Compositions and methods for modulating complement factor b expression

Abstract

The present embodiments provide methods, compounds, and compositions for treating, preventing, or ameliorating a disease associated with dysregulation of the complement alternative pathway by administering a Complement Factor B (CFB) specific inhibitor to a subject.

1 - 263 . (canceled) 
     
     
         264 . A modified single-stranded oligonucleotide covalently attached to a conjugate group, wherein the modified single-stranded oligonucleotide consists of 10 to 30 linked nucleosides and has a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 455, 453, 448, 237, 444, 450, 228, 549, or 198, and wherein the conjugate group covalently attached to the modified single stranded oligonucleotide comprises: 
       
         
           
           
               
               
           
         
       
     
     
         265 . The modified single-stranded oligonucleotide covalently attached to a conjugate group of  claim 264 , wherein the modified single-stranded oligonucleotide consists of 20 to 30 linked nucleosides and has a nucleobase sequence comprising the nucleobase sequence of any of SEQ ID NOs: 455, 453, 448, 237, 444, 450, 228, or 198. 
     
     
         266 . The modified single-stranded oligonucleotide covalently attached to a conjugate group of  claim 264 , wherein the modified single-stranded oligonucleotide consists of the nucleobase sequence of any of SEQ ID NOs: 455, 453, 448, 237, 444, 450, 228, 549 or 198. 
     
     
         267 . The modified single-stranded oligonucleotide covalently attached to a conjugate group of  claim 264 , wherein the modified single-stranded oligonucleotide has:
 a gap segment consisting of linked deoxynucleosides;   a 5′ wing segment consisting of linked nucleosides; and   a 3′ wing segment consisting of linked nucleosides;   wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.   
     
     
         268 . The modified single-stranded oligonucleotide covalently attached to a conjugate group of  claim 264 , wherein the modified single-stranded oligonucleotide consists of 20 linked nucleosides and has a nucleobase sequence consisting of the nucleobase sequence of any of SEQ ID NOs: 455, 453, 448, 237, 444, 450, 228, or 198, and wherein the modified single-stranded oligonucleotide has:
 a gap segment consisting of ten linked deoxynucleosides;   a 5′ wing segment consisting of five linked nucleosides; and   a 3′ wing segment consisting of five linked nucleosides;   wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar; wherein each internucleoside linkage of the modified single-stranded oligonucleotide is a phosphorothioate linkage, and wherein each cytosine is 5-methylcytosine.   
     
     
         269 . The modified single-stranded oligonucleotide covalently attached to a conjugate group of  claim 268 , wherein the modified single-stranded oligonucleotide has a nucleobase sequence consisting of the nucleobase sequence of SEQ ID NO: 455. 
     
     
         270 . The modified single-stranded oligonucleotide covalently attached to a conjugate group of  claim 268 , wherein the modified single-stranded oligonucleotide has a nucleobase sequence consisting of the nucleobase sequence of SEQ ID NO: 453. 
     
     
         271 . The modified single-stranded oligonucleotide covalently attached to a conjugate group of  claim 268 , wherein the modified single-stranded oligonucleotide has a nucleobase sequence consisting of the nucleobase sequence of SEQ ID NO: 448. 
     
     
         272 . The modified single-stranded oligonucleotide covalently attached to a conjugate group of  claim 268 , wherein the modified single-stranded oligonucleotide has a nucleobase sequence consisting of the nucleobase sequence of SEQ ID NO: 237. 
     
     
         273 . The modified single-stranded oligonucleotide covalently attached to a conjugate group of  claim 264 , wherein the modified single-stranded oligonucleotide is at least 85% complementary to SEQ ID NO: 1. 
     
     
         274 . The modified single-stranded oligonucleotide covalently attached to a conjugate group of  claim 264 , wherein the modified single-stranded oligonucleotide comprises at least one modified internucleoside linkage, at least one modified sugar, or at least one modified nucleobase. 
     
     
         275 . The modified single-stranded oligonucleotide covalently attached to a conjugate group of  claim 274 , wherein the modified single-stranded oligonucleotide comprises at least one modified internucleoside linkage. 
     
     
         276 . The modified single-stranded oligonucleotide covalently attached to a conjugate group of  claim 275 , wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         277 . The modified single-stranded oligonucleotide covalently attached to a conjugate group of  claim 276 , wherein the modified single-stranded oligonucleotide comprises at least 1 phosphodiester internucleoside linkage. 
     
     
         278 . The modified single-stranded oligonucleotide covalently attached to a conjugate group of  claim 277 , wherein each internucleoside linkage of the modified single-stranded oligonucleotide is selected from a phosphodiester internucleoside linkage and a phosphorothioate internucleoside linkage. 
     
     
         279 . The modified single-stranded oligonucleotide covalently attached to a conjugate group of  claim 274 , wherein each internucleoside linkage of the modified single-stranded oligonucleotide comprises a phosphorothioate internucleoside linkage. 
     
     
         280 . The modified single-stranded oligonucleotide covalently attached to a conjugate group of  claim 274 , wherein the modified sugar is a bicyclic sugar. 
     
     
         281 . The modified single-stranded oligonucleotide covalently attached to a conjugate group of  claim 280 , wherein the bicyclic sugar is selected from the group consisting of: 4′-(CH 2 )—O-2′ (LNA); 4′-(CH 2 ) 2 —O-2′ (ENA); and 4′-CH(CH 3 )—O-2′ (cEt). 
     
     
         282 . The modified single-stranded oligonucleotide covalently attached to a conjugate group of  claim 274 , wherein the modified sugar is 2′-O-methoxyethyl. 
     
     
         283 . The modified single-stranded oligonucleotide covalently attached to a conjugate group of  claim 274 , wherein the modified nucleobase is 5-methylcytosine. 
     
     
         284 . A modified double-stranded oligonucleotide comprising the modified single-stranded oligonucleotide covalently attached to a conjugate group of  claim 264 , and a second single stranded oligonucleotide hybridized to said modified single stranded oligonucleotide. 
     
     
         285 . The modified single-stranded oligonucleotide covalently attached to a conjugate group of  claim 264 , wherein the conjugate group is linked to the modified oligonucleotide at the 5′ end of the modified oligonucleotide. 
     
     
         286 . The modified single-stranded oligonucleotide covalently attached to a conjugate group of  claim 264 , wherein the conjugate group is linked to the modified oligonucleotide at the 3′ end of the modified oligonucleotide. 
     
     
         287 . A method of treating a disease associated with dysregulation of the complement alternative pathway in a subject comprising administering to the subject the modified single-stranded oligonucleotide covalently attached to a conjugate group of  claim 264 , or a pharmaceutically acceptable salt thereof, thereby treating the disease. 
     
     
         288 . The method of  claim 287 , wherein the disease is macular degeneration, age related macular degeneration (AMD), wet AMD, dry AMD, or Geographic Atrophy. 
     
     
         289 . The method of  claim 287 , wherein the disease is a kidney disease. 
     
     
         290 . The method of  claim 289 , wherein the kidney disease is lupus nephritis, systemic lupus erythematosus (SLE), dense deposit disease (DDD), C3 glomerulonephritis (C3GN), CFHR5 nephropathy, or atypical hemolytic uremic syndrome (aHUS).