Antisense Oligonucleotide modulation of tumor necrosis factor-alpha (TNF-alpha) expression

Abstract

Compositions and methods are provided for inhibiting the expression of human tumor necrosis factor-α (TNF-α). Antisense oligonucleotides targeted to nucleic acids encoding TNF-α are preferred. Methods of using these oligonucleotides for inhibition of TNF-α expression and for treatment of diseases, particularly inflammatory and autoimmune diseases, associated with overexpression of TNF-α are provided.

What is claimed is:  
     
         1 . A method of treating an inflammatory disorder in an individual comprising administering to said individual an effective amount of an oligonucleotide up to 30 nucleotides in length complementary to a nucleic acid molecule encoding human tumor necrosis factor-α.  
     
     
         2 . The method of  claim 1 , wherein said oligonucleotide inhibits the expression of said human tumor necrosis factor-α and comprises at least an 8 nucleobase portion of SEQ ID NO: 24, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 34, SEQ ID NO: 39, SEQ ID NO: 88, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 149, SEQ ID NO: 157, SEQ ID NO: 264, SEQ ID NO: 271, SEQ ID NO: 272, SEQ ID NO: 290, SEQ ID NO: 297, SEQ ID NO: 299, SEQ ID NO: 315, SEQ ID NO: 334, SEQ ID NO: 418, SEQ ID NO: 423, SEQ ID NO: 425, SEQ ID NO: 427, SEQ ID NO: 431, SEQ ID NO: 432, SEQ ID NO: 435, SEQ ID NO: 437, SEQ ID NO: 438, SEQ ID NO: 439, SEQ ID NO: 441, SEQ ID NO: 455, SEQ ID NO: 457, SEQ ID NO: 458, SEQ ID NO: 460, SEQ ID NO: 463, SEQ ID NO: 465, SEQ ID NO: 466, SEQ ID NO: 468, SEQ ID NO: 472, SEQ ID NO: 474, SEQ ID NO: 475, SEQ ID NO: 483, SEQ ID NO: 485, SEQ ID NO: 494 or SEQ ID NO: 496.  
     
     
         3 . The method of  claim 1 , wherein said antisense oligonucleotide is administered orally, topically or parenterally.  
     
     
         4 . The method of  claim 1 , wherein said inflammatory disorder is inflammatory bowel disease, Crohn's disease, colitis or rheumatoid arthritis.  
     
     
         5 . The method of  claim 1 , wherein said oligonucleotide comprises at least one modified intersugar linkage.  
     
     
         6 . The method of  claim 4 , wherein said intersugar linkage is a phosphorothioate linkage.  
     
     
         7 . The method of  claim 1 , wherein said oligonucleotide comprises at least one 2′-O-methoxyethyl modification.  
     
     
         8 . The method of  claim 1 , wherein said oligonucleotide comprises at least one 5-methyl cytidine.  
     
     
         9 . The method of  claim 7 , wherein every 2′-O-methoxyethyl modified cytidine residue is a 5-methyl cytidine.  
     
     
         10 . The method of  claim 7 , wherein every cytidine residue is a 5-methyl cytidine.  
     
     
         11 . The method of  claim 1 , wherein said modified intersugar linkage is a methylene(methylimino) intersugar linkage.