Antisense nucleic acid that induces skipping of exon 50

Abstract

The present specification provides a drug that causes highly-efficient skipping of exon 50 in the human dystrophin gene. The present specification provides an antisense oligomer which induces skipping of exon 50 in the human dystrophin gene.

1 . An antisense oligomer which is selected from the group consisting of (a) to (d) below:
 (a) an antisense oligomer comprising a base sequence of any of SEQ ID NOs: 3 to 5;   (b) an antisense oligomer which comprises a base sequence having deletion, substitution, insertion and/or addition of 1 to 5 base(s) in the base sequence of any of SEQ ID NOs: 3 to 5, and has an activity to induce skipping of exon 50 in the human dystrophin gene;   (c) an antisense oligomer which comprises a base sequence having at least 80% sequence identity to a base sequence of any of SEQ ID NOs: 3 to 5 and has an activity to induce skipping of exon 50 in the human dystrophin gene; and   (d) an antisense oligomer that hybridizes under stringent conditions to an oligonucleotide consisting of a base sequence complementary to the base sequence of any of SEQ ID NOs: 3 to 5 and has an activity to induce skipping of exon 50 in the human dystrophin gene,   or a pharmaceutically acceptable salt or hydrate thereof.   
     
     
         2 . The antisense oligomer according to  claim 1 , wherein the antisense oligomer is selected from the group consisting of (e) to (h) below:
 (e) an antisense oligomer which consists of a base sequence of any of SEQ ID NOs: 3 to 5;   (f) an antisense oligomer which consists of a base sequence having deletion and/or substitution of 1 to 5 base(s) in the base sequence of any of SEQ ID NOs: 3 to 5, and has an activity to induce skipping of exon 50 in the human dystrophin gene;   (g) an antisense oligomer which consists of a base sequence having at least 80% sequence identity to a base sequence of any of SEQ ID NOs: 3 to 5 and has an activity to induce skipping of exon 50 in the human dystrophin gene; and   (h) an antisense oligomer that hybridizes under high stringent conditions to an oligonucleotide consisting of a base sequence complementary to the base sequence of any of SEQ ID NOs: 3 to 5 and has an activity to induce skipping of exon 50 in the human dystrophin gene,   or a pharmaceutically acceptable salt or hydrate thereof.   
     
     
         3 . The antisense oligomer or the pharmaceutically acceptable salt or hydrate thereof according to  claim 1 , wherein the antisense oligomer is an antisense oligomer that comprises a base sequence having at least 90% sequence identity to a base sequence of any of SEQ ID NOs: 3 to 5 and has an activity to induce skipping of exon 50 in the human dystrophin gene. 
     
     
         4 . The antisense oligomer or the pharmaceutically acceptable salt or hydrate thereof according to  claim 1 , wherein the antisense oligomer is an oligonucleotide. 
     
     
         5 . The antisense oligomer or the pharmaceutically acceptable salt or hydrate thereof according to  claim 4 , wherein the sugar moiety and/or the phosphate bond moiety of at least one nucleotide constituting the oligonucleotide are/is modified. 
     
     
         6 . The antisense oligomer or the pharmaceutically acceptable salt or hydrate thereof according to  claim 4 , 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 or the pharmaceutically acceptable salt or hydrate thereof according to  claim 4 , wherein the phosphate bond moiety 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 or the pharmaceutically acceptable salt or hydrate thereof according to  claim 1 , wherein the antisense oligomer is a morpholino oligomer. 
     
     
         9 . The antisense oligomer or the pharmaceutically acceptable salt or hydrate thereof according to  claim 8 , wherein the antisense oligomer is a phosphorodiamidate morpholino oligomer. 
     
     
         10 . The antisense oligomer or the pharmaceutically acceptable salt or hydrate thereof according to  claim 8 , wherein the 5′ end is any one of chemical formulae (1) to (3) below: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The antisense oligomer or the pharmaceutically acceptable salt or hydrate thereof according to  claim 1 , wherein the length of the antisense oligomer is 19 or 20 bases. 
     
     
         12 . A pharmaceutical composition for the treatment of muscular dystrophy, comprising the antisense oligomer or the pharmaceutically acceptable salt or hydrate thereof according to  claim 1 . 
     
     
         13 . The pharmaceutical composition according to  claim 12 , further comprising a pharmaceutically acceptable carrier. 
     
     
         14 - 18 . (canceled) 
     
     
         19 . A method for treatment of muscular dystrophy, which comprises administering to a patient with muscular dystrophy an effective amount of the antisense oligomer or the pharmaceutically acceptable salt or hydrate thereof according to  claim 1 , or a pharmaceutical composition according to comprising the antisense oligomer or the pharmaceutically acceptable salt or hydrate thereof according to  claim 1 . 
     
     
         20 . The method for treatment according to  claim 19 , wherein the patient is a human. 
     
     
         21 - 22 . (canceled) 
     
     
         23 . The method for treatment according to  claim 19 , wherein the patient has a mutation that is amenable to exon 50 skipping in the dystrophin gene. 
     
     
         24 . The method for treatment according to  claim 19 , wherein the patient has the dystrophin gene that has at least a frameshift mutation caused by a deletion of an exon in the vicinity of exon 50 and in which the amino acid reading frame is corrected by exon 50 skipping. 
     
     
         25 . The method for treatment according to  claim 19 , wherein the patient has a frameshift mutation caused by a deletion of exon 51, a deletion of exons 51-53, a deletion of exons 51-55, or a deletion of exons 51-57 in the dystrophin gene.