Methods and compositions for treating a subject with a smad7 antisense oligonucleotide

Abstract

The present invention relates to treatment of inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis) using antisense nucleotides that are directed against polymorphic forms (e.g., those containing single nucleotide polymorphisms) of the SMAD7 mRNA. The invention thus relates to treatment methods for subjects having polymorphic forms of SMAD7 and antisense oligonucleotides that specifically target SMAD7 mRNA transcripts containing polymorphisms.

1 - 12 . (canceled) 
     
     
         13 . A method of treating or managing inflammatory bowel disease (IBD) in a patient having IBD that carries at least one copy of a first polymorphic form of SMAD7 that differs from the consensus SMAD7 nucleotide sequence, wherein the method comprises administering to said patient an effective amount of a first SMAD7 antisense oligonucleotide that specifically targets said first polymorphic form of SMAD7. 
     
     
         14 . The method of  claim 13 , wherein the first polymorphic form includes a single nucleotide polymorphism. 
     
     
         15 . The method of  claim 13 , wherein the first polymorphic form includes a polymorphism listed in Table 1 or in Table 2. 
     
     
         16 . The method of  claim 13 , wherein the first polymorphic form includes a polymorphism in the region corresponding to nucleic acid positions 108-128 of SEQ ID NO:1. 
     
     
         17 . (canceled) 
     
     
         18 . The method of  claim 16 , wherein the first SMAD7 polymorphic form comprises the nucleic acid sequence of SEQ ID NO:9 (5′-GCTGCGGAGAGAAGGGGCGAC -3′). 
     
     
         19 . The method of  claim 18 , wherein the first SMAD7 antisense oligonucleotide comprises the nucleotide sequence of SEQ ID NO:11 (5′-GTCGCCCCTTCTCTCCGCAGC-3′), wherein at least one internucleotide linkage is a phosphorothioate linkage. 
     
     
         20 . The method of  claim 19 , wherein the first SMAD7 antisense oligonucleotide is an antisense oligonucleotide phosphorothioate comprising the following sequence: 5′-GTXGCCCCTTCTCTCXGCAGC-3′ (SEQ ID NO:13) wherein X is a nucleotide comprising 5-methyl-2′-deoxycytidine and wherein all internucleotide linkages are phosphorothioate linkages. 
     
     
         21 - 36 . (canceled) 
     
     
         37 . The method of  claim 13 , wherein the IBD is Crohn's Disease (CD) or ulcerative colitis (UC). 
     
     
         38 . The method of  claim 13 , wherein the first SMAD7 antisense oligonucleotide is administered to the patient having IBD at a dose of between 10 mg/day to about 300 mg/day. 
     
     
         39 . The method of  claim 38 , wherein the first SMAD7 antisense oligonucleotide is administered at a dose of about 10 mg/day, 20 mg/day, about 30 mg/day, about 40 mg/day, about 50 mg/day, about 60 mg/day, about 70 mg/day, about 80 mg/day, about 90 mg/day, about 100 mg/day, about 110 mg/day, about 120 mg/day, about 130 mg/day, about 140 mg/day, about 150 mg/day, about 160 mg/day, about 170 mg/day, about 180 mg/day, about 190 mg/day, about 200 mg/day, about 210 mg/day, about 220 mg/day, about 230 mg/day, about 240 mg/day, about 250 mg/day, about 260 mg/day, about 270 mg/day, about 280 mg/day, about 290 mg/day, or about 300 mg/day. 
     
     
         40 . The method of  claim 39 , wherein the first SMAD7 antisense oligonucleotide is administered at a dose of about 40 mg/day, about 80 mg/day, or about 160 mg/day. 
     
     
         41 . The method of  claim 19 , wherein the first SMAD7 antisense oligonucleotide comprises the nucleotide sequence of SEQ ID NO:11 (5′-GTCGCCCCTTCTCTCCGCAGC-3′), wherein all of the internucleotide linkages are phosphorothioate linkages. 
     
     
         42 . The method of  claim 19 , wherein the 2′-deoxyribonucleotides are replaced by corresponding ribonucleotides. 
     
     
         43 . The method of  claim 20 , wherein the 2′-deoxyribonucleotides are replaced by corresponding ribonucleotides. 
     
     
         44 . The method of  claim 13 , wherein the first SMAD7 antisense oligonucleotide is administered in the form of a pharmaceutical composition comprising the first SMAD7 antisense oligonucleotide and a pharmaceutically acceptable adjuvant and/or excipient. 
     
     
         45 . The method of  claim 44 , wherein the pharmaceutical composition is formulated for oral administration. 
     
     
         46 . The method of  claim 44 , wherein the pharmaceutical composition is formulated for parenteral administration. 
     
     
         47 . The method of  claim 46 , wherein the parenteral administration is selected from the group consisting of: intravenous administration, intramuscular administration, subcutaneous administration, intralesional administration, and intraperitoneal administration.