Complement component C3 iRNA compositions and methods of use thereof
The present invention relates to RNAi agents, e.g., double stranded RNA (dsRNA) agents, targeting the complement component C3 gene (C3). The invention also relates to methods of using such RNAi agents to inhibit expression of a C3 gene and to methods of preventing and treating a C3-associated disorder, e.g., cold agglutinin disease (CAD), warm autoimmune hemolytic anemia, and paroxysmal nocturnal hemoglobinuria (PNH), lupis nephritis (LN), bullous pemphigoid, pemphigus , e.g., pemphigus vulgaris (PV) and pemphigus foliaceus (PF), and C3 glomerulopathy.
1. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C3 in a cell, or a pharmaceutically acceptable salt thereof, comprising a sense strand differing by no more than 4 bases from the nucleotide sequence 5′-gsasgccgUfuCfUfCfuacaauuacu-3′ of SEQ ID NO:4188 and an antisense strand differing by no more than 4 bases from the nucleotide sequence 5′-asGfsuaaUfuGfUfagagAfaCfggcucsgsg-3′ of SEQ ID NO:4367,
wherein a, g, c and u are 2′-O-methyl (2′-OMe) 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.
2. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , comprising a sense strand differing by no more than 3 bases from the nucleotide sequence 5′-gsasgccgUfuCfUfCfuacaauuacu-3′ of SEQ ID NO:4188 and an antisense strand differing by no more than 3 bases from the nucleotide sequence 5′-asGfsuaaUfuGfUfagagAfaCfggcucsgsg-3′ of SEQ ID NO:4367.
3. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , comprising a sense strand differing by no more than 2 bases from the nucleotide sequence 5′-gsasgccgUfuCfUfCfuacaauuacu-3′ of SEQ ID NO:4188 and an antisense strand differing by no more than 2 bases from the nucleotide sequence 5′-asGfsuaaUfuGfUfagagAfaCfggcucsgsg-3′ of SEQ ID NO:4367.
4. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , comprising a sense strand differing by no more than 1 base from the nucleotide sequence 5′-gsasgccgUfuCfUfCfuacaauuacu-3′ of SEQ ID NO:4188 and an antisense strand differing by no more than 1 base from the nucleotide sequence 5′-asGfsuaaUfuGfUfagagAfaCfggcucsgsg-3′ of SEQ ID NO:4367.
5. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , comprising a sense strand comprising the nucleotide sequence 5′-gsasgccgUfuCfUfCfuacaauuacu-3′ of SEQ ID NO:4188 and an antisense strand comprising the nucleotide sequence 5′-asGfsuaaUfuGfUfagagAfaCfggcucsgsg-3′ of SEQ ID NO:4367.
6. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , comprising a sense strand consisting of the nucleotide sequence 5′-gsasgccgUfuCfUfCfuacaauuacu-3′ of SEQ ID NO:4188 and an antisense strand consisting of the nucleotide sequence 5′-asGfsuaaUfuGfUfagagAfaCfggcucsgsg-3′ of SEQ ID NO:4367.
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 complement component C3 in a cell, or a pharmaceutically acceptable salt thereof, comprising a sense strand comprising the nucleotide sequence 5′-gsasgccgUfuCfUfCfuacaauuacu-3′ of SEQ ID NO:4188 and an antisense strand comprising the nucleotide sequence 5′-asGfsuaaUfuGfUfagagAfaCfggcucsgsg-3′ of SEQ ID NO:4367,
wherein a, g, c and u are 2′-O-methyl (2′-OMe) 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 3′-end of the sense strand of the dsRNA agent, or a pharmaceutically acceptable salt thereof, is conjugated to a ligand as shown in the following schematic
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 complement component C3 in a cell, or a pharmaceutically acceptable salt thereof, consisting of a sense strand consisting of the nucleotide sequence 5′-gsasgccgUfuCfUfCfuacaauuacu-3′ of SEQ ID NO:4188 and an antisense strand consisting of the nucleotide sequence 5′-asGfsuaaUfuGfUfagagAfaCfggcucsgsg-3′ of SEQ ID NO:4367,
wherein a, g, c and u are 2′-O-methyl (2′-OMe) 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 3′-end of the sense strand of the dsRNA agent, or a pharmaceutically acceptable salt thereof, is conjugated to a ligand as shown in the following schematic
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 .