Compositions and their uses directed to il-4r alpha

Abstract

Disclosed herein are compounds, compositions and methods for modulating the expression of IL-4R alpha in a cell, tissue or animal. Also provided are methods of target validation. Also provided are uses of disclosed compounds and compositions in the manufacture of a medicament for treatment of diseases and disorders related to expression of IL 4R-α, airway hyperresponsiveness, and/or pulmonary inflammation.

1 . An oligomeric compound of 12 to 35 nucleobases targeted to a nucleic acid molecule encoding human IL 4R-α (SEQ ID NO: 1), wherein said oligomeric compound inhibits the expression of human IL 4R-α by at least 50%, and wherein the oligomeric compound comprises at least a 12 nucleobase portion of SEQ ID NOs: 112, 113, 158, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 176, 177, 178, 179, 182, 183, 184, 185, 186, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 208, 209, 210, 211, 213, 214, 215, 216, 218, 219, 226, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 254, 256, 257, 258, 259, 260, 261, 264, 265, 266, 268, 269, 270, 272, 273, 274, 275, 276, 277, 279, 280, 281, 282, 283, 284, 286, 288, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302 or 303. 
     
     
         2 . The compound of  claim 1 , wherein the compound comprises at least a 17 nucleobase portion of SEQ ID NOs: 112, 113, 158, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 176, 177, 178, 179, 182, 183, 184, 185, 186, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 208, 209, 210, 211, 213, 214, 215, 216, 218, 219, 226, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 254, 256, 257, 258, 259, 260, 261, 264, 265, 266, 268, 269, 270, 272, 273, 274, 275, 276, 277, 279, 281, 282, 283, 284, 286, 288, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302 or 303. 
     
     
         3 . (canceled) 
     
     
         4 . The compound of  claim 1  wherein the compound is at least about 80% complementary to a 20 nucleobase portion of SEQ ID NO. 1. 
     
     
         5 . The compound of  claim 1  wherein the compound is at least about 80% identical to SEQ ID NO. 281. 
     
     
         6 . The compound of  claim 1  wherein the compound is a single stranded compound. 
     
     
         7 . The compound of  claim 1  having at least one modified internucleoside linkage, sugar moiety, or nucleobase. 
     
     
         8 . The compound of  claim 7  comprising a chimeric oligonucleotide. 
     
     
         9 . The compound of  claim 7  wherein the modified internucleoside linkage comprises a phosphorothioate linkage. 
     
     
         10 . The compound of  claim 7  wherein the modified sugar moiety comprises a 2′-MOE modification. 
     
     
         11 . The compound of  claim 7  wherein the modified nucleobase comprises 5-methylcytosine. 
     
     
         12 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable penetration enhancer, carrier, or diluent. 
     
     
         13 . A method for the prevention, amelioration, and/or treatment of pulmonary inflammation and/or airway hyperresponsiveness comprising administration of the compound of  claim 1  to an individual in need of such intervention 
     
     
         14 . The method of  claim 13  wherein administration comprises topical administration to a respiratory tract of an animal. 
     
     
         15 . The method of  claim 13  wherein administration comprises aerosol administration. 
     
     
         16 . The compound of  claim 7  wherein the modified sugar moiety comprises a bicyclic sugar. 
     
     
         17 . The compound of  claim 8  wherein the chimeric oligonucleotide comprises:
 (a) a gap segment consisting of linked deoxynucleosides; 
 (b) a 5′ wing segment consisting of linked nucleosides; 
 (c) a 3′ wing segment consisting of linked nucleosides; 
 
       wherein the gap segment is positioned immediately adjacent to and between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.