Antisense nucleic acids

• US 9,840,706 B2
• Filed: 06/16/2015
• Issued: 12/12/2017
• Est. Priority Date: 06/17/2014
• 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: Watanabe, Naoki, Tone, Yuuichirou, Takeda, Shin'ichi, Nagata, Tetsuya
• Primary Examiner(s): Gibbs, Terra C
• Application Number:
  US15/314,535
• Publication Number:
  US 20170204410A1
• Time in Patent Office: 910 Days
• Field of Search: 536 231, 536 245, 514 44
• CPC Class Codes: A61K 31/712 Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
• CPC Class Codes: A61K 31/7125 Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• 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 2310/3233 Morpholino-type ring
• CPC Class Codes: C12N 2320/10 in screening processes
• CPC Class Codes: C12N 2320/33 Alteration of splicing
• CPC Class Codes: C12N 2330/30 chemically synthesised
• CPC Class Codes: C12Q 1/6876 Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
• CPC Class Codes: C12Q 2600/136 Screening for pharmacological compounds
• CPC Class Codes: C12Q 2600/178 miRNA, siRNA or ncRNA

Abstract

Provided is a drug that allows highly-efficient skipping of exon. The present invention provides an antisense oligomer wherein two or more unit oligomers targeting sequences that are neither consecutive nor overlap with each other in the same exon are connected.

Claims

1. An antisense oligomer consisting of the nucleotide sequence of SEQ ID NO:

6, 7, 8, or 9, or a pharmaceutically acceptable salt or hydrate thereof, wherein the antisense oligomer induces skipping of exon 44 of a human dystrophin gene, and wherein the antisense oligomer is (i) an oligonucleotide comprising at least one nucleotide having the sugar moiety and/or the phosphate-binding region modified, or (ii) a morpholino oligomer.

2. The antisense oligomer according to claim 1, 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, NH₂, NHR, NR₂, N₃, CN, F, Cl, Br and I (wherein R is an alkyl or an aryl and R′

is an alkylene), or a pharmaceutically acceptable salt or hydrate thereof.

3. The antisense oligomer according to claim 1, wherein the modified phosphate-binding region 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, or a pharmaceutically acceptable salt or hydrate thereof.

4. The antisense oligomer according to claim 1, which is a morpholino oligomer, or a pharmaceutically acceptable salt or hydrate thereof.

5. The antisense oligomer according to claim 4, which is a phosphorodiamidate morpholino oligomer, or a pharmaceutically acceptable salt or hydrate thereof.

6. The antisense oligomer according to claim 4, wherein the 5′

end is any one of chemical formulae (1) to (3) below, or a pharmaceutically acceptable salt or hydrate thereof.

7. 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.

8. The pharmaceutical composition according to claim 7, further comprising a pharmaceutically acceptable carrier.

9. 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 or 2-6.

10. The method for treatment according to claim 9, wherein the patient with muscular dystrophy has a mutation(s) which is to be targeted for exon 44 skipping in dystrophin gene.

11. The method for treatment according to claim 9, wherein the patient is a human.

12. A method for treatment of muscular dystrophy, which comprises administering to a patient with muscular dystrophy the pharmaceutical composition of claim 7 or claim 8.