Antisense nucleic acids
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. 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 a base sequence selected from the group consisting of 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, and the 156th to the 175th nucleotides of SEQ ID NO: 5, and wherein the antisense oligomer is a morpholino oligomer or a peptide nucleic acid (PNA).
2. The antisense oligomer according to claim 1 , which is a morpholino oligomer.
3. The antisense oligomer according to claim 2 , which is a phosphorodiamidate morpholino oligomer.
4. The antisense oligomer according to claim 2 , wherein the 5′ end is any one of the groups of chemical formulae (1) to (3) below:
5. A pharmaceutical composition for the treatment of muscular dystrophy, comprising as an active ingredient the antisense oligomer according to claim 1 , or a pharmaceutically acceptable salt or hydrate thereof.
6. A method of treating muscular dystrophy, comprising administering to a patient in need thereof a therapeutically effective amount of the antisense oligomer according to claim 1 .
7. A method of treating muscular dystrophy, comprising administering to a patient in need thereof a therapeutically effective amount of pharmaceutical composition of claim 5 .
8. An antisense oligonucleotide which causes skipping of the 55th exon in a human dystrophin gene, wherein the base sequence of the antisense oligonucleotide consists of a base sequence selected from the group consisting of 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, and the 156th to the 175th nucleotides of SEQ ID NO: 5, wherein the antisense oligonucleotide consists of modified nucleotides, and wherein each modified nucleotide comprises a modified sugar moiety and/or a modified phosphate-binding region.
9. The antisense oligonucleotide according to claim 8 , 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).
10. The antisense oligonucleotide according to claim 8 , 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.
11. A pharmaceutical composition for the treatment of muscular dystrophy, comprising as an active ingredient the antisense oligonucleotide according to claim 8 , or a pharmaceutically acceptable salt or hydrate thereof.
12. A method of treating muscular dystrophy, comprising administering to a patient in need thereof a therapeutically effective amount of the antisense oligonucleotide according to claim 8 .
13. A method of treating muscular dystrophy, comprising administering to a patient in need thereof a therapeutically effective amount of pharmaceutical composition of claim 11 .