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 receptor-1 (TNFR1) gene wherein the interfering RNA comprises a sense strand and an antisense strand each 19-49 nucleotides in length, wherein the sense strand comprises a nucleotide sequence of any of SEQ ID NO:59-SEQ ID NO:154, SEQ ID NO:202-SEQ ID NO:204 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. 
     
     
         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 the chemically modified nucleotides independently contain 2′ amino groups, 2′ O-methyl groups, or 2′ methoxyethyl groups, 
     
     
         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 . The interfering RNA of  claim 3 , wherein, the sense strand comprises a nucleotide sequence of SEQ ID NO:204 or SEQ ID NO:205 except that the T's can be T's or U's, and the antisense strand comprises a nucleotide sequence that is complementary SEQ ID NO:204 or SEQ ID NO:205. 
     
     
         13 . A composition for inhibiting the expression of a tumor necrosis factor α receptor-1 (TNFR1) comprising an interfering RNA wherein the interfering RNA comprises a sense strand and an antisense strand, the sense strand comprises a nucleotide sequence of any of SEQ ID NO:59-SEQ ID NO:154, SEQ ID NO:202-SEQ ID NO:204 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. 
     
     
         14 . The composition of  claim 13  wherein the interfering RNA comprises one or more chemically modified nucleotides, one or more deoxyribonucleotides, and/or one or more non-phosphodiester linkages. 
     
     
         15 . The composition of  claim 14  wherein the chemically modified nucleotides are independently contain 2′ amino groups, 2′ O-methyl groups, or 2′ methoxyethyl groups, 
     
     
         16 . The composition of  claim 14  wherein the interfering RNA comprises one or more chemically modified nucleotides and one or more non-phosphodiester linkages. 
     
     
         17 . The composition of  claim 14  wherein non-nucleotide material is bound to the 5′ end and/or 3′ end of the sense strand and/or the antisense strand. 
     
     
         18 . The composition of  claim 14  wherein the non-nucleotide material is bound internally to the sense strand and/or the antisense strand. 
     
     
         19 . The composition of  claim 17  wherein the non-nucleotide material improves cellular uptake, enhances cellular targeting, assists in tracing, improves stability, and/or reduces activation of the interferon pathway. 
     
     
         20 . The composition of  claim 14  wherein the sense strand and/or the antisense strand contains a 3′ overhang. 
     
     
         21 . The composition of  claim 14  wherein the sense strand and/or the antisense strand contains a 5′ overhang. 
     
     
         22 . The composition of  claim 14 , wherein the interfering RNA molecule at least one blunt end. 
     
     
         23 . 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 SEQ ID NO: 3, SEQ ID NOs:14-58 or SEQ ID NOs:155-201.