Pharmaceutical composition for treatment of duchenne muscular dystrophy

• US 20010056077A1
• Filed: 07/31/2001
• Published: 12/27/2001
• Est. Priority Date: 05/21/1999
• Status: Active Grant

• Current Assignee: JCR Pharmaceuticals Co., Ltd.
• Original Assignee: JCR Pharmaceuticals Co., Ltd.
• Inventors: Matsuo, Masafumi
• Granted Patent: US 6,653,466 B2
• Time in Patent Office: Days
• US Class Current: 514/44.00A
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• 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: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• 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 2310/315 Phosphorothioates

Abstract

A therapeutic pharmaceutical composition for patients of Duchenne muscular dystrophy with entire loss of exon 20 in dystrophin mature mRNA is provided. The composition comprise as an active principle an antisense oligonucleotide consisting of a 20 to 50-nucleotide sequence against exon 19 of the dystrophin pre-mRNA.

Claims

1. Use of an antisense oligonucleotide for the manufacture of a therapeutic pharmaceutical composition for Duchenne muscular dystrophy with entire loss of exon 20 in the production of dystrophin mature mRNA, wherein said antisense oligonucleotide consists of a 20 to 50-nucleotide sequence against exon 19 of the dystrophin pre-mRNA.

2. The use of

claim 1

wherein said antisense oligonucleotide comprises a nucleotide sequence complementary to the nucleotide sequence set forth under SEQ ID NO:

1 in the Sequence Listing.

3. The use of

claim 1

or

2

wherein said antisense oligonucleotide is an oligoDNA, a phosphorothioate oligoDNA, or a phosphorothioate oligoRNA.

4. The use of

claim 1

wherein said antisense oligonucleotide is an oligoDNA, a phosphorothioate oligoDNA or a phosphorothioate oligoRNA any of which has a nucleotide sequence complementary to the nucleotide sequence set forth under SEQ ID NO:

2 in the Sequence Listing.

5. A therapeutic pharmaceutical composition for Duchenne muscular dystrophy with entire loss of exon 20 in the production dystrophin mature mRNA, wherein said therapeutic pharmaceutical composition comprises, in a pharmaceutically acceptable injectable medium, an antisense oligonucleotide consisting of a 20 to 50-nucleotide sequence against exon 19 of the dystrophin pre-mRNA.

6. The pharmaceutical composition of

claim 5

wherein said antisense oligonucleotide comprises a nucleotide sequence complementary to the nucleotide sequence set forth under SEQ ID NO:

1 in the Sequence Listing.

7. The therapeutic pharmaceutical composition of

claim 5

or

6

wherein said antisense oligonucleotide is an oligoDNA, a phosphorothioate oligoDNA, or a phosphorothioate oligoRNA.

8. The therapeutic pharmaceutical composition of

claim 5

wherein said antisense oligonucleotide is an oligoDNA, a phosphorothioate oligoDNA or a phosphorothioate oligoRNA any of which has a nucleotide sequence complementary to the nucleotide sequence set forth under SEQ ID NO:

2 in the Sequence Listing.

9. The therapeutic pharmaceutical composition of one of

claims 5

to

8

comprising 0.05-5 μ

moles/ml of said antisense oligonucleotide, 0.02-10 %w/v of at least one carbohydrate or polyalcohol, and 0.01-0.4 %w/v of at least one pharmaceutically acceptable surfactant.

10. The therapeutic pharmaceutical composition of one of

claims 5

to

9

containing 0.03-0.09 M of at least one pharmaceutically acceptable neutral salt.

11. The therapeutic pharmaceutical composition of

claim 10

wherein said neutral salt is selected from the group consisting of sodium chloride, potassium chloride, and calcium chloride.

12. The therapeutic pharmaceutical composition of one of

claims 5

to

11

containing 0.002-0.05 M of a pharmaceutically acceptable buffering agent.

13. The therapeutic pharmaceutical composition of

claim 12

wherein said buffering agent is selected from the group consisting of sodium citrate, sodium glycinate, sodium phosphate, and tris(hydroxymethyl)aminomethane.

14. The therapeutic pharmaceutical composition of one of

claims 9

to

13

wherein said carbohydrate is selected from the group consisting of monosaccharides and disaccharides.

15. The therapeutic pharmaceutical composition of one of

claims 9

to

13

wherein said carbohydrate or polyalcohol is selected from the group consisting of glucose, galactose, mannose, lactose, maltose, mannitol, and sorbitol.

16. The therapeutic pharmaceutical composition of one of

claims 9

to

15

wherein said surfactant is polyoxyethylene sorbitan mono- to tri-ester, alkyl phenyl polyoxyethylene, sodium taurocholate, sodium cholate, or a polyalcohol ester.

17. The therapeutic pharmaceutical composition of

claim 15

wherein said polyoxyethylene sorbitan ester is an ester selected from the group consisting of oleate, laurate, stearate, and palmitate.

18. The therapeutic pharmaceutical composition of one of

claims 9

to

17

which is in a lyophilized form.

19. A method of treatment of a human patient with Duchenne muscular dystrophy with entire loss of exon 20 in the production dystrophin mature mRNA comprising administering to said patient an therapeutically effective amount of an antisense oligonucleotide consisting of 20 to 50-nucleotide sequence against exon 19 of the dystrophin pre-mRNA in a pharmaceutically acceptable injectable medium.

20. The method of treatment of

claim 19

wherein said antisense oligonucleotide comprises a nucleotide sequence complementary to the nucleotide sequence set forth under SEQ ID NO:

1 in the Sequence Listing.

21. The method of treatment of

claim 19

wherein said antisense oligonucleotide is an oligoDNA, a phosphorothioate oligoDNA, or a phosphorothioate oligoRNA.

22. The method of treatment of

claim 19

wherein said antisense oligonucleotide is an oligoDNA, a phosphorothioate oligoDNA or a phosphorothioate oligoRNA any of which has a nucleotide sequence complementary to the nucleotide sequence set forth under SEQ ID NO:

2 in the Sequence Listing.