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 method of inhibiting complement component C5 expression in a cell, the method comprising:
(a) contacting the cell with a double-stranded ribonucleic acid (dsRNA) agent that inhibits expression of complement component C5, or a pharmaceutically acceptable salt thereof, wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the antisense strand comprises at least 17 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence 5′-UAUUAUAAAAAUAUCUUGCUUUU-3′ of SEQ ID NO:113, and wherein the dsRNA agent comprises at least one modified nucleotide; 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.
2 . The method of claim 1 , wherein the cell is within a subject.
3 . The method of claim 2 , wherein the subject is a human.
4 . 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 a double-stranded ribonucleic acid (dsRNA) agent that inhibits expression of complement component C5, or a pharmaceutically acceptable salt thereof, wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the antisense strand comprises at least 17 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence 5′-UAUUAUAAAAAUAUCUUGCUUUU-3′ of SEQ ID NO:113, and wherein the dsRNA agent comprises at least one modified nucleotide, thereby treating the subject.
5 . The method of claim 4 , wherein the subject is a human.
6 . The method of claim 4 , wherein the disease or disorder is a complement component C5-associated disease.
7 . The method of claim 6 , wherein the complement component C5-associated disease is selected from the group consisting of paroxysmal nocturnal hemoglobinuria (PNH), macular degeneration (e.g., age-related macular degeneration (AMD)), atypical hemolytic uremic syndrome (aHUS), asthma, rheumatoid arthritis (RA), antiphospholipid antibody syndrome, lupus nephritis, ischemia-reperfusion injury, typical or infectious hemolytic uremic syndrome (tHUS), dense deposit disease (DDD), neuromyelitis optica (NMO), multifocal motor neuropathy (MMN), multiple sclerosis (MS), hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, thrombotic thrombocytopenia purpura (TTP), spontaneous fetal loss; Pauci-immune vasculitis, epidermolysis bullosa, recurrent fetal loss; pre-eclampsia, traumatic brain injury, cold agglutinin disease, dermatomyositis bullous pemphigoid, Shiga toxin E. coli -related hemolytic uremic syndrome, C3 nephropathy, anti-neutrophil cytoplasmic antibody-associated vasculitis, humoral and vascular transplant rejection, graft dysfunction, myocardial infarction, an allogenic transplant, sepsis, Coronary artery disease, dermatomyositis, Graves' disease, atherosclerosis, Alzheimer's disease, systemic inflammatory response sepsis, septic shock, spinal cord injury, glomerulonephritis, Hashimoto's thyroiditis, type I diabetes, psoriasis, pemphigus, autoimmune hemolytic anemia (AIHA), ITP, Goodpasture syndrome, Degos disease, antiphospholipid syndrome (APS), catastrophic APS (CAPS), a cardiovascular disorder, myocarditis, a cerebrovascular disorder, a peripheral vascular disorder, a renovascular disorder, a mesenteric/enteric vascular disorder, vasculitis, Henoch-Schönlein purpura nephritis, systemic lupus erythematosus-associated vasculitis, vasculitis associated with rheumatoid arthritis, immune complex vasculitis, Takayasu's disease, dilated cardiomyopathy, diabetic angiopathy, Kawasaki's disease (arteritis), venous gas embolus (VGE), restenosis following stent placement, rotational atherectomy, membraneous nephropathy, Guillain-Barre syndrome, and percutaneous transluminal coronary angioplasty (PTCA).
8 . The method of claim 7 , wherein the complement component C5-associated disease is paroxysmal nocturnal hemoglobinuria (PNH).
9 . The method of claim 7 , wherein the complement component C5-associated disease is myasthenia gravis.
10 . The method of claim 7 , wherein the complement component C5-associated disease is macular degeneration.
11 . The method of claim 7 , wherein the complement component C5-associated disease is age-related macular degeneration (AMD).
12 . The method of claim 4 , wherein the sense strand comprises at least 17 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence 5′-AAGCAAGAUAUUUUUAUAAUA-3′ of SEQ ID NO:62, and the antisense strand comprises at least 17 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence 5′-UAUUAUAAAAAUAUCUUGCUUUU-3′ of SEQ ID NO: 113.
13 . The method of claim 4 , wherein the sense strand comprises at least 19 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence 5′-AAGCAAGAUAUUUUUAUAAUA-3′ of SEQ ID NO:62, and the antisense strand comprises at least 19 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence 5′-UAUUAUAAAAAUAUCUUGCUUUU-3′ of SEQ ID NO: 113.
14 . The method of claim 4 , wherein the sense strand comprises the nucleotide sequence 5′-AAGCAAGAUAUUUUUAUAAUA-3′ of SEQ ID NO: 62, and the antisense strand comprises the nucleotide sequence 5′-UAUUAUAAAAAUAUCUUGCUUUU-3′ of SEQ ID NO:113.
15 . The method of claim 4 , wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand comprise a nucleotide modification.
16 . The method of claim 4 , wherein at least one of the nucleotide modifications is selected from the group consisting of a 3′-terminal deoxy-thymine (dT) nucleotide modification, a 2′-O-methyl nucleotide modification, a 2′-fluoro nucleotide modification, a 2′-deoxy-nucleotide modification, a locked nucleotide modification, an abasic nucleotide modification, a 2′-amino-nucleotide modification, a 2′-alkyl-nucleotide modification, a morpholino nucleotide modification, a phosphoramidate modification, a non-natural base comprising nucleotide modification, a nucleotide comprising a 5′-phosphorothioate group modification, and a terminal nucleotide linked to a cholesteryl derivative or a dodecanoic acid bisdecylamide group modification.
17 . The method of claim 4 , wherein the double stranded region is at least 17 nucleotides in length; 19-21 nucleotides in length; 19 nucleotides in length; or 21-23 nucleotides in length.
18 . The method of claim 4 , wherein each strand is no more than 30 nucleotides in length.
19 . The method of claim 4 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide; or a 3′ overhang of at least 2 nucleotides.
20 . The method of claim 4 , further comprising a ligand.
21 . The method of claim 20 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent.
22 . The method of claim 20 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.
23 . The method of claim 22 , wherein the ligand is
24 . The method of claim 23 , wherein the dsRNA agent is conjugated to the ligand as shown in the following schematic
and, wherein X is O or S.
25 . The method of claim 24 , wherein X is O.
26 . The method of claim 4 , wherein the dsRNA agent further comprises at least one phosphorothioate or methylphosphonate internucleotide linkage.
27 . The method of claim 4 , wherein the sense strand comprises the nucleotide sequence 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ of SEQ ID NO: 2876, and the antisense strand comprises the nucleotide sequence 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ of SEQ ID NO:2889,
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; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage.
28 . The method of claim 4 , wherein the sense strand consists of the nucleotide sequence 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ of SEQ ID NO:2876, and the antisense strand consists of the nucleotide sequence 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ of SEQ ID NO:2889,
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; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage.
29 . The method of claim 4 , wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof, is administered to the subject subcutaneously.
30 . The method of claim 4 , further comprising administering to the subject an anti-complement component C5 antibody, or antigen-binding fragment thereof.
31 . The method of claim 4 , wherein the anti-complement component C5 antibody, or antigen-binding fragment thereof, is eculizumab.