Antisense nucleic acids

Abstract

Provided is a drug that allows highly-efficient skipping of exon 51 in the human dystrophin gene. The present invention provides an antisense oligomer which enables exon 51 in the human dystrophin gene to be skipped.

1 . An antisense oligomer which is selected from a group consisting of (a) to (c) below, or a pharmaceutically acceptable salt or hydrate thereof:
 (a) an antisense oligomer comprising a nucleotide sequence of SEQ ID NO: 1 or 2;   (b) an antisense oligomer which consists of a nucleotide sequence having deletion, substitution, insertion and/or addition of 1 to 5 nucleotides in the nucleotide sequence of SEQ ID NO: 1 or 2, and has an activity to cause skipping of the 51st exon in the human dystrophin gene; and   (c) the antisense oligomer which has a nucleotide sequence having at least 80% identity with a nucleotide sequence of SEQ ID NO: 1 or 2 and has an activity to cause skipping of the 51st exon in the human dystrophin gene.   
     
     
         2 . An antisense oligomer which is selected from a group consisting of (e) to (h) below, or a pharmaceutically acceptable salt or hydrate thereof:
 (e) an antisense oligomer which consists of a nucleotide sequence of SEQ ID NO: 1 or 2;   (f) an antisense oligomer which consists of a nucleotide sequence having deletion, substitution, insertion and/or addition of 1 to 3 nucleotides in the nucleotide sequence of SEQ ID NO: 1 or 2, and has an activity to cause skipping of the 51st exon in the human dystrophin gene;   (g) an antisense oligomer which consists of a nucleotide sequence having at least 80% identity with a nucleotide sequence of SEQ ID NO: 1 or 2 and has an activity to cause skipping of the 51st exon in the human dystrophin gene; and   (h) an antisense oligomer that hybridizes under high stringent conditions to an oligonucleotide consisting of a nucleotide sequence complementary to a nucleotide sequence of SEQ ID NO: 1 or 2 and has an activity to cause skipping of the 51st exon in the human dystrophin gene.   
     
     
         3 . An antisense oligomer which is selected from a group consisting of (i) and (j) below, or a pharmaceutically acceptable salt or hydrate thereof:
 (i) an antisense oligomer which consists of a nucleotide sequence of SEQ ID NO: 1 or 2; and   (j) an antisense oligomer which has a nucleotide sequence having at least 90% identity with a nucleotide sequence of SEQ ID NO: 1 or 2 and has an activity to cause skipping of the 51st exon in the human dystrophin gene.   
     
     
         4 . The antisense oligomer according to  claim 1 , which is an oligonucleotide, or a pharmaceutically acceptable salt or hydrate thereof. 
     
     
         5 . The antisense oligomer according to  claim 4 , or a pharmaceutically acceptable salt or hydrate thereof, wherein the sugar moiety and/or the phosphate-binding region of at least one nucleotide constituting the oligonucleotide is modified. 
     
     
         6 . The antisense oligomer according to  claim 4 , or a pharmaceutically acceptable salt or hydrate thereof, 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). 
     
     
         7 . The antisense oligomer according to  claim 4 , or a pharmaceutically acceptable salt or hydrate thereof, 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. 
     
     
         8 . The antisense oligomer according to  claim 1 , which is a morpholino oligomer, or a pharmaceutically acceptable salt or hydrate thereof. 
     
     
         9 - 10 . (canceled) 
     
     
         11 . The antisense oligomer according to  claim 8 , which is a phosphorodiamidate morpholino oligomer, or a pharmaceutically acceptable salt or hydrate thereof. 
     
     
         12 . The antisense oligomer according to  claim 8 , or a pharmaceutically acceptable salt or hydrate thereof, wherein the 5′ end is any one of chemical formulae (1) to (3) below: 
       
         
           
           
               
               
           
         
       
     
     
         13 . A pharmaceutical composition for the treatment of muscular dystrophy, comprising as an active ingredient the antisense oligomer, or a pharmaceutically acceptable salt or hydrate thereof according to  claim 1 . 
     
     
         14 . The pharmaceutical composition according to  claim 13 , comprising a pharmaceutically acceptable carrier. 
     
     
         15 . A method for treatment of muscular dystrophy, which comprises administering to a patient with muscular dystrophy the antisense oligomer, or a pharmaceutically acceptable salt or hydrate thereof according to  claim 1 . 
     
     
         16 . The method for treatment according to  claim 15 , wherein the patient with muscular dystrophy is a patient with deletions of nucleotides within exons 29-50, 50, 45-50, 48-50, 49-50, 52, 52-63, 13-50, 19-50, 43-50 or 47-50. 
     
     
         17 . The method for treatment according to  claim 15 , wherein the patient is a human. 
     
     
         18 . The use of the antisense oligomer, or a pharmaceutically acceptable salt or hydrate thereof according to  claim 1  in manufacturing of the pharmaceutical composition for the treatment of muscular dystrophy. 
     
     
         19 . The antisense oligomer, or a pharmaceutically acceptable salt or hydrate thereof according to  claim 1 , for use in the treatment of muscular dystrophy. 
     
     
         20 . The antisense oligomer, or a pharmaceutically acceptable salt or hydrate thereof according to  claim 19 , wherein the patient with muscular dystrophy in the said treatment is a patient with deletions of nucleotides within exons 29-50, 50, 45-50, 48-50, 49-50, 52, 52-63, 13-50, 19-50, 43-50 or 47-50. 
     
     
         21 . The antisense oligomer, or a pharmaceutically acceptable salt or hydrate thereof according to claim, wherein the patient is a human.