ANTISENSE NUCLEIC ACIDS

• US 20150166995A1
• Filed: 02/06/2015
• Published: 06/18/2015
• 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: NAGATA, Tetsuya, WATANABE, Naoki, SATOU, Youhei, TAKEDA, Shin'ichi
• Granted Patent: US 9,708,361 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• 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 a pharmaceutical composition which causes skipping of the 53rd exon in the human dystrophin gene with a high efficiency.

The present invention provides an oligomer which efficiently enables to cause skipping of the 53rd exon in the human dystrophin gene.

Claims

1. An antisense oligomer which causes skipping of the 53rd exon in the human dystrophin gene, consisting of a nucleotide sequence complementary to any one of the sequences consisting of:

the 31st to the 55th, the 32nd to the 53rd, the 32nd to the 56th, the 32nd to the 61st, the 33rd to the 54th, the 33rd to the 57th, the 34th to the 58th, the 35th to the 59th, the 36th to the 53rd, the 36th to the 55th, the 36th to the 57^th, the 36th to the 60th, or the 37th to the 61st nucleotides from the 5′

end of the 53rd exon in the human dystrophin gene.

15. The antisense oligomer according to claim 1, which is an oligonucleotide.

16. The antisense oligomer according to claim 15, wherein the sugar moiety and/or the phosphate-binding region of at least one nucleotide constituting the oligonucleotide is modified.

17. The antisense oligomer according to claim 16, 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.

18. The antisense oligomer according to claim 16, 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.

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

20. The antisense oligomer according to claim 19, which is a phosphorodiamidate morpholino oligomer.

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

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

22. The antisense oligomer according to claim 1, consisting of a nucleotide sequence complementary to the sequences consisting of the 32nd to the 56th nucleotides from the 5′

end of the 53rd exon in the human dystrophin gene.

23. The antisense oligomer according to claim 1, consisting of the nucleotide sequence shown by any one selected from the group consisting of SEQ ID NOS:

4, 8, 11, 15, 18, 25, 32, 34, 36, 57, 103, 104, 105, and 109.

24. The antisense oligomer according to claim 1, consisting of the nucleotide sequence shown by SEQ ID NO:

11.

25. 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.

2-14. -14. (canceled)