Antisense nucleic acids

Abstract

The present invention provides a pharmaceutical agent which causes skipping of the 55th, 45th, 50th or 44th exon in the human dystrophin gene with a high efficiency.The present invention provides an oligomer which efficiently enables to cause skipping of the 55th, 45th, 50th or 44th exon in the human dystrophin gene.

1 - 20 . (canceled) 
     
     
         21 . An antisense oligomer which causes skipping of the 50th exon in a human dystrophin gene, consisting of a nucleotide sequence complementary to any one of the nucleotide sequences consisting of the 106th to the 126th, the 107th to the 127th, the 108th to the 127th, the 108th to the 128th, or the 109th to the 129th nucleotides, from the 5′ end of the human dystrophin gene's 50th exon, wherein the 50th exon of the human dystrophin gene consists of position 1 to 109 of the nucleotide sequence SEQ ID NO: 3, and wherein the antisense oligomer is a morpholino oligomer, a peptide nucleic acid (PNA), or an oligonucleotide comprising at least one nucleotide having a modified sugar moiety and/or a modified phosphate-binding region. 
     
     
         22 . A pharmaceutical composition for the treatment of muscular dystrophy, comprising as an active ingredient the antisense oligomer of  claim 21 , or a pharmaceutically acceptable salt or hydrate thereof. 
     
     
         23 . A method of treating muscular dystrophy, comprising administering to a patient in need thereof a therapeutically effective amount of the antisense oligomer of  claim 21 . 
     
     
         24 . The method of  claim 23 , wherein the antisense oligomer consists of a complementary sequence to the nucleotide sequences consisting of the 106th to the 126th or the 107th to the 127th nucleotides, from the 5′ end of the human dystrophin gene's 50th exon. 
     
     
         25 . The method of  claim 23 , wherein the antisense oligomer consists of the nucleotide sequence selected from the group consisting of the 4th to the 24th and the 3rd to the 23rd nucleotides of SEQ ID NO: 7. 
     
     
         26 . The method of  claim 23 , wherein the antisense oligomer consists of a complementary sequence to the nucleotide sequences consisting of the 108th to the 127th, the 108th to the 128th, or the 109th to the 129th nucleotides, from the 5′ end of the human dystrophin gene's 50th exon. 
     
     
         27 . The method of  claim 23 , wherein the antisense oligomer consists of the nucleotide sequence selected from the group consisting of the 3rd to the 22nd, the 2nd to the 22nd, or the 1st to the 21st nucleotides of SEQ ID NO: 7. 
     
     
         28 . The method of  claim 23 , wherein the modified sugar moiety 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). 
     
     
         29 . The method of  claim 23 , wherein the modified phosphate-binding region 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. 
     
     
         30 . The method of  claim 23 , wherein the antisense oligomer is a morpholino oligomer. 
     
     
         31 . The method of  claim 30 , wherein the antisense oligomer is a phosphorodiamidate morpholino oligomer. 
     
     
         32 . The method of  claim 30 , wherein the 5′ end of the morpholino oligomer is any one of the groups of chemical formulae (1) to (3) below: 
       
         
           
           
               
               
           
         
       
     
     
         33 . The method of  claim 23 , wherein the antisense oligomer is a PNA. 
     
     
         34 . The method of  claim 23 , wherein the antisense oligomer is administered intravenously. 
     
     
         35 . A method of treating muscular dystrophy, comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of  claim 22 . 
     
     
         36 . The method of  claim 35 , wherein the pharmaceutical composition is administered intravenously. 
     
     
         37 . An antisense oligomer which causes skipping of the 55th exon in a human dystrophin gene, wherein the base sequence of the antisense oligomer consists of the base sequence of the 157th to the 177th, the 157th to the 176th, the 160th to the 181st, the 159th to the 181st, the 159th to the 180th, the 157th to the 178th, the 156th to the 178th, the 155th to the 178th, the 156th to the 177th, the 155th to the 177th, the 155th to the 176th, the 157th to the 175th, or the 156th to the 175th nucleotides of SEQ ID NO: 5, and wherein the antisense oligomer is a morpholino oligomer, a peptide nucleic acid (PNA), or an oligonucleotide comprising at one nucleotide having a modified sugar moiety and/or a modified phosphate-binding region. 
     
     
         38 . A pharmaceutical composition for the treatment of muscular dystrophy, comprising as an active ingredient the antisense oligomer of  claim 37 , or a pharmaceutically acceptable salt or hydrate thereof. 
     
     
         39 . A method of treating muscular dystrophy, comprising administering to a patient in need thereof a therapeutically effective amount of the antisense oligomer of  claim 37 . 
     
     
         40 . The method of  claim 39 , wherein the modified sugar moiety 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). 
     
     
         41 . The method of  claim 39 , wherein the modified phosphate-binding region 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. 
     
     
         42 . The method of  claim 39 , wherein the antisense oligomer is a morpholino oligomer. 
     
     
         43 . The method of  claim 42 , wherein the antisense oligomer is a phosphorodiamidate morpholino oligomer. 
     
     
         44 . The method of  claim 42 , wherein the 5′ end of the morpholino oligomer is any one of the groups of chemical formulae (1) to (3) below: 
       
         
           
           
               
               
           
         
       
     
     
         45 . The method of  claim 39 , wherein the antisense oligomer is a PNA. 
     
     
         46 . The method of  claim 39 , wherein the antisense oligomer is administered intravenously. 
     
     
         47 . A method of treating muscular dystrophy, comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of  claim 38 . 
     
     
         48 . The method of  claim 47 , wherein the pharmaceutical composition is administered intravenously.