ANTISENSE NUCLEIC ACIDS

• US 20180265866A1
• Filed: 09/15/2016
• Published: 09/20/2018
• Est. Priority Date: 09/15/2015
• 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: ENYA, Yukiko, TONE, Yuichiro, TAKEDA, Shin'ichi, AOKI, Yoshitsugu
• Granted Patent: US 10,144,931 B2
• Time in Patent Office: Days
• 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 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: C07H 21/04 with deoxyribosyl as saccharide radical
• 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 2310/313 Phosphorodithioates
• CPC Class Codes: C12N 2310/314 Phosphoramidates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/3233 Morpholino-type ring

Abstract

The present invention provides an oligomer which allows exon 45 skipping in the human dystrophin gene.

Claims

1-21. -21. (canceled)

22. An antisense oligomer consisting of a nucleotide sequence selected from the group consisting of SEQ ID NOs:

25, 30, 33, 79, and 80, 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 phosphorothioate bond, an alkylphosphonate bond, a phosphoramidate bond, and a boranophosphate bond.

23. The antisense oligomer, or pharmaceutically acceptable salt or hydrate thereof according to claim 22, wherein the antisense oligomer consists of the nucleotide sequence of SEQ ID NO:

25.

24. The antisense oligomer, or pharmaceutically acceptable salt or hydrate thereof according to claim 22, wherein the antisense oligomer consists of the nucleotide sequence of SEQ ID NO:

30.

25. The antisense oligomer, or pharmaceutically acceptable salt or hydrate thereof according to claim 22, wherein the antisense oligomer consists of the nucleotide sequence of SEQ ID NO:

33.

26. The antisense oligomer, or pharmaceutically acceptable salt or hydrate thereof according to claim 22, wherein the antisense oligomer consists of the nucleotide sequence of SEQ ID NO:

79.

27. The antisense oligomer, or pharmaceutically acceptable salt or hydrate thereof according to claim 22, wherein the antisense oligomer consists of the nucleotide sequence of SEQ ID NO:

80.

28. The antisense oligomer, or pharmaceutically acceptable salt or hydrate thereof according to claim 22, which is a phosphorodiamidate morpholino oligomer, or pharmaceutically acceptable salt or hydrate thereof.

29. The antisense oligomer, or pharmaceutically acceptable salt or hydrate thereof according to claim 22, wherein the antisense oligomer is a morpholino oligomer or phosphorodiamidate morpholino oligomer, and wherein the 5′

-terminal end of the antisense oligomer is any one of the groups represented by chemical formulae (1) to (3) shown below, or pharmaceutically acceptable salt or hydrate thereof,

30. A pharmaceutical composition for treatment of muscular dystrophy, which comprises an antisense oligomer consisting of any one nucleotide sequence selected from the group consisting of SEQ ID NOs:

25, 30, 33, 79, and 80, or pharmaceutically acceptable salt or hydrate thereof as an active ingredient.

31. The pharmaceutical composition according to claim 30, further comprising a pharmaceutically acceptable carrier.

35. A method for treating muscular dystrophy, comprising the step of administering a muscular dystrophy patient with the pharmaceutical composition according to claim 30.

36. The method for treating muscular dystrophy according to claim 35, wherein the muscular dystrophy patient has a mutation to be targeted by exon 45 skipping in the dystrophin gene.

37. The method for treating muscular dystrophy according to claim 35, wherein the muscular dystrophy patient is a human patient.

38. A method for treating muscular dystrophy, comprising the step of administering a muscular dystrophy patient with the pharmaceutical composition according to claim 31.

39. The method for treating muscular dystrophy according to claim 38, wherein the muscular dystrophy patient has a mutation to be targeted by exon 45 skipping in the dystrophin gene.

40. The method for treating muscular dystrophy according to claim 38, wherein the muscular dystrophy patient is a human patient.

32. A method for treating muscular dystrophy, comprising the step of administering a muscular dystrophy patient with an antisense oligomer consisting of a nucleotide sequence selected from the group consisting of SEQ ID NOs:

25, 30, 33, 79, and 80, or pharmaceutically acceptable salt or hydrate thereof.

33. The method for treating muscular dystrophy according to claim 32, wherein the muscular dystrophy patient has a mutation to be targeted by exon 45 skipping in the dystrophin gene.

34. The method for treating muscular dystrophy according to claim 32, wherein the muscular dystrophy patient is a human patient.