Complement component C3 iRNA compositions and methods of use thereof

11866,701

16/760593

November 01, 2018

The invention relates to iRNA, e.g., double stranded ribonucleic acid (dsRNA), compositions targeting the complement factor C3 gene, and methods of using such iRNA, e.g., dsRNA, compositions to inhibit expression of a C3 gene and to treat subjects having a complement component C3-associated disease, e.g., paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), atypical hemolytic uremic syndrome (aHUS), neuromyelitis optica (NMO), multifocal motor neuropathy (MMN), myasthenia gravis (MG), and C3 glomerulonephritis.

Alnylam Pharmaceuticals, Inc. (Cambridge, MA, US)

Alnylam Pharmaceuticals, Inc. (Cambridge, MA, US)

1. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C3 in a cell, wherein said dsRNA comprises a sense strand and an antisense strand forming a double stranded region, wherein each strand is independently 15-30 nucleotides in length, wherein the antisense strand comprises at least 15 contiguous nucleotides from the complement of nucleotides 4614-4632 of SEQ ID NO:1, wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand comprise a nucleotide modification, and wherein at least one strand is conjugated to a ligand.

2. The dsRNA agent of claim 1 , further comprising at least one phosphorothioate or methylphosphonate internucleotide linkage.

3. The dsRNA agent of claim 1 , wherein at least one strand comprises a 3′ overhang of at least one nucleotide.

4. The dsRNA agent of claim 1 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent.

5. The dsRNA agent of claim 1 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.

6. The dsRNA agent of claim 5 , wherein the ligand is [chemical expression included]

7. The dsRNA agent of claim 5 , wherein the dsRNA agent is conjugated to the ligand as shown in the following schematic [chemical expression included] and, wherein X is O or S.

8. The dsRNA agent of claim 7 , wherein the X is O.

9. An isolated cell comprising the dsRNA agent of claim 1 .

10. A pharmaceutical composition for inhibiting expression of a complement component C3 gene comprising the dsRNA agent of claim 1 .

11. The dsRNA agent of claim 1 , wherein the antisense strand comprises at least 17 contiguous nucleotides from the complement of nucleotides 4614-4632 of SEQ ID NO:1.

12. The dsRNA agent of claim 1 , wherein the antisense strand comprises at least 19 contiguous nucleotides from the complement of nucleotides 4614-4632 of SEQ ID NO:1.

13. The dsRNA agent of claim 1 , wherein the sense strand comprises the nucleotide sequence 5′-UGAUGAACUGUGCCGCUGU-3′(SEQ ID NO:248) and the antisense strand comprises the nucleotide sequence 5′-ACAGCGGCACAGUUCAUCA-3′ (SEQ ID NO:516).

14. The dsRNA agent of claim 1 , wherein each strand is independently 19-25 nucleotides in length.

15. The dsRNA agent of claim 1 , wherein at least one of the nucleotide modifications is selected from the group consisting of a 2′-O-methyl nucleotide modification, a nucleotide comprising a 5′-phosphorothioate nucleotide group modification, a deoxy-nucleotide modification, a 3′-terminal deoxy-thymine (dT) nucleotide modification, a 2′-fluoro nucleotide modification, a 2′-deoxy-nucleotide modification, a terminal nucleotide linked to a cholesteryl derivative or a dodecanoic acid bisdecylamide group nucleotide modification, a 2′-deoxy-2′-fluoro nucleotide modification, a locked nucleotide modification, an unlocked nucleotide modification, a conformationally restricted nucleotide modification, a constrained ethyl nucleotide modification, an abasic nucleotide modification, a 2′-amino-nucleotide modification, a 2′-O-allyl-nucleotide modification, a 2′-C-alkyl-nucleotide modification, a 2′-hydroxyl-nucleotide modification, a 2′-methoxyethyl nucleotide modification, a 2′-O-alkyl-nucleotide modification, a morpholino nucleotide modification, a phosphoramidate modification, a non-natural base nucleotide modification, a tetrahydropyran nucleotide modification, a 1,5-anhydrohexitol nucleotide modification, a cyclohexenyl nucleotide modification, a 5′-phosphate nucleotide modification, and a 5′-phosphate mimic nucleotide modification.

16. The dsRNA agent of claim 2 , wherein the phosphorothioate or methylphosphonate internucleotide linkage is at the 3′-terminus of one strand.

17. The dsRNA agent of claim 16 , wherein the strand is the antisense strand.

18. The dsRNA agent of claim 16 , wherein the strand is the sense strand.

19. The dsRNA agent of claim 2 , wherein the phosphorothioate or methylphosphonate internucleotide linkage is at the 5′-terminus of one strand.

20. The dsRNA agent of claim 19 , wherein the strand is the antisense strand.

21. The dsRNA agent of claim 19 , wherein the strand is the sense strand.

22. The dsRNA agent of claim 2 , wherein the phosphorothioate or methylphosphonate internucleotide linkage is at both the 5′- and 3′-terminus of one strand.

23. The dsRNA agent of claim 22 , wherein the strand is the antisense strand.

24. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C3 in a cell, wherein said dsRNA comprises a sense strand and an antisense strand forming a double stranded region, wherein each strand is independently 15-30 nucleotides in length, wherein the antisense strand comprises at least 15 contiguous nucleotides from the complement of nucleotides 4614-4632 of SEQ ID NO:1, wherein all of the nucleotide of the sense strand and all of the nucleotides of the antisense strand comprise a nucleotide modification, wherein the dsRNA agent comprises 6-8 phosphorothioate internucleotide linkages, and wherein at least one strand is conjugated to an N-acetylgalactosamine ligand.

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