RNAi-Mediated Inhibition of Tumor Necrosis Factor Alpha-Related Conditions

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 the ocular conditions dry eye, allergic conjunctivitis, or ocular inflammation, or such as dermatitis, rhinitis, or asthma, for example.

What is claimed is: 
     
         1 . An interfering RNA for inhibiting the expression of a tumor necrosis factor α converting enzyme (TACE) gene, wherein the interfering RNA comprises a sense strand and an antisense strand each 19-49 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence that is complementary to any of SEQ ID NO:3, SEQ ID NO:14-SEQ ID NO:58, or SEQ ID NO:155-SEQ ID NO:201. 
     
     
         2 . The compositions of  claim 1 , wherein each strand of the interfering RNA molecule is 19 to 27 nucleotides in length. 
     
     
         3 . The interfering RNA of  claim 1 , wherein the interfering RNA comprises one or more chemically modified nucleotides, one or more deoxyribonucleotides, and/or one or more non-phosphodiester linkages. 
     
     
         4 . The interfering RNA of  claim 3 , wherein one or more of the chemically modified nucleotides have a sugar modification selected from the group consisting of: a 2′ amino group, a 2′ O-methyl group, and a 2′ methoxyethyl group. 
     
     
         5 . The interfering RNA of  claim 3 , wherein the interfering RNA comprises one or more chemically modified nucleotides and one or more non-phosphodiester linkages. 
     
     
         6 . The interfering RNA of  claim 3 , wherein non-nucleotide material is bound to the 5′ end and/or 3′ end of the sense strand and/or the antisense strand. 
     
     
         7 . The interfering RNA of  claim 3 , wherein the non-nucleotide material is bound internally to the sense strand and/or the antisense strand. 
     
     
         8 . The interfering RNA of  claim 6 , wherein the non-nucleotide material improves cellular uptake, enhances cellular targeting, assists in tracing, improves stability, and/or reduces activation of the interferon pathway. 
     
     
         9 . The interfering RNA of  claim 3 , wherein the sense strand and/or the antisense strand contains a 3′ overhang. 
     
     
         10 . The interfering RNA of  claim 3 , wherein the sense strand and/or the antisense strand contains a 5′ overhang. 
     
     
         11 . The interfering RNA of  claim 3 , wherein the interfering RNA molecule at least one blunt end. 
     
     
         12 . A composition for inhibiting the expression of a tumor necrosis factor α converting enzyme (TACE) gene comprising:
 an interfering RNA that comprises a sense strand and an antisense strand, wherein the sense strand comprises a nucleotide sequence of any of SEQ ID NO:3, SEQ ID NO:14-SEQ ID NO:58, or SEQ ID NO:155-SEQ ID NO:201 except that the T's can be T's or U's, and the antisense strand comprises a nucleotide sequence that is complementary to any of SEQ ID NO:59-SEQ ID NO:154, SEQ ID NO:202-SEQ ID NO:204; and 
 a pharmaceutically acceptable carrier. 
 
     
     
         13 . The composition of  claim 12 , wherein the interfering RNA comprises one or more chemically modified nucleotides, one or more deoxyribonucleotides, and/or one or more non-phosphodiester linkages. 
     
     
         14 . The composition of  claim 13 , wherein one or more of the chemically modified nucleotides have a sugar modification selected from the group consisting of: a 2′ amino group, a 2′ O-methyl group, and a 2′ methoxyethyl group. 
     
     
         15 . The composition of  claim 13 , wherein the interfering RNA comprises one or more chemically modified nucleotides and one or more non-phosphodiester linkages. 
     
     
         16 . The composition of  claim 13 , wherein non-nucleotide material is bound to the 5′ end and/or 3′ end of the sense strand and/or the antisense strand. 
     
     
         17 . The composition of  claim 13 , wherein the non-nucleotide material is bound internally to the sense strand and/or the antisense strand. 
     
     
         18 . The composition of  claim 16 , wherein the non-nucleotide material improves cellular uptake, enhances cellular targeting, assists in tracing, improves stability, and/or reduces activation of the interferon pathway. 
     
     
         19 . The composition of  claim 14 , wherein the sense strand and/or the antisense strand contains a 3′ overhang and/or a 5′ overhang. 
     
     
         20 . An interfering RNA for inhibiting the expression of a tumor necrosis factor α receptor-1 (TNFR1) wherein the interfering RNA comprises a sense strand and an antisense strand, wherein said antisense strand is complementary to any of any of SEQ ID NO:59-SEQ ID NO:154, or SEQ ID NO:202-SEQ ID NO:204.