TTR), comprising a sense strand and an antisense strand forming a double stranded region,
wherein the sense strand comprises the nucleotide sequence 5′-usgsggauUfuCfAfUfguaaccaaga-3′ of SEQ ID NO:10 and the antisense strand comprises the nucleotide sequence 5′-usCfsuugGfuuAfcaugAfaAfucccasusc-3′ of SEQ ID NO:7,
wherein a, c, g, and u are 2′-O-methyl (2′-OMe) A, C, G, and U, respectively; Af, Cf, Gf, and Uf are 2′-fluoro A, C, G, and U, respectively; s is a phosphorothioate linkage; and
wherein the sense strand of the double stranded RNAi agent is conjugated to a ligand.
2. The salt of the double stranded RNAi agent of claim 1 , wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker.
3. The salt of the double stranded RNAi agent of claim 2 , wherein the ligand is
4. The salt of the double stranded RNAi agent of claim 1 , wherein the ligand is attached to the 3′ end of the sense strand.
5. The salt of the double stranded RNAi agent of claim 4 , wherein the RNAi agent is conjugated to the ligand as shown in the following schematic
wherein X is O or S.
6. The salt of the double stranded RNAi agent of claim 5 , wherein X is O.
7. The salt of the double stranded RNAi agent of claim 1 , wherein the salt is a sodium salt.
8. A pharmaceutical composition comprising the salt of the double stranded RNAi agent of any one of claims 1-7 .
9. The pharmaceutical composition of claim 8 , further comprising a buffered solution.
10. The pharmaceutical composition of claim 9 , wherein the buffered solution comprises acetate, citrate, prolamine, carbonate, or phosphate or any combination thereof.
11. The pharmaceutical composition of claim 9 , wherein the buffer solution comprises phosphate.
12. The pharmaceutical composition of claim 8 , further comprising an unbuffered solution.
13. The pharmaceutical composition of claim 12 , wherein the unbuffered solution is saline or water.
14. A salt of a double stranded ribonucleic acid (RNAi) agent for inhibiting expression of transthyretin (TTR), comprising a sense strand and an antisense strand forming a double stranded region,
wherein the sense strand consists of the nucleotide sequence 5′-usgsggauUfuCfAfUfguaaccaaga-3′ of SEQ ID NO:10 and the antisense strand consists of the nucleotide sequence 5′-usCfsuugGfuuAfcaugAfaAfucccasusc-3′ of SEQ ID NO:7,
wherein a, c, g, and u are 2′-O-methyl (2′-OMe) A, C, G, and U, respectively; Af, Cf, Gf, and Uf are 2′-fluoro A, C, G, and U, respectively; s is a phosphorothioate linkage; and
wherein the sense strand of the double stranded RNAi agent is conjugated to a ligand.
15. The salt of the double stranded RNAi agent of claim 14 , wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker.
16. The salt of the double stranded RNAi agent of claim 15 , wherein the ligand is
17. The salt of the double stranded RNAi agent of claim 14 , wherein the ligand is attached to the 3′ end of the sense strand.
18. The salt of the double stranded RNAi agent of claim 17 , wherein the RNAi agent is conjugated to the ligand as shown in the following schematic
wherein X is O or S.
19. The salt of the double stranded RNAi agent of claim 18 , wherein X is O.
20. The salt of the double stranded RNAi agent of claim 14 , wherein the salt is a sodium salt.
21. A pharmaceutical composition comprising the salt of the double stranded RNAi agent of any one of claims 14-20 .
22. The pharmaceutical composition of claim 21 , further comprising a buffered solution.
23. The pharmaceutical composition of claim 22 , wherein the buffered solution comprises acetate, citrate, prolamine, carbonate, or phosphate or any combination thereof.
24. The pharmaceutical composition of claim 22 , wherein the buffer solution comprises phosphate.
25. The pharmaceutical composition of claim 21 , further comprising an unbuffered solution.
26. The pharmaceutical composition of claim 25 , wherein the unbuffered solution is saline or water.
27. A salt of a double stranded ribonucleic acid (RNAi) agent for inhibiting expression of transthyretin (TTR), consisting of a sense strand and an antisense strand forming a double stranded region,
wherein the sense strand consists of the nucleotide sequence 5′-usgsggauUfuCfAfUfguaaccaaga-3′ of SEQ ID NO: 10 and the antisense strand consists of the nucleotide sequence 5′-usCfsuugGfuuAfcaugAfaAfucccasusc-3′ of SEQ ID NO:7,
wherein a, c, g, and u are 2′-O-methyl (2′-OMe) A, C, G, and U, respectively; Af, Cf, Gf, and Uf are 2′-fluoro A, C, G, and U, respectively; s is a phosphorothioate linkage; and
wherein the sense strand of the double stranded RNAi agent is conjugated to a ligand as shown in the following schematic
wherein X is O.
28. A pharmaceutical composition comprising the salt of the double stranded RNAi agent of claim 27 .
29. The pharmaceutical composition of claim 28 , further comprising a buffered solution.
30. The pharmaceutical composition of claim 29 , wherein the buffered solution comprises acetate, citrate, prolamine, carbonate, or phosphate or any combination thereof.
31. The pharmaceutical composition of claim 29 , wherein the buffer solution comprises phosphate.
32. The pharmaceutical composition of claim 28 , further comprising an unbuffered solution.
33. The pharmaceutical composition of claim 32 , wherein the unbuffered solution is saline or water.
34. A method of treating a subject suffering from a transthyretin (TTR)-associated disease, comprising administering to the subject a therapeutically effective amount of the salt of the double stranded RNAi agent of claim 27 or the pharmaceutical composition of claim 28 , thereby treating the subject.
35. The method of claim 34 , wherein the subject is a human.
36. The method of claim 34 , wherein the subject carries a TTR gene mutation that is associated with the development of a TTR-associated disease.
37. The method of claim 34 , wherein the TTR-associated disease is selected from the group consisting of senile systemic amyloidosis (SSA), systemic familial amyloidosis, familial amyloidotic polyneuropathy (FAP), familial amyloidotic cardiomyopathy (FAC), leptomeningeal/Central Nervous System (CNS) amyloidosis, and hyperthyroxinemia.
38. The method of claim 34 , wherein the subject has a TTR-associated amyloidosis.
39. The method of claim 34 , wherein the subject has a TTR-associated amyloidosis, and the method treats polyneuropathy of TTR-associated amyloidosis.
40. The method of claim 34 , wherein the salt of the double stranded RNAi agent is administered to the subject by an administration means selected from the group consisting of subcutaneous, intravenous, intramuscular, intrabronchial, intrapleural, intraperitoneal, intraarterial, lymphatic, cerebrospinal, and any combinations thereof.
41. The method of claim 34 , wherein the salt of the double stranded RNAi agent is administered to the subject via subcutaneous administration.
42. The method of claim 41 , wherein the subcutaneous administration is self administration.
43. The method of claim 42 , wherein the self-administration is via a pre-filled syringe or auto-injector syringe.
44. The method of claim 34 , wherein the salt of the double stranded RNAi agent is chronically administered to the subject.