Antisense oligonucleotides (odn) against smad7 and uses thereof in medical field

Abstract

The invention relates to antisense oligonucleotidic sequences (ODN) against Smad7 suitably modified, and their uses in medical field as therapeutic biological agents, in particular in the treatment of chronic inflammatory bowel disease, such as Crohn's disease and ulcerative colitis.

1 . An antisense oligonucleotide phosphorothioate against Smad7 up to 21 nucleotides in length which comprise a portion of at least 10 nucleotides of the following sequence (SEQ ID No 2): 
       
         
           
                 
                 
               
                     
                   5′-GTXYCCCCTTCTCCCXYCAG-3′ 
                 
             
                
               
            
           
         
         wherein X is a nucleotide comprising a nitrogenous base selected from the group consisting of cytosine, 5-methylcytosine and 2′-O-methylcytosine and wherein Y is a nucleotide comprising a nitrogenous base selected from the group consisting of guanine, 5-methylguanine e 2′-O-methylguanine, provided that at least one of the nucleotides X or Y comprises a methylated nitrogenous base; or the complementary sequence thereto. 
       
     
     
         2 . Antisense oligonucleotide according to  claim 1 , wherein at least one nucleotide of the sequence is methylphosphonate. 
     
     
         3 . Antisense oligonucleotide according to  claim 2 , wherein said at least one methylphosphonate nucleotide is placed either at only one of the 3′ or 5′ ends or at both 3′ and 5′ ends or along the antisense oligonucleotidic sequence. 
     
     
         4 . Antisense oligonucleotide according to  claim 2 , wherein the methylphosphonate nucleotide is Y. 
     
     
         5 . Antisense oligonucleotide according to  claim 2 , wherein the methylphosphonate nucleotide is X. 
     
     
         6 . Antisense oligonucleotide according to  claim 1 , wherein at least one nucleotide of the sequence is a 2′-O-methylribonucleotide 5′-monophosphate. 
     
     
         7 . Antisense oligonucleotide according to  claim 6 , wherein said at least one 2′-O-methylribonucleotide 5′-monophosphate is placed at only one of the 3′ or 5′ ends or at both 3′ and 5′ ends or along the oligonucleotidic sequence. 
     
     
         8 . Antisense oligonucleotide according to  claim 1 , wherein 2′-deoxyribonucleotides are replaced by the corresponding ribonucleotides. 
     
     
         9 . Antisense oligonucleotide according  claim 1 , wherein said oligonucleotides comprise (SEQ ID No 4): 
       
         
           
                 
                 
               
                     
                   5′-ZTXGCCCCTTCTCCCXGCAZ-3′ 
                 
             
                
               
            
           
         
         wherein X is 5-methyl 2′-deoxycitidine 5′-monophosphate and Z is 2′-deoxyguanosine methylphosphonate. 
       
     
     
         10 . Antisense oligonucleotide according  claim 1 , wherein said oligonucleotides comprise (SEQ ID No 15): 
       
         
           
                 
                 
               
                     
                   5′-ZTXGCCCCTTCTCCCXGCAZC-3′ 
                 
             
                
               
            
           
         
         wherein X is 5-methyl 2′-deoxycytidine 5′-monophosphate and Z is 2′-deoxyguanosine methylphosphonate. 
       
     
     
         11 . Antisense oligonucleotide according to  claim 1  having sequence (SEQ ID No 3): 
       
         
           
                 
                 
               
                     
                   5′-GTXGCCCCTTCTCCCXGCAG-3′ 
                 
             
                
               
            
           
         
         wherein X is 5-methyl 2′-deoxycytidine 5′-monophosphate. 
       
     
     
         12 . Antisense oligonucleotide according to  claim 11  further having a cytosine nucleotide at 3′ end (SEQ ID No 16). 
     
     
         13 . A Pharmaceutical composition comprising at least one of the antisense oligonucleotides as according to  claim 1  and one or more pharmaceutically acceptable adjuvants and/or excipients. 
     
     
         14 . A method for the treatment of pathologies associated with Smad7 expression, comprising administering an effective amount of an oligonucleotide according to  claim 1  to a subject in need thereof. 
     
     
         15 . The method according to  claim 14 , wherein the subject has a chronic inflammatory disease. 
     
     
         16 . The method according to  claim 15 , wherein the subject has Crohn's disease or ulcerative colitis.