COMPLEMENT FACTOR B (CFB) IRNA COMPOSITIONS AND METHODS OF USE THEREOF
The present invention relates to RNAi agents, e.g., dsRNA agents, targeting the complement factor B (CFB) gene. The invention also relates to methods of using such RNAi agents to inhibit expression of a CFB gene and to methods of treating or preventing a CFB-associated disease in a subject.
1 .- 30 . (canceled)
31 . A method of inhibiting expression of a complement factor B (CFB) gene in a cell, the method comprising contacting the cell with a dsRNA agent that inhibits the expression of CFB, or a pharmaceutically acceptable salt thereof,
wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof, comprises a sense strand and an antisense strand forming a double stranded region,
wherein the sense strand comprises a nucleotide sequence which differs by no more than 4 nucleotides from the nucleotide sequence 5′-gsasauuccuGfAfAfuuuuaugacu-3′ of SEQ ID NO:1271 and the antisense strand comprises a nucleotide sequence which differs by no more than 4 nucleotides from the nucleotide sequence 5′-asdGsucdAudAaaaudTcAfggaauucscsu-3′ of SEQ ID NO:1922,
wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U. respectively; Af and Gf, are 2′-fluoro A and G, respectively; dG is a 2′-deoxyguanosine-3′-phosphate nucleotide; dA is a 2′-deoxyadenosine-3′-phosphate nucleotide; dT is a 2′-deoxythymidine-3′-phosphate nucleotide; and s is a phosphorothioate linkage, thereby inhibiting expression of the CFB gene in the cell.
32 . The method of claim 31 , wherein the cell is within a subject.
33 . The method of claim 32 , wherein the subject is a human.
34 . The method of claim 31 , wherein the sense strand comprises a nucleotide sequence which differs by no more than 3 nucleotides from the nucleotide sequence 5′-gsasauuccuGfAfAfuuuuaugacu-3′ of SEQ ID NO:1271 and the antisense strand comprises a nucleotide sequence which differs by no more than 3 nucleotides from the nucleotide sequence 5′-asdGsucdAudAaaaudTcAfggaauucscsu-3′ of SEQ ID NO:1922.
35 . The method of claim 31 , wherein the sense strand comprises a nucleotide sequence which differs by no more than 2 nucleotides from the nucleotide sequence 5′-gsasauuccuGfAfAfuuuuaugacu-3′ of SEQ ID NO:1271 and the antisense strand comprises a nucleotide sequence which differs by no more than 2 nucleotides from the nucleotide sequence 5′-asdGsucdAudAaaaudTcAfggaauucscsu-3′ of SEQ ID NO:1922.
36 . The method of claim 31 , wherein the sense strand comprises a nucleotide sequence which differs by no more than 1 nucleotide from the nucleotide sequence 5′-gsasauuccuGfAfAfuuuuaugacu-3′ of SEQ ID NO:1271 and the antisense strand comprises a nucleotide sequence which differs by no more than 1 nucleotide from the nucleotide sequence 5′-asdGsucdAudAaaaudTcAfggaauucscsu-3′ of SEQ ID NO:1922.
37 . The method of claim 31 , wherein the sense strand comprises the nucleotide sequence 5′-gsasauuccuGfAfAfuuuuaugacu-3′ of SEQ ID NO:1271 and the antisense strand comprises the nucleotide sequence 5′-asdGsucdAudAaaaudTcAfggaauucscsu-3′ of SEQ ID NO:1922.
38 . The method of claim 31 , wherein the sense strand consists of the nucleotide sequence 5′-gsasauuccuGfAfAfuuuuaugacu-3′ of SEQ ID NO:1271 and the antisense strand consists of the nucleotide sequence 5′-asdGsucdAudAaaaudTcAfggaauucscsu-3′ of SEQ ID NO:1922.
39 . The method of claim 31 , wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof, further comprises a ligand.
40 . The method of claim 39 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent or a pharmaceutically acceptable salt thereof.
41 . The method of claim 39 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.
42 . The method of claim 41 , wherein the ligand is conjugated to the dsRNA agent, or a pharmaceutically acceptable salt thereof, through a monovalent, bivalent, or trivalent linker.
43 . The method of claim 41 , wherein the ligand is
44 . The method of claim 43 , 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 r S.
45 . The method of claim 44 , wherein X is O.
46 . A method of treating a subject having a disorder that would benefit from reduction in complement factor B expression, the method comprising administering to the subject a therapeutically effective amount of a dsRNA agent that inhibits the expression of CFB, or a pharmaceutically acceptable salt thereof,
wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof, comprises a sense strand and an antisense strand forming a double stranded region,
wherein the sense strand comprises a nucleotide sequence which differs by no more than 4 nucleotides from the nucleotide sequence 5′-gsasauuccuGfAfAfuuuuaugacu-3′ of SEQ ID NO:1271 and the antisense strand comprises a nucleotide sequence which differs by no more than 4 nucleotides from the nucleotide sequence 5′-asdGsucdAudAaaaudTcAfggaauucscsu-3′ of SEQ ID NO:1922,
wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U. respectively; Af and Gf, are 2′-fluoro A and G, respectively; dG is a 2′-deoxyguanosine-3′-phosphate nucleotide; dA is a 2′-deoxyadenosine-3′-phosphate nucleotide; dT is a 2′-deoxythymidine-3′-phosphate nucleotide; and s is a phosphorothioate linkage, thereby treating the subject having the disorder that would benefit from reduction in complement factor B expression.
