Antisense nucleic acid that induces skipping of exon 50

Patent metadata

Field	Value
Publication number	US-2023073008-A1
Application number	US-202017788826-A
Country	US
Kind code	A1
Filing date	Dec 25, 2020
Priority date	Dec 26, 2019
Publication date	Mar 9, 2023
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 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.

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

• C12N2310/3145

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

• C12N2310/3233

  Morpholino-type ring · CPC title

• C12N2310/321

  2'-O-R Modification · CPC title