METHOD FOR EFFICIENT EXON (44) SKIPPING IN DUCHENNE MUSCULAR DYSTROPHY AND ASSOCIATED MEANS

• US 20120059042A1
• Filed: 11/11/2010
• Published: 03/08/2012
• Est. Priority Date: 05/14/2008
• Status: Active Grant

• Current Assignee: Academisch Ziekenhuis Leiden, BioMarin Technologies B.V.
• Original Assignee: Academisch Ziekenhuis Leiden, Prosensa Technologies B.V.
• Inventors: Platenburg, Gerard Johannes, van Deutekom, Judith Christina Theodora, van Ommen, Garrit-Jan Boudewijn, Aartsma-Rus, Annemieke, de Kimpe, Josephus Johannes
• Granted Patent: US 9,139,828 B2
• Time in Patent Office: Days
• US Class Current: 514/44.A
• 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: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 2310/111 spanning the whole gene, or a large part of it
• CPC Class Codes: C12N 2310/314 Phosphoramidates
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/3233 Morpholino-type ring
• CPC Class Codes: C12N 2310/346 having a combination of backbone and sugar modifications
• CPC Class Codes: C12N 2310/3513 Protein; Peptide
• CPC Class Codes: C12N 2310/3517 Marker; Tag
• CPC Class Codes: C12N 2310/3521 Methyl
• CPC Class Codes: C12N 2320/33 Alteration of splicing

Abstract

The invention relates to a nucleic acid molecule that binds and/or is complementary to the nucleotide molecule having sequence 5′-GUGGCUAACAGAAGCU (SEQ ID NO 1) and to its use in a method for inducing skipping of exon 44 of the DMD gene in a DMD patient.

Claims

1. A nucleic acid molecule that binds and/or is complementary to a nucleotide having nucleotide sequence:

2. A molecule according to claim 1, wherein said molecule comprises an antisense oligonucleotide comprising or consisting of from 8 to 60 nucleotides.

3. A molecule according to claim 2, whereby said antisense oligonucleotide comprises or consists of the following sequences:

SEQ ID NO;

5 to SEQ ID NO;

42, SEQ ID NO;

49 or SEQ ID NO;

54.

4. A molecule according to claim 3, wherein said molecule comprises or consists of the nucleotide sequence SEQ ID NO:

5.

5. A molecule according to any of claims 1-4, comprising a 2′

-O alkyl phosphorothioate antisense oligonucleotide.

6. A molecule according to claim 5, wherein said molecule comprises a 2′

-O methyl phosphorothioate ribose.

7. A viral-based vector, comprising a Pol III-promoter driven expression cassette for expression of a molecule as defined in any one of claims 1 to 6, preferably said molecule binding to and/or being complementary to the nucleotide sequence

8. A pharmaceutical composition comprising a molecule as defined in any of claims 1-6, or the vector of claim 7, and a pharmaceutical acceptable carrier.

9. Use of the molecule as defined in any of claims 1-6, or the vector of claim 7, for modulating splicing of the DMD pre-mRNA.

10. Use of the molecule as defined in any of claims 1-6, or the vector of claim 7, for the preparation of a medicament for the treatment of a DMD or BMD patient.

11. A method for inducing skipping of exon 44 of the DMD gene in a cell, the method comprising providing said cell with a molecule as defined in any one of claims 1 to 6, or the vector of claim 7.