ANTISENSE NUCLEIC ACIDS

• US 20170067048A1
• Filed: 03/11/2015
• Published: 03/09/2017
• Est. Priority Date: 03/12/2014
• Status: Active Grant

• Current Assignee: National Center of Neurology and Psychiatry, Nippon Shinyaku Company Limited
• Original Assignee: National Center of Neurology and Psychiatry, Nippon Shinyaku Company Limited
• Inventors: WAKAYAMA, Tatsushi, SATOU, Youhei, SEO, Haruna, TAKEDA, Shin'ichi, NAGATA, Tetsuya
• Granted Patent: US 9,988,629 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: C12N 15/111 General methods applicable to biologically active non-coding nucleic acids
• CPC Class Codes: C12N 15/113 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 Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/314 Phosphoramidates
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/322 2'-R Modification
• CPC Class Codes: C12N 2310/3233 Morpholino-type ring
• CPC Class Codes: C12N 2310/3521 Methyl
• CPC Class Codes: C12N 2310/3525 MOE, methoxyethoxy
• CPC Class Codes: C12N 2310/3533 Halogen
• CPC Class Codes: C12N 2310/3535 Nitrogen
• CPC Class Codes: C12N 2320/33 Alteration of splicing

Abstract

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.

Claims

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 51 st 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.

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, NH₂, NHR, NR₂, N₃, 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.

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 19, wherein the patient is a human.

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 51 st 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 51 st 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.

9-10. -10. (canceled)