Methods and means for treating DNA repeat instability associated genetic disorders

• US 8,263,760 B2
• Filed: 08/06/2010
• Issued: 09/11/2012
• Est. Priority Date: 02/08/2008
• Status: Expired due to Fees

• Current Assignee: BioMarin Technologies B.V.
• Original Assignee: Prosensa Holding B.V.
• Inventors: de Kimpe, Josephus Johannes, Platenburg, Gerardus Johannes
• Primary Examiner(s): Bowman, Amy
• Application Number:
  US12/852,057
• Publication Number:
  US 20110184050A1
• Time in Patent Office: 767 Days
• Field of Search: None
• US Class Current: 536/24.5
• 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 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• 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 2310/14 interfering N.A.
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/331 Universal or degenerate base
• CPC Class Codes: C12N 2310/346 having a combination of backbone and sugar modifications
• CPC Class Codes: C12N 2310/3521 Methyl

Abstract

The current invention provides for methods and medicaments that apply an oligonucleotide comprising aninosine and/or an uracile and/or a nucleotide containing a base able to form a wobble base pair, said oligonucleotide being preferably RNAse H substantially independent and being complementary only to a repetitive sequence in a human gene transcript, for the manufacture of a medicament for the diagnosis, treatment or prevention of a cis-element repeat instability associated genetic disorders in humans. The invention hence provides a method of treatment for cis-element repeat instability associated genetic disorders. The invention also pertains to a modified oligonucleotide which can be applied in a method of the invention to prevent the accumulation and/or translation of repeat expanded transcripts in cells.

Claims

1. An oligonucleotide comprising an inosine, wherein said oligonucleotide consists of a sequence that is complementary to a repetitive sequence selected from the group consisting of (CAG)n, (GCG)n, (CUG)n, (CGG)n, (GAA)n, (GCC)n and (CCUG)n, and is 9 to 50 nucleotides long.

2. An oligonucleotide according to claim 1, consisting of a sequence that is complementary to a repetitive sequence selected from the group consisting of (CAG)n, (GCG)n, (CUG)n, (CGG)n, (GAA)n, (GCC)n and (CCUG)n, wherein the oligoucleotide is 9 to 50 nucleotides long and wherein the oligonucleotide is a RNAse H substantially independent oligonucleotide.

3. An oligonucleotide according to claim 1, wherein said oligonucleotide comprises a radioactive label or fluorescent label.

4. An oligonucleotide according to claim 2, wherein said oligonucleotide comprises a radioactive label or fluorescent label.

5. A pharmaceutically acceptable composition comprising an oligonucleotide as defined in any one of claims 1 to 4 and at least one excipient and/or targeting ligand for delivery of the oligonucleotide to the cell and/or enhancing the intracellular delivery of the oligonucleotide.

6. A nucleic acid vector capable of conferring expression of an oligonucleotide as defined by any one of claims 1 to 4 in human cells.

7. An oligonucleotide according to any one of claims 1-4, wherein the oligonucleotide consists of (CIG)₇ and is a 2′

-O-methyl RNA phosphorothioate oligonucleotide.

8. The nucleic acid vector of claim 6, wherein said vector is a viral vector.