RNAi MODULATION OF HIF-1 AND THERAPUTIC USES THEREOF

Abstract

The features of the present invention relate to compounds, compositions and methods useful for modulating the expression of HIF-1α, such as by the mechanism of RNA interference (RNAi). The compounds and compositions include iRNA agents that can be unmodified or chemically-modified.

1 . An iRNA agent, comprising a sense sequence and an antisense sequence, wherein the sense sequence comprises a sequence that differs by no more than 1, 2, or 3 nucleotides from the nucleotide sequence of SEQ ID NO:8. 
     
     
         2 . The iRNA agent of  claim 1 , wherein the antisense sequence comprises a sequence that differs by no more than 1, 2, or 3 nucleotides from the nucleotide sequence of SEQ ID NO:32. 
     
     
         3 . The iRNA agent of  claim 1 , wherein the sense sequence comprises SEQ ID NO:8. 
     
     
         4 . The iRNA agent of  claim 1 , wherein the sense sequence comprises SEQ ID NO:8 and the antisense sequence comprises SEQ ID NO:32 
     
     
         5 . The iRNA agent of  claim 1 , wherein the sense sequence consists of SEQ ID NO:8 and the antisense sequence consists of SEQ ID NO:32. 
     
     
         6 . The iRNA agent of  claim 1 , wherein the sense sequence consists of SEQ ID NO:56 and the antisense sequence consists of SEQ ID NO:80. 
     
     
         7 . The iRNA agent of  claim 1 , wherein the sense sequence consists of SEQ ID NO:104 and the antisense sequence consists of SEQ ID NO:128. 
     
     
         8 . The iRNA agent of  claim 1 , wherein the sense sequence consists of SEQ ID NO:152 and the antisense sequence consists of SEQ ID NO:176. 
     
     
         9 . The iRNA agent of  claim 1 , wherein the iRNA agent further comprises a non-nucleotide moiety. 
     
     
         10 . The iRNA of  claim 1 , wherein the sense and antisense sequences are stabilized against nucleolytic degradation. 
     
     
         11 . The iRNA agent of  claim 1 , further comprising one 3′-overhang wherein said 3′-overhang comprises from 1 to 6 nucleotides. 
     
     
         12 . The iRNA of  claim 11 , further comprising a second 3′-overhang wherein said second 3′-overhang comprises from 1 to 6 nucleotides. 
     
     
         13 . The iRNA agent of  claim 1 , further comprising a phosphorothioate at the first internucleotide linkage at the 5′ end of the antisense and sense sequences. 
     
     
         14 . The iRNA agent of  claim 1 , further comprising a phosphorothioate at the first internucleotide linkage at the 3′ end of the antisense and sense sequences. 
     
     
         15 . The iRNA agent of  claim 1 , further comprising a phosphorothioate at the first internucleotide linkage at the 5′ end of the antisense and sense sequences, and a phosphorothioate at the first internucleotide linkage at the 3′ end of the antisense and sense sequences. 
     
     
         16 . The iRNA agent of  claim 1 , further comprising a 2′-modified nucleotide. 
     
     
         17 . The iRNA agent of  claim 16 , wherein the 2′-modified nucleotide comprises a modification selected from the group consisting of: 2′-deoxy, 2′-deoxy-2′-fluoro, 2′-O-methyl, 2′-β-methoxyethyl (2′-O-MOE), 2′-O-aminopropyl (2′-O-AP), 2′-O-dimethylaminoethyl (2′-O-DMAOE), 2′-O-dimethylaminopropyl (2′-O-DMAP), 2′-O-dimethylaminoethyloxyethyl (2′-O-DMAEOE), and 2′-O—N-methylacetamido (2′-O-NMA). 
     
     
         18 . A pharmaceutical composition comprising an iRNA agent of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         19 . A method of reducing the amount of HIF-1α RNA in a cell of a subject, comprising contacting the cell with the iRNA agent of  claim 1 . 
     
     
         20 . A method of making the iRNA agent of  claim 1 , the method comprising the synthesis of the iRNA agent, wherein the sense and antisense sequences comprise at least one modification that stabilizes the iRNA agent against nucleolytic degradation. 
     
     
         21 . A method of inhibiting HIF-1α expression comprising administering an effective amount of the iRNA agent of  claim 1 . 
     
     
         22 . A method of treating a human diagnosed as having or at risk for having age-related macular degeneration (AMD), comprising administering to a subject in need of such treatment a therapeutically effective amount of the iRNA agent of  claim 1 .