Antisense nucleic acids

• US 9,708,361 B2
• Filed: 02/06/2015
• Issued: 07/18/2017
• Est. Priority Date: 09/01/2010
• 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, Takeda, Shin'ichi, Satou, Youhei, Nagata, Tetsuya
• Primary Examiner(s): McGarry, Sean
• Application Number:
  US14/615,504
• Publication Number:
  US 20150166995A1
• Time in Patent Office: 893 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 which causes skipping of the 53rd exon in the human dystrophin gene, consisting of the nucleotide sequence of SEQ ID NO:

57, wherein the antisense oligomer is an oligonucleotide in which the sugar moiety and/or the phosphate-binding region of at least one nucleotide constituting the oligonucleotide is modified, or a morpholino oligomer.

2. 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.

3. 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.

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

5. The antisense oligomer according to claim 4, which is a phosphorodiamidate morpholino oligomer.

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

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

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.