Antisense nucleic acids

• US 10,329,319 B2
• Filed: 06/12/2017
• Issued: 06/25/2019
• Est. Priority Date: 09/01/2010
• Status: Active Grant

• Current Assignee: National Center of Neurology and Psychiatry, Nippon Shinyaku Company Limited
• Original Assignee: Nippon Shinyaku Company Limited
• Inventors: Watanabe, Naoki, Satou, Youhei, Takeda, Shin'ichi, Nagata, Tetsuya
• Primary Examiner(s): McGarry, Sean
• Application Number:
  US15/619,996
• Publication Number:
  US 20170320903A1
• Time in Patent Office: 743 Days
• Field of Search: None
• 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: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: C07H 21/04 with deoxyribosyl as saccharide radical
• CPC Class Codes: C07K 14/4708 Duchenne dystrophy
• 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 2310/3145 with the nitrogen in 3' or 5'-position
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/3525 MOE, methoxyethoxy
• CPC Class Codes: C12N 2320/33 Alteration of splicing

Abstract

The present invention provides an oligomer which efficiently enables to cause skipping of the 53rd exon in the human dystrophin gene. Also provided is a pharmaceutical composition which causes skipping of the 53rd exon in the human dystrophin gene with a high efficiency.

Claims

1. An antisense oligomer consisting of any one nucleotide sequence selected from the group consisting of SEQ ID NOS:

8, 15, 32, 34, and 36, or pharmaceutically acceptable salt or hydrate thereof,

wherein the antisense oligomer is a morpholino oligomer, a peptide nucleic acid (PNA), or an oligonucleotide comprising at least one nucleotide having;

(i) a modified sugar moiety, wherein the 2′

—

OH group of a ribose is replaced by any one selected from the group consisting of 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

(ii) a modified phosphate-binding region selected from the group consisting of a phosphorothioate bond, a phosphorodithioate bond, an alkylphosphonate bond, a phosphoramidate bond, and a boranophosphate bond.

2. The antisense oligomer according to claim 1, or pharmaceutically acceptable salt or hydrate thereof, wherein the antisense oligomer is an oligonucleotide.

3. The antisense oligomer according to claim 1, or pharmaceutically acceptable salt or hydrate thereof, wherein the antisense oligomer is a morpholino oligomer.

4. The antisense oligomer according to claim 3, or pharmaceutically acceptable salt or hydrate thereof, wherein the antisense oligomer is a phosphorodiamidate morpholino oligomer.

5. The antisense oligomer according to claim 3, or pharmaceutically acceptable salt or hydrate thereof, wherein the 5′

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

6. 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.

7. The pharmaceutical composition for the treatment of muscular dystrophy of claim 6, which is administered for the treatment of Duchenne muscular dystrophy.