ANTISENSE NUCLEIC ACIDS

• US 20190315796A1
• Filed: 06/24/2019
• Published: 10/17/2019
• 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
• Granted Patent: US 10,647,741 B2
• Time in Patent Office: Days
• 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

1-14. -14. (canceled)

15. A method comprising administering to a patient with DMD an antisense phosphorodiamidate morpholino oligomer (PMO) consisting of a 25-mer oligomer that is 100% complementary to the 36^th to the 60^th nucleotides from the 5′

end of the 53^rd exon in said human dystrophin pre-mRNA, wherein the 53^rd exon in said human dystrophin pre-mRNA consists of a nucleotide sequence corresponding to SEQ ID NO;

1, wherein said PMO hybridizes to said human dystrophin pre-mRNA with Watson-Crick base pairing, and wherein skipping of the 53^rd exon is induced in said patient.

16. The method according to claim 15, wherein each phosphorodiamidate morpholino monomer of said PMO has the formula:

17. The method according to claim 16, wherein the 5′

end of said PMO has a formula selected from the group consisting of;

18. A method of inducing exon 53 skipping in a patient with DMD comprising administering to said patient an antisense phosphorodiamidate morpholino oligomer (PMO) consisting of a 25-mer oligomer that is 100% complementary to the 36^th to the 60^th nucleotides from the 5′

end of the 53^rd exon in said human dystrophin pre-mRNA, wherein the 53^rd exon in said human dystrophin pre-mRNA consists of a nucleotide sequence corresponding to SEQ ID NO;

1, and wherein said PMO hybridizes to said human dystrophin pre-mRNA with Watson-Crick base pairing.

19. The method according to claim 18, wherein each phosphorodiamidate morpholino monomer of said PMO has the formula:

20. The method according to claim 19, wherein the 5′

end of said PMO has a formula selected from the group consisting of;

21. A method comprising administering to a patient with DMD an antisense phosphorodiamidate morpholino oligomer (PMO) consisting of a 25-mer oligomer that is 100% complementary to the target sequence 5′

-GAACACCUUCAGAACCGGAGGCAAC-3′

(SEQ ID NO;

     124) wherein the 53^rd exon in said human dystrophin pre-mRNA consists of a nucleotide sequence corresponding to SEQ ID NO;

1, wherein said PMO hybridizes to said human dystrophin pre-mRNA with Watson-Crick base pairing, and wherein skipping of the 53^rd exon is induced in said patient.

22. The method according to claim 21, wherein each phosphorodiamidate morpholino monomer of said PMO has the formula:

23. The method according to claim 22, wherein the 5′

end of said PMO has a formula selected from the group consisting of;

24. A method of inducing exon 53 skipping in a patient with DMD comprising administering to said patient an antisense phosphorodiamidate morpholino oligomer (PMO) consisting of a 25-mer oligomer that is 100% complementary to the target sequence 5′

-GAACACCUUCAGAACCGGAGGCAAC-3′

(SEQ ID NO;

     124), wherein the 53^rd exon in said human dystrophin pre-mRNA consists of a nucleotide sequence corresponding to SEQ ID NO;

1, and wherein said PMO hybridizes to said human dystrophin pre-mRNA with Watson-Crick base pairing.

25. The method according to claim 24, wherein each phosphorodiamidate morpholino monomer of said PMO has the formula:

26. The method according to claim 25, wherein the 5′

end of said PMO has a formula selected from the group consisting of;