Methods and means for efficient skipping of exon 45 in Duchenne muscular dystrophy pre-mRNA

Patent metadata

Field	Value
Publication number	US-9926557-B2
Application number	US-201113094548-A
Country	US
Kind code	B2
Filing date	Apr 26, 2011
Priority date	Oct 26, 2007
Publication date	Mar 27, 2018
Grant date	Mar 27, 2018

Abstract

The invention relates to a method for inducing or promoting skipping of exon 45 of DMD pre-mRNA in a Duchenne Muscular Dystrophy patient, preferably in an isolated (muscle) cell, the method comprising providing an isolated muscle cell with a molecule that binds to a continuous stretch of at least 21 nucleotides within said exon. The invention further relates to such molecule used in the method.

First claim

The invention claimed is:

1. A pharmaceutical composition comprising an antisense oligonucleotide and an excipient selected from the group consisting of polyethylenimine, and polypropylenimine, wherein said antisense oligonucleotide consists of the base sequence: 5′-UUUGCCGCUGCCCAAUGCCAUCCUG-3′ (SEQ ID: NO: 3), said oligonucleotide comprising a modification.

2. The pharmaceutical composition according to claim 1 , wherein the oligonucleotide comprises at least one nucleotide analogue or equivalent, wherein a nucleotide analogue or equivalent is defined as a residue having a modified base, and/or a modified backbone, and/or a non-natural internucleoside linkage, or a combination of these modifications.

3. The pharmaceutical composition according to claim 2 , wherein the nucleotide analogue has a modified base.

4. The pharmaceutical composition according to claim 2 , wherein the nucleotide analogue has a modified backbone.

5. The pharmaceutical composition according to claim 2 , wherein the nucleotide analogue comprises one or more sugar moieties that are mono-or disubstituted at the 2′, 3′ and/or 5′ position.

6. The pharmaceutical composition according to claim 5 , wherein said oligonucleotide comprises a 2′-O-substituted phosphorothioate antisense oligonucleotide.

7. The pharmaceutical composition according to claim 5 , wherein said oligonucleotide comprises a 2′-O-methyl ribose.

8. The pharmaceutical composition according to claim 6 , wherein all the sugar moieties are 2′-O-methyl substituted.

9. The pharmaceutical composition according to claim 4 , wherein the modified backbone is selected from the group consisting of a morpholino backbone, a carbamate backbone, a siloxane backbone, a sulfide backbone, a sulfoxide backbone, a sulfone backbone, a formacetyl backbone, a thioformacetyl backbone, a methyleneformacetyl backbone, a riboacetyl backbone, an alkene containing backbone, a sulfamate backbone, a sulfonate backbone, a sulfonamide backbone, a methyleneimino backbone, a methylenehydrazino backbone and an amide backbone.

10. The pharmaceutical composition according to claim 1 , wherein the oligonucleotide comprises phosphorodiamidate morpholino oligomer (PMO), peptide nucleic acid, and/or locked nucleic acid.

11. The pharmaceutical composition according to claim 1 , further comprising a molecule which is able to induce or promote skipping of exon 7, 44, 46, 51, 53, 59, or 67 of the pre-mRNA of the DMD gene of a patient.

Assignees

• De Kimpe Josephus Johannes
• Platenburg Gerardus Johannes
• Van Deutekom Judith Christina Theodora
• Aartsma Rus Annemieke
• Van Ommen Garrit Jan Boudewijn
• Biomarin Tech Bv
• Academisch Ziekenhuis Leiden

Inventors

• De Kimpe Josephus Johannes
• Platenburg Gerardus Johannes
• Van Deutekom Judith Christina Theodora
• Aartsma-Rus Annemieke
• Van Ommen Garrit-Jan Boudewijn

Classifications

• A61P39/06

  Free radical scavengers or antioxidants · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P3/14

  for calcium homeostasis (vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04) · CPC title

• A61P21/02

  Muscle relaxants, e.g. for tetanus or cramps · CPC title