METHODS AND MEANS FOR EFFICIENT SKIPPING OF AT LEAST ONE OF THE FOLLOWING EXONS OF THE HUMAN DUCHENNE MUSCULAR DYSTROPHY GENE: 43, 46, 50-53

• US 20110263682A1
• Filed: 04/26/2011
• Published: 10/27/2011
• Est. Priority Date: 10/26/2007
• Status: Abandoned Application

• Current Assignee: Academisch Ziekenhuis Leiden, BioMarin Technologies B.V.
• Original Assignee: Academisch Ziekenhuis Leiden, Prosensa B.V., Prosensa Holding B.V., Prosensa Technologies B.V.
• Inventors: Platenburg, Gerardus Johannes, Aartsma-Rus, Annemieke, Van Deutekom, Judith Christina Theodora, De Kimpe, Josephus Johannes, Van Ommen, Garrit-Jan Boudewijn
• Application Number:
  US13/094,571
• Publication Number:
  US 20110263682A1
• Time in Patent Office: Days
• US Class Current: 514/44.00A
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 38/1719 Muscle proteins, e.g. myosin or actin
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/14 for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 39/06 Free radical scavengers or antioxidants
• 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 2310/31 : of the backbone
• CPC Class Codes: C12N 2310/313 : Phosphorodithioates
• CPC Class Codes: C12N 2310/314 : Phosphoramidates
• CPC Class Codes: C12N 2310/315 : Phosphorothioates
• CPC Class Codes: C12N 2310/3181 : Peptide nucleic acid, PNA
• CPC Class Codes: C12N 2310/321 : 2'-O-R Modification
• CPC Class Codes: C12N 2310/3231 : having an additional ring, e.g. LNA, ENA
• 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 2310/3521 : Methyl
• CPC Class Codes: C12N 2320/31 : Combination therapy
• CPC Class Codes: C12N 2320/33 : Alteration of splicing

Abstract

The invention relates a method wherein a molecule is used for inducing and/or promoting skipping of at least one of exon 43, exon 46, exons 50-53 of the DMD pre-mRNA in a patient, preferably in an isolated cell of a patient, the method comprising providing said cell and/or said patient with a molecule. The invention also relates to said molecule as such.

Claims

1. A molecule, which binds to a continuous stretch of at least 8 nucleotides within one of the following nucleotide sequences selected from:

2. A molecule according to claim 1, wherein the molecule comprises or consists of the antisense nucleotide sequence selected from SEQ ID NO:

8-358, and/or SEQ ID NO 529-535 as depicted in tables 1 to 6.

3. A molecule according to claim 2, wherein the molecule comprises or consists of the antisense nucleotide sequence selected from SEQ ID NO:

16, SEQ ID NO;

65, SEQ ID NO;

70, SEQ ID NO;

91, SEQ ID NO;

110, SEQ ID NO;

117, SEQ ID NO;

127, SEQ ID NO;

165, SEQ ID NO;

166, SEQ ID NO;

167, SEQ ID NO;

246, SEQ ID NO;

299 and SEQ ID NO;

357.

4. A molecule according to claim 1, comprising a 2′

-O-alkyl phosphorothioate antisense oligonucleotide.

5. A molecule according to claim 4, comprising a 2′

-O methyl phosphorothioate ribose.

6. A viral-based vector, comprising an expression cassette that drives expression of a molecule as defined in claim 1.

7. A molecule according to claim 1 for use as a medicament, preferably for modulating splicing of the DMD pre-mRNA of a DMD or BMD patient or for the treatment of a DMD or BMD patient.

8. A pharmaceutical composition comprising a molecule as defined in claim 1, a pharmaceutical acceptable carrier, and optionally combined with a molecule which is able to induce or promote skipping of at least one of exon 6, 7, 11, 17, 19, 21, 43, 44, 45, 50-53, 55, 57, 59, 62, 63, 65, 66, 69, or 75 of the DMD pre-mRNA of a patient.

9. A method for inducing and/or promoting skipping of at least one of exon 43, exon 46, and exons 50-53 of the DMD pre-mRNA in a patient, preferably in an isolated cell of a patient, the method comprising providing said cell and/or said patient with a molecule as defined in claim 1.

10. A method according to claim 9, wherein an additional molecule is used which is able to induce or promote skipping of at least one of exon 6, 7, 11, 17, 19, 21, 43, 44, 45, 50-53, 55, 57, 59, 62, 63, 65, 66, 69, or 75 of the DMD pre-mRNA of a patient.

11. A method of treating a patient with DMD or BMD comprising administering the molecule of claim 1, wherein following administration, splicing of the DMD pre-mRNA of said patient is modulated, thereby treating said patient.