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 12 to 35 nucleobases in length targeted to a nucleic acid molecule encoding human IL 4R-α (SEQ ID NO: 1), wherein the compound inhibits the expression of human IL 4R-α, wherein the compound is targeted to nucleotides 2056 to 2101 of SEQ ID NO:1. 
     
     
         2 . The compound of  claim 1 , wherein the compound is at least about 80% identical to a 20-nucleobase portion of the complement of nucleotides 2056 to 2101 of SEQ ID NO:1. 
     
     
         3 . The compound of  claim 2 , wherein the compound is at least about 80% identical to a 20-nucleobase portion of the complement of nucleotides 2056 to 2088 of SEQ ID NO. 1. 
     
     
         4 . The compound of  claim 3 , wherein the compound is at least about 80% identical to SEQ ID NO. 276. 
     
     
         5 . The compound of  claim 1 , wherein the compound is a single stranded compound. 
     
     
         6 . The compound of  claim 1  having at least one modified internucleoside linkage, sugar moiety, or nucleobase. 
     
     
         7 . The compound of  claim 6  comprising a chimeric oligonucleotide. 
     
     
         8 . The compound of  claim 6 , wherein the modified internucleoside linkage comprises a phosphorothioate linkage. 
     
     
         9 . The compound of  claim 6 , wherein the modified sugar moiety comprises a 2′-O-(2-methoxyethyl) (2′-MOE) modification. 
     
     
         10 . The compound of  claim 6 , wherein the modified nucleobase comprises 5-methylcytosine. 
     
     
         11 . The compound of  claim 1 , wherein the compound is 20 nucleobases in length, wherein nucleotides 6 to 15 of said compound are 2′-deoxynucleotides, and nucleotides 1 to 5 and 16 to 20 of said compound are 2′-O-methoxyethyl nucleotides, and wherein every internucleoside linkage is a phosphorothioate linkage, and every cytidine residue is a 5-methylcytidine. 
     
     
         12 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable penetration enhancer, carrier, or diluent. 
     
     
         13 . A method for treating a respiratory disorder comprising administration of the compound of  claim 1  to an individual in need of such intervention. 
     
     
         14 . The method of  claim 13 , wherein the respiratory disorder is Th2-mediated. 
     
     
         15 . The method of  claim 13 , wherein the respiratory disorder is selected from the group consisting of allergic and non-allergic asthma, Chronic Obstructive Pulmonary Disease (COPD), pulmonary fibrosis, allergic rhinitis, nasal polyposis, pulmonary inflammation, and airway hyperresponsiveness. 
     
     
         16 . The method of  claim 13 , wherein administration comprises topical administration to a respiratory tract of the individual. 
     
     
         17 . The method of  claim 13 , wherein administration comprises aerosol administration.