Antisense nucleic acid that induces skipping of exon 50

Patent metadata

Field	Value
Publication number	US-2022333112-A1
Application number	US-202217847333-A
Country	US
Kind code	A1
Filing date	Jun 23, 2022
Priority date	Dec 26, 2019
Publication date	Oct 20, 2022
Grant date	—

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.

First claim

1 . An antisense oligomer selected from the group consisting of (a) to (f) below:
(a) an antisense oligomer comprising the 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 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; (d) an antisense oligomer which consists of the base sequence of any of SEQ ID NOs: 3 to 5; (e) 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; and (f) an antisense oligomer which consists of a base sequence having at least 80% sequence identity 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, wherein the antisense oligomer is (i) a morpholino oligomer or (ii) an oligonucleotide comprising at least one nucleotide having a modified sugar moiety or a modified phosphate bond moiety.

2 . (canceled)

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 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.

4 . (canceled)

5 . The antisense oligomer or the pharmaceutically acceptable salt or hydrate thereof according to claim 1 , wherein the antisense oligomer is the oligonucleotide comprising at least one nucleotide having a modified sugar moiety or a modified phosphate bond moiety.

6 . The antisense oligomer or the pharmaceutically acceptable salt or hydrate thereof according to claim 5 , 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).

7 . The antisense oligomer or the pharmaceutically acceptable salt or hydrate thereof according to claim 5 , wherein the modified phosphate bond moiety 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 the 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 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 carries a mutation in the dystrophin gene to be converted to in-frame by exon 50 skipping.

24 . The method for treatment according to claim 23 , wherein the mutation is a frameshift mutation caused by a deletion of an exon in the vicinity of exon 50 of the dystrophin gene.

25 . The method for treatment according to claim 24 , wherein the frameshift mutation is 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.

Assignees

• Nippon Shinyaku Co Ltd
• Nat Center Neurology & Psychiatry

Inventors

• Enya Yukiko
• SUNADOI Yuta
• Waki Reiko
• MUCHIMA Kaname
• Takeda Shin'Ichi
• Aoki Yoshitsugu

Classifications

• C12N2310/11

  Antisense · CPC title

• C12N2320/33

  Alteration of splicing · CPC title

• C12N15/113 Primary

  Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)} · CPC title

• C12N2310/3233

  Morpholino-type ring · CPC title

• C12N2310/3145

  with the nitrogen in 3' or 5'-position · CPC title