ANTISENSE NUCLEIC ACIDS

• US 20170067052A1
• Filed: 10/31/2016
• Published: 03/09/2017
• Est. Priority Date: 12/28/2011
• 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: WATANABE, Naoki, SEO, Haruna, TAKEDA, Shin'ichi, NAGATA, Tetsuya
• Granted Patent: US 9,890,381 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• 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: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 2320/33 Alteration of splicing

Abstract

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.

Claims

1. An antisense oligomer which causes skipping of the 55th exon in the human dystrophin gene, consisting of a nucleotide sequence complementary to any one of the nucleotide sequences consisting of the 14th to the 34th or the 15th to the 34th nucleotides, from the 5′

end of the 55th exon in the human dystrophin gene, wherein the antisense oligomer is a morpholino oligomer, or an oligonucleotide which 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 1, consisting of the nucleotide sequence shown by any one selected from the group consisting of the 157th to the 177th and the 157th to the 176th nucleotides of SEQ ID NO:

5.

15. The antisense oligomer according to claim 1, 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).

16. The antisense oligomer according to claim 1, 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.

17. The antisense oligomer according to claim 1, which is a morpholino oligomer.

18. The antisense oligomer according to claim 17, which is a phosphorodiamidate morpholino oligomer.

19. The antisense oligomer according to claim 17, wherein the 5′

end of the morpholino oligomer is any one of the groups of chemical formulae (1) to (3) below;

20. 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.

21. 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.

22. A method of treating muscular dystrophy, comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 20.

2-5. -5. (canceled)

7-14. -14. (canceled)