Complement component C5 iRNA compositions and methods of use thereof
The invention relates to iRNA, e.g., double-stranded ribonucleic acid (dsRNA), compositions targeting the complement component C5 gene, and methods of using such iRNA, e.g., dsRNA, compositions to inhibit expression of C5 and to treat subjects having a complement component C5-associated disease, e.g., paroxysmal nocturnal hemoglobinuria.
1. A double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5, wherein said dsRNA comprises a sense strand and an antisense strand forming a double stranded region, wherein the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of 5′-UUAUAGUGAGUUAUUUUGUCAAU-3′ (SEQ ID NO:105), wherein substantially all of the nucleotides of the sense strand and substantially all of the nucleotides of the antisense strand are modified nucleotides.
2. The double stranded RNAi agent of claim 1 , wherein all of the nucleotides of said sense strand and all of the nucleotides of said antisense strand comprise a modification.
3. The dsRNA agent of claim 1 , wherein at least one of said modified nucleotides is selected from the group consisting of a 3′-terminal deoxy-thymine (dT) nucleotide, a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, a 2′-amino-modified nucleotide, a 2′-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide, a nucleotide comprising a 5′-phosphorothioate group, and a terminal nucleotide linked to a cholesteryl derivative or a dodecanoic acid bisdecylamide group.
4. The dsRNA agent of claim 1 , wherein each strand is no more than 30 nucleotides in length.
5. The dsRNA agent of claim 1 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide; or at least one strand comprises a 3′ overhang of at least 2 nucleotides.
6. The dsRNA agent of claim 1 , further comprising a ligand.
7. The dsRNA agent of claim 6 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent.
8. The dsRNA agent of claim 6 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.
9. The dsRNA agent of claim 8 , wherein the ligand is
10. The dsRNA agent of claim 8 , wherein the dsRNA agent is conjugated to the ligand as shown in the following schematic
and, wherein X is 0 or S.
11. The dsRNA agent of claim 1 , wherein the double-stranded region is 15-30 nucleotide pairs in length; 17-23 nucleotide pairs in length; 7-25 nucleotide pairs in length; 23-27 nucleotide pairs in length; 19-21 nucleotide pairs in length; or 21-23 nucleotide pairs in length.
12. The dsRNA agent of claim 1 , wherein each strand has 15-30 nucleotides; or 19-30 nucleotides.
13. The dsRNA agent of claim 1 , wherein the agent further comprises at least one phosphorothioate or methylphosphonate internucleotide linkage.
14. An isolated cell containing the dsRNA agent of claim 1 .
15. A pharmaceutical composition for inhibiting expression of a complement component C5 gene comprising the dsRNA agent of claim 1 .
16. A method of inhibiting complement component C5 expression in a cell the method comprising:
(a) contacting the cell with the dsRNA agent of claim 1 or a pharmaceutical composition of claim 15 ; and
(b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a complement component C5 gene, thereby inhibiting expression of the complement component C5 gene in the cell.
17. The method of claim 16 , wherein said cell is within a subject.
18. The method of claim 17 , wherein the subject is a human.
19. A method of treating a subject having a disease or disorder that would benefit from reduction in complement component C5 expression, the method comprising administering to the subject a therapeutically effective amount of the dsRNA agent of claim 1 , or a pharmaceutical composition of claim 15 , thereby treating the subject.