RNAi-Related Inhibition of TNF-alpha Signaling Pathway for Treatment of Ocular Angiogenesis

Abstract

RNA interference is provided for inhibition of tumor necrosis factor α (TNFα) by silencing TNFα cell surface receptor TNF receptor-1 (TNFR1) mRNA expression, or by silencing TNFα converting enzyme (TACE/ADAM17) mRNA expression. Silencing such TNFα targets, in particular, is useful for treating patients having a TNFα-related condition or at risk of developing a TNFα-related condition, such as ocular angiogenesis, retinal ischemia, and diabetic retinopathy.

What is claimed is: 
     
         1 . A composition comprising a double-stranded interfering RNA molecule having a length of about 19 to about 49 nucleotides, the interfering RNA molecule comprising:
 (a) a sense strand comprising any one of SEQ ID NO:2, SEQ ID NOs:59-154, except that the T's can be T's or U's, and   (b) an antisense strand complementary to any one of SEQ ID NO:59-154.   
     
     
         2 . The compositions of  claim 1 , wherein each strand of the interfering RNA molecule 19 to about 27 nucleotides in length. 
     
     
         3 . The composition of  claim 2 , wherein each strand of the interfering RNA molecule is independently about 19 nucleotides to about 25 nucleotides in length. 
     
     
         4 . The composition of  claim 3 , wherein each strand of the interfering RNA molecule is independently about 19 nucleotides to about 21 nucleotides in length. 
     
     
         5 . The composition of  claim 1 , wherein the sense and antisense strands are connected by a linker to form a shRNA. 
     
     
         6 . The composition of  claim 1 , wherein the interfering RNA molecule has blunt ends. 
     
     
         7 . The composition of  claim 1 , wherein at least one strand of the interfering RNA molecule comprises a 3′ overhang. 
     
     
         8 . The composition of  claim 7 , wherein the 3′ overhang comprises about 1 to about 6 nucleotides. 
     
     
         9 . The composition of  claim 8 , wherein the 3′ overhang comprises 2 nucleotides. 
     
     
         10 . The composition of  claim 1 , wherein the interfering RNA molecule comprises at least one modification. 
     
     
         11 . The composition of  claim 1  wherein the interfering RNA molecule sense strand and/or antisense strand contains one or more chemically modified nucleotides. 
     
     
         12 . The composition of  claim 1  wherein the interfering RNA molecule has at least one blunt end. 
     
     
         13 . The composition of  claim 11  wherein the chemically modified nucleotide comprises a ribose 2′-OH modification. 
     
     
         14 . The composition of  claim 13  wherein the ribose 2′-OH modification is selected from the group consisting of: 2′-amino group, 2′-O-methyl group, 2′-methoxyethyl group, and 2′-0,4′-C methylene bridge. 
     
     
         15 . The composition of  claim 1  the a phosphate group of a sense strand and/or antisense strand nucleotide is modified by substituting one or more of the oxygens of the phosphate group with nitrogen or with sulfur. 
     
     
         16 . The composition of  claim 1 , wherein the interfering RNA molecule is a shRNA, a siRNA, or a miRNA.