47 . The method of claim 46 , wherein the disorder is a complement factor B-associated disorder.
48 . The method of claim 47 , wherein the complement factor B-associated disease is selected from the group consisting of paroxysmal nocturnal hemoglobinuria (PNH), 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); macular degeneration; hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome; thrombotic thrombocytopenic purpura (TTP); spontaneous fetal loss; Pauci-immune vasculitis; epidermolysis bullosa; recurrent fetal loss; pre-eclampsia, traumatic brain injury, myasthenia gravis, cold agglutinin disease, dermatomyositis bullous pemphigoid, Shiga toxin E. coli -related hemolytic uremic syndrome, C3 neuropathy, anti-neutrophil cytoplasmic antibody-associated vasculitis, Churg-Strauss syndrome, and microscopic polyangiitis), 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-Schonlein 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), and restenosis following stent placement, rotational atherectomy, and percutaneous transluminal coronary angioplasty (PTCA).
49 . The method of claim 46 , wherein the subject is human.
50 . The method of claim 46 , wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof, is administered to the subject subcutaneously.
51 . The method of claim 46 , further comprising administering to the subject an additional therapeutic agent for the treatment of a CFB-associated disease.
52 . The method of claim 46 , wherein the sense strand comprises a nucleotide sequence which differs by no more than 3 nucleotides from the nucleotide sequence 5′-gsasauuccuGfAfAfuuuuaugacu-3′ of SEQ ID NO:1271 and the antisense strand comprises a nucleotide sequence which differs by no more than 3 nucleotides from the nucleotide sequence 5′-asdGsucdAudAaaaudTcAfggaauucscsu-3′ of SEQ ID NO:1922.
53 . The method of claim 46 , wherein the sense strand comprises a nucleotide sequence which differs by no more than 2 nucleotides from the nucleotide sequence 5′-gsasauuccuGfAfAfuuuuaugacu-3′ of SEQ ID NO:1271 and the antisense strand comprises a nucleotide sequence which differs by no more than 2 nucleotides from the nucleotide sequence 5′-asdGsucdAudAaaaudTcAfggaauucscsu-3′ of SEQ ID NO:1922.
54 . The method of claim 46 , wherein the sense strand comprises a nucleotide sequence which differs by no more than 1 nucleotide from the nucleotide sequence 5′-gsasauuccuGfAfAfuuuuaugacu-3′ of SEQ ID NO:1271 and the antisense strand comprises a nucleotide sequence which differs by no more than 1 nucleotide from the nucleotide sequence 5′-asdGsucdAudAaaaudTcAfggaauucscsu-3′ of SEQ ID NO:1922.
55 . The method of claim 46 , wherein the sense strand comprises the nucleotide sequence 5′-gsasauuccuGfAfAfuuuuaugacu-3′ of SEQ ID NO:1271 and the antisense strand comprises the nucleotide sequence 5′-asdGsucdAudAaaaudTcAfggaauucscsu-3′ of SEQ ID NO:1922.
56 . The method of claim 46 , wherein the sense strand consists of the nucleotide sequence 5′-gsasauuccuGfAfAfuuuuaugacu-3′ of SEQ ID NO:1271 and the antisense strand consists of the nucleotide sequence 5′-asdGsucdAudAaaaudTcAfggaauucscsu-3′ of SEQ ID NO:1922.
57 . The method of claim 46 , wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof, further comprises a ligand.
58 . The method of claim 57 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent or a pharmaceutically acceptable salt thereof.
59 . The method of claim 57 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.
60 . The method of claim 59 , wherein the ligand is conjugated to the dsRNA agent, or a pharmaceutically acceptable salt thereof, through a monovalent, bivalent, or trivalent linker.
61 . The method of claim 59 , wherein the ligand is
62 . The method of claim 61 , 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.
63 . The method of claim 62 , wherein X is O.
64 . The method of claim 46 , wherein the sense strand comprises the nucleotide sequence 5′-gsasauuccuGfAfAfuuuuaugacu-3′ of SEQ ID NO:1271 and the antisense strand comprises the nucleotide sequence 5′-asdGsucdAudAaaaudTcAfggaauucscsu-3′ of SEQ ID NO:1922,
wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U. respectively; Af and Gf are 2′-fluoro A and G, respectively; dG is a 2′-deoxyguanosine-3′-phosphate nucleotide; dA is a 2′-deoxyadenosine-3′-phosphate nucleotide; dT is a 2′-deoxythymidine-3′-phosphate nucleotide; and s is a phosphorothioate linkage, and
wherein the 3′-end of the sense strand is conjugated to a ligand as shown in the following schematic
wherein X is O.
65 . A double stranded ribonucleic acid (dsRNA) for inhibiting expression of complement factor B (CFB) in a cell, wherein the dsRNA comprises a sense strand and an antisense strand forming a double stranded region,
(a) wherein the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from any one of the antisense nucleotide sequences in any one of Tables 2-3; or
(b) wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than three nucleotides from any one of the nucleotide sequence of nucleotides 504-526, 640-662, 641-663, 995-1017, 997-1019, 1034-1056, 1141-1163, 1145-1167, 1389-1411, 1473-1495, 1826-1848, 1828-1850, 1842-1864, 2242-2264, 2391-2413, 2393-2415, 2438-2460, or 2453-2475 of SEQ ID NO: 1, and the antisense strand comprises at least 15 contiguous nucleotides differing by no more than three nucleotides from the corresponding nucleotide sequence of SEQ ID NO:8.