RNAi-RELATED INHIBITION OF TNF alpha SIGNALING PATHWAY FOR TREATMENT OF GLAUCOMA

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 associated with elevated intraocular pressure (TOP), including glaucoma and ocular hypertension.

What is claimed is: 
     
         1 . A method of treating a TNFα-related ocular disorder in a patient in need thereof, comprising administering to the patient an interfering RNA molecule that attenuates expression of the TNFR1 or TACE mRNA via RNA interference, wherein the TNFα-related ocular disorder is ocular hypertension or glaucoma. 
     
     
         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 or TNFR1 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 an aerosol, buccal, dermal, intradermal, inhaling, intramuscular, intranasal, intraocular, intrapulmonary, intravenous, intraperitoneal, nasal, ocular, oral, otic, parenteral, patch, subcutaneous, sublingual, topical, or transdermal route. 
     
     
         11 . 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. 
     
     
         12 . The method of  claim 1 , wherein the patient has or is at risk of developing an TNFα-related ocular disorder. 
     
     
         13 . 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 and SEQ ID NO: 14-SEQ ID NO: 58. 
     
     
         14 . The method of  claim 1 , wherein the interfering RNA molecule recognizes a portion of TNFR1 mRNA that corresponds to any of SEQ ID NO: 155-SEQ ID NO: 201. 
     
     
         15 . 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. 
     
     
         16 . The method of  claim 1 , wherein the interfering RNA molecule recognizes a portion of TNFR1 mRNA, wherein the portion comprises nucleotide 124, 328, 387, 391, 393, 395, 406, 421, 423, 444, 447, 455, 459, 460, 467, 469, 470, 471, 475, 479, 513, 517, 531, 543, 556, 576, 587, 588, 589, 595, 601, 602, 611, 612, 651, 664, 667, 668, 669, 677, 678, 785, 786, 788, 791, 792, 804, 813, 824, 838, 843, 877, 884, 929, 959, 960, 961, 963, 964, 965, 970, 973, 974, 1000, 1002, 1013, 1026, 1053, 1056, 1057, 1058, 1161, 1315, 1318, 1324, 1357, 1360, 1383, 1393, 1420, 1471, 1573, 1671, 2044, 2045, 2046, 2047, 2048, 2089, 2090, 2091, or, 2092 of SEQ ID NO: 2. 
     
     
         17 . The method of  claim 1 , wherein the interfering RNA molecule comprises at least one modification. 
     
     
         18 . The composition of  claim 1 , wherein the interfering RNA molecule is a shRNA, a siRNA, or a miRNA. 
     
     
         19 . 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.