ANTISENSE NUCLEIC ACIDS
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.