RNAi Modulation Of TGF-BETA And Therapeutic Uses Thereof

Abstract

The present invention concerns methods of treatment using transforming growth factor beta (TGF-beta) modulators. More specifically, the invention concerns methods of treating disorders associated with undesirable TGF-beta signaling, by administering short interfering RNA which down-regulate the expression of TGF-beta, and agents useful therein.

1 . An isolated iRNA agent, comprising an antisense strand and a sense strand substantially complementary to said antisense strand, wherein the iRNA agent mediates the cleavage of a TGF-beta mRNA within the target sequence of iRNA agent AL-DP-6857. 
     
     
         2 . The iRNA agent of  claim 1 , wherein the target sequence is nucleotides 1711 to 1733 of NM — 000660.3. 
     
     
         3 . The iRNA agent of  claim 1 , wherein the iRNA agent further comprises a non-nucleotide moiety. 
     
     
         4 . The iRNA of  claim 1 , wherein the iRNA agent is stabilized against nucleolytic degradation. 
     
     
         5 . The iRNA agent of  claim 1 , wherein the sense strand and/or the antisense strand further comprises at least one 3′-overhang wherein the 3′-overhang comprises from 1 to 6 nucleotides. 
     
     
         6 . The iRNA agent of  claim 1 , further comprising a phosphorothioate at the first internucleotide linkage at the 5′ end of the sense strand and/or the antisense strand. 
     
     
         7 . The iRNA agent of  claim 1 , further comprising a phosphorothioate at the first internucleotide linkage at the 3′ end of the sense strand and/or the antisense strand. 
     
     
         8 . The iRNA agent of  claim 1 , further comprising a 2′-modified nucleotide in the sense strand and/or the antisense strand. 
     
     
         9 . The iRNA agent of  claim 8 , wherein the 2′-modified nucleotide comprises a modification selected from the group consisting of: 2′-deoxy, 2′-deoxy-2′-fluoro, 2′-O-methyl, 2′-O-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). 
     
     
         10 . The iRNA agent of  claim 1 , wherein the sense strand comprises 15 or more contiguous nucleotides of the nucleotide sequence of SEQ ID NO:81. 
     
     
         11 . The iRNA agent of  claim 1 , wherein the iRNA agent is AL-DP-6857. 
     
     
         12 . The iRNA agent of  claim 1 , wherein the antisense strand comprises 15 or more contiguous nucleotides of the nucleotide sequence of SEQ ID NO:82. 
     
     
         13 . The iRNA agent of  claim 1 , wherein the sense strand comprises SEQ ID NO:83. 
     
     
         14 . The iRNA agent of  claim 1 , wherein the antisense strand comprises SEQ ID NO:84. 
     
     
         15 . The iRNA agent of  claim 1 , wherein the iRNA agent is AL-DP-6270. 
     
     
         16 . A vector encoding the iRNA agent of  claim 1 . 
     
     
         17 . A cell comprising the iRNA agent of  claim 1 . 
     
     
         18 . A method of making the iRNA agent of  claim 1 , the method comprising the synthesis of the iRNA agent, wherein the sense and antisense strands comprise at least one modification that stabilizes the iRNA agent against nucleolytic degradation. 
     
     
         19 . A pharmaceutical composition comprising the iRNA agent of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         20 . A method of treating a human diagnosed as having a disease or disorder associated with undesired TGF-beta signaling, comprising administering to a subject in need of such treatment a therapeutically effective amount of the iRNA agent of  claim 1 . 
     
     
         21 . The method of  claim 20 , wherein the human is diagnosed as having idiopathic pulmonary fibrosis, diabetic nephropathy or chronic liver disease. 
     
     
         22 . A method of reducing the levels of a TGF-beta mRNA in a cell of a subject, or of TGF-beta protein secreted by a cell of a subject, comprising the step of administering the iRNA agent of  claim 1  to said subject. 
     
     
         23 . The method of  claim 22 , wherein said iRNA agent mediates the cleavage of a TGF-beta mRNA within the target sequence of iRNA agent AL-DP-6857. 
     
     
         24 . The method of  claim 22 , wherein said administration comprises pulmonary administration.