Antisense nucleic acids

Abstract

The present invention provides an oligomer which efficiently enables to cause skipping of the 53rd exon in the human dystrophin gene. Also provided is a pharmaceutical composition which causes skipping of the 53rd exon in the human dystrophin gene with a high efficiency.

1 . An antisense oligomer which causes skipping of the 53rd exon in the human dystrophin gene, consisting of a nucleotide sequence complementary to any one of the sequences consisting of the 31st to the 53rd, the 31st to the 54th, the 31st to the 55th, the 31st to the 56th, the 31st to the 57th, the 31st to the 58th, the 32nd to the 53rd, the 32nd to the 54th, the 32nd to the 55th, the 32nd to the 56th, the 32nd to the 57th, the 32nd to the 58th, the 33rd to the 53rd, the 33rd to the 54th, the 33rd to the 55th, the 33rd to the 56th, the 33rd to the 57th, the 33rd to the 58th, the 34th to the 53rd, the 34th to the 54th, the 34th to the 55th, the 34th to the 56th, the 34th to the 57th, the 34th to the 58th, the 35th to the 53rd, the 35th to the 54th, the 35th to the 55th, the 35th to the 56th, the 35th to the 57th, the 35th to the 58th, the 36th to the 53rd, the 36th to the 54th, the 36th to the 55th, the 36th to the 56th, the 36th to the 57th, or the 36th to the 58th nucleotides, from the 5′ end of the 53rd exon in the human dystrophin gene. 
     
     
         2 . The antisense oligomer according to  claim 1 , which is an oligonucleotide. 
     
     
         3 . The antisense oligomer according to  claim 2 , wherein the sugar moiety and/or the phosphate-binding region of at least one nucleotide constituting the oligonucleotide is modified. 
     
     
         4 . The antisense oligomer according to  claim 3 , wherein the sugar moiety of at least one nucleotide constituting the oligonucleotide is a ribose in which the 2′—OH group is replaced by any one selected from the group consisting of OR, R, R′OR, SH, SR, NH 2 , NHR, NR 2 , N 3 , CN, F, Cl, Br and I (wherein R is an alkyl or an aryl and R′ is an alkylene). 
     
     
         5 . The antisense oligomer according to  claim 3  or  4 , wherein the phosphate-binding region of at least one nucleotide constituting the oligonucleotide is any one selected from the group consisting of a phosphorothioate bond, a phosphorodithioate bond, an alkylphosphonate bond, a phosphoramidate bond and a boranophosphate bond. 
     
     
         6 . The antisense oligomer according to  claim 1 , which is a morpholino oligomer. 
     
     
         7 . The antisense oligomer according to  claim 6 , which is a phosphorodiamidate morpholino oligomer. 
     
     
         8 . The antisense oligomer according to  claim 6  or  7 , wherein the 5′ end is any one of the groups of chemical formulae (1) to (3) below: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The antisense oligomer according to any one of  claims 1  to  8 , consisting of a nucleotide sequence complementary to the sequences consisting of the 32nd to the 56th or the 36th to the 56th nucleotides from the 5 end of the 53rd exon in the human dystrophin gene. 
     
     
         10 . The antisense oligomer according to any one of  claims 1  to  8 , consisting of the nucleotide sequence shown by any one selected from the group consisting of SEQ ID NOS: 2 to 37. 
     
     
         11 . The antisense oligomer according to any one of  claims 1  to  8 , consisting of the nucleotide sequence shown by any one selected from the group consisting of SEQ ID NOS: 11, 17, 23, 29 and 35. 
     
     
         12 . The antisense oligomer according to any one of  claims 1  to  8 , consisting of the nucleotide sequence shown by SEQ ID NO: 11 or 35. 
     
     
         13 . A pharmaceutical composition for the treatment of muscular dystrophy, comprising as an active ingredient the antisense oligomer according to any one of  claims 1  to  12 , or a pharmaceutically acceptable salt or hydrate thereof.