RNAi-RELATED INHIBITION OF TNFa SIGNALING PATHWAY FOR TREATMENT OF MACULAR EDEMA

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 or at risk of developing macular edema.

1 . A method of treating macular edema in a patient in need thereof, comprising administering to the patient an interfering RNA molecule that attenuates expression of the TACE mRNA via RNA interference. 
     
     
         2 . The method of  claim 1 , wherein the interfering RNA molecule is double stranded and each strand is independently about 19 to about 27 nucleotides in length. 
     
     
         3 . The method of  claim 2 , wherein each strand is independently about 19 nucleotides to about 25 nucleotides in length. 
     
     
         4 . The method of  claim 2 , wherein each strand is independently about 19 nucleotides to about 21 nucleotides in length. 
     
     
         5 . The method of  claim 2 , wherein the sense and antisense strands are connected by a linker to form a shRNA that can attenuate expression of TACE mRNA in a patient. 
     
     
         6 . The method of  claim 2 , wherein the interfering RNA molecule has blunt ends. 
     
     
         7 . The method of  claim 2 , wherein at least one strand of the interfering RNA molecule comprises a 3′ overhang. 
     
     
         8 . The method of  claim 7 , wherein the 3′ overhang comprises about 1 to about 6 nucleotides. 
     
     
         9 . The method of  claim 8 , wherein the 3′ overhang comprises 2 nucleotides. 
     
     
         10 . The method of  claim 1 , wherein the interfering RNA molecule is administered via in vivo expression from an expression vector capable of expressing the interfering RNA molecule. 
     
     
         11 . The method of  claim 1 , wherein the patient has or is at risk of developing a TNFα-related ocular disorder. 
     
     
         12 . The method of  claim 1 , wherein the interfering RNA molecule recognizes a portion of TACE mRNA that corresponds to any of SEQ ID NO: 3, SEQ ID NO: 14-SEQ ID NO: 58, and SEQ ID NO: 155-SEQ ID NO: 201. 
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 1 , wherein the interfering RNA molecule recognizes a portion of TACE mRNA, wherein the portion comprises nucleotide 297, 333, 334, 335, 434, 470, 493, 547, 570, 573, 618, 649, 689, 755, 842, 844, 846, 860, 878, 894, 900, 909, 910, 913, 942, 970, 984, 1002, 1010, 1053, 1064, 1137, 1162, 1215, 1330, 1334, 1340, 1386, 1393, 1428, 1505, 1508, 1541, 1553, 1557, 1591, 1592, 1593, 1597, 1604, 1605, 1626, 1632, 1658, 1661, 1691, 1794, 1856, 1945, 1946, 1947, 1958, 2022, 2094, 2100, 2121, 2263, 2277, 2347, 2349, 2549, 2578, 2595, 2606, 2608, 2629, 2639, 2764, 2766, 2767, 2769, 3027, 3028, 3261, 3264, 3284, 3313, 3317, 3332, or 3337 of SEQ ID NO: 1. 
     
     
         15 . (canceled) 
     
     
         16 . The method of  claim 1 , wherein the interfering RNA molecule comprises at least one modification. 
     
     
         17 . The method of  claim 1 , wherein the interfering RNA molecule is a shRNA, a siRNA, or a miRNA. 
     
     
         18 . The method of  claim 1 , wherein the interfering RNA molecule is administered via a topical, intravitreal, transcleral, periocular, conjunctival, subtenon, intracameral, subretinal, subconjunctival, retrobulbar, or intracanalicular route.