Coagulation factor V (F5) iRNA compositions and methods of use thereof
The present invention relates to RNAi agents, e.g., dsRNA agents, targeting the Coagulation Factor V (F5) gene. The invention also relates to methods of using such RNAi agents to inhibit expression of an F5 gene and to methods of treating or preventing an F5-associated disease, e.g., a disorder associated with thrombosis, in a subject.
1. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of coagulation Factor V (F5) in a cell, or a pharmaceutically acceptable salt thereof, comprising a sense strand differing by no more than 4 unmodified or modified bases from the nucleotide sequence 5′-ascsaguuuuCfCfAfcuauuucucu-3′ of SEQ ID NO:2739 and an antisense strand differing by no more than 4 unmodified or modified bases from the nucleotide sequence 5′-asdGsagdAadAuagudGgAfaaacugususa-3′ of SEQ ID NO:2940,
wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af and Cf, are 2′-fluoro A and C, respectively; s is a phosphorothioate linkage; dG is 2-deoxyguanosine-3′-phosphate; and dA is 2-deoxyadenosine-3-phosphate.
2. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , comprising a sense strand differing by no more than 3 unmodified or modified bases from the nucleotide sequence 5′-ascsaguuuuCfCfAfcuauuucucu-3′ of SEQ ID NO:2739 and an antisense strand differing by no more than 3 unmodified or modified bases from the nucleotide sequence 5′-asdGsagdAadAuagudGgAfaaacugususa-3′ of SEQ ID NO:2940.
3. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , comprising a sense strand differing by no more than 2 unmodified or modified bases from the nucleotide sequence 5′-ascsaguuuuCfCfAfcuauuucucu-3′ of SEQ ID NO:2739 and an antisense strand differing by no more than 2 unmodified or modified bases from the nucleotide sequence 5′-asdGsagdAadAuagudGgAfaaacugususa-3′ of SEQ ID NO:2940.
4. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , comprising a sense strand differing by no more than 1 unmodified or modified base from the nucleotide sequence 5′-ascsaguuuuCfCfAfcuauuucucu-3′ of SEQ ID NO:2739 and an antisense strand differing by no more than 1 unmodified or modified base from the nucleotide sequence 5′-asdGsagdAadAuagudGgAfaaacugususa-3′ of SEQ ID NO:2940.
5. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , comprising a sense strand comprising the nucleotide sequence 5′-ascsaguuuuCfCfAfcuauuucucu-3′ of SEQ ID NO:2739 and an antisense strand comprising the nucleotide sequence 5′-asdGsagdAadAuagudGgAfaaacugususa-3′ of SEQ ID NO:2940.
6. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , comprising a sense strand consisting of the nucleotide sequence 5′-ascsaguuuuCfCfAfcuauuucucu-3′ of SEQ ID NO:2739 and an antisense strand consisting of the nucleotide sequence 5′-asdGsagdAadAuagudGgAfaaacugususa-3′ of SEQ ID NO:2940.
7. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , further comprising a ligand.
8. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 7 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent.
9. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 7 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.
10. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 9 , wherein the ligand is one or more GalNAc derivatives attached through a monovalent, bivalent, or trivalent linker.
11. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 10 , wherein the ligand is
12. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 11 , wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof, is conjugated to the ligand as shown in the following schematic
wherein X is O or S.
13. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 12 , wherein X is O.
14. An isolated cell containing the dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 .
15. A pharmaceutical composition, comprising the dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 .
16. The pharmaceutical composition of claim 15 , wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof, is in an unbuffered solution.
17. The pharmaceutical composition of claim 16 , wherein the unbuffered solution is saline or water.
18. The pharmaceutical composition of claim 15 , wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof, is in a buffer solution.
19. The pharmaceutical composition of claim 18 , wherein the buffer solution comprises acetate, citrate, prolamine, carbonate, or phosphate or any combination thereof.
20. The pharmaceutical composition of claim 19 , wherein the buffer solution is phosphate buffered saline (PBS).
21. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of coagulation Factor V (F5) in a cell, or a pharmaceutically acceptable salt thereof, comprising a sense strand comprising the nucleotide sequence 5′-ascsaguuuuCfCfAfcuauuucucu-3′ of SEQ ID NO:2739 and an antisense strand comprising the nucleotide sequence 5′-asdGsagdAadAuagudGgAfaaacugususa-3′ of SEQ ID NO:2940,
wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af and Cf, are 2′-fluoro A and C, respectively; s is a phosphorothioate linkage; dG is 2-deoxyguanosine-3-phosphate; and dA is 2-deoxyadenosine-3-phosphate,
wherein the 3′-end of the sense strand of the dsRNA agent is conjugated to a ligand as shown in the following schematic
and wherein X is O.
22. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 21 , which is in a sodium salt form.
23. An isolated cell containing the dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 21 .
24. A pharmaceutical composition comprising the dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 21 .
25. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of coagulation Factor V (F5) in a cell, or a pharmaceutically acceptable salt thereof, consisting of a sense strand consisting of the nucleotide sequence 5′-ascsaguuuuCfCfAfcuauuucucu-3′ of SEQ ID NO:2739 and an antisense strand consisting of the nucleotide sequence 5′-asdGsagdAadAuagudGgAfaaacugususa-3′ of SEQ ID NO:2940,
wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af and Cf, are 2′-fluoro A and C, respectively; s is a phosphorothioate linkage; dG is 2-deoxyguanosine-3-phosphate; and dA is 2-deoxyadenosine-3-phosphate,
wherein the 3′-end of the sense strand of the dsRNA agent is conjugated to a ligand as shown in the following schematic
and wherein X is O.
26. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 25 , which is in a sodium salt form.
27. An isolated cell containing the dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 25 .
28. A pharmaceutical composition comprising the dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 25 .