Treatment of genetic disorders associated with DNA repeat instability

• US 10,689,646 B2
• Filed: 12/27/2017
• Issued: 06/23/2020
• Est. Priority Date: 08/11/2006
• Status: Active Grant

• Current Assignee: Vico Therapeutics B.V.
• Original Assignee: BioMarin Technologies B.V.
• Inventors: De Kimpe, Josephus Johannes, Platenburg, Gerard Johannes, Wansink, Derick Gert
• Primary Examiner(s): Angell, J. E.
• Application Number:
  US15/855,848
• Publication Number:
  US 20180112214A1
• Time in Patent Office: 909 Days
• Field of Search: None
• 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 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 15/11 DNA or RNA fragments; Modified forms thereof DNA or RNA not used in recombinant technology, C07H21/00; Non-coding nucleic acids having a biological activity
• 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 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/346 having a combination of backbone and sugar modifications
• CPC Class Codes: C12N 2310/3521 Methyl
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers

Abstract

The current invention provides for methods and medicaments that apply oligonucleotide molecules 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 modified oligonucleotides which can be applied in method of the invention to prevent the accumulation and/or translation of repeat expanded transcripts in cells.

Claims

1. A method for treating myotonic dystrophy type 1 in a subject, comprising administering to the subject an oligonucleotide comprising 10 to 50 nucleotides that is complementary to a repetitive nucleotide unit sequence of a pre-mRNA transcript, wherein the repetitive nucleotide unit is a CUG repetitive nucleotide unit.

2. The method according to claim 1, wherein said repeats are present in a coding sequence of the gene transcript.

3. The method according to claim 1, wherein said repeats are present in a non-coding sequence of the gene transcript.

4. The method according to claim 1, wherein the oligonucleotide comprises a ribonucleotide and/or a deoxyribonucleotide.

5. The method according to claim 4, wherein the oligonucleotide comprises a 2′

-O-substituted phosphorothioate nucleotide.

6. The method of claim 5, wherein said oligonucleotide comprises a 2′

-O-methyl phosphorothioate nucleotide or a 2′

-O-meth[y]oxy ethyl phosphorothioate nucleotide.

7. The method according to claim 1, wherein the oligonucleotide is administered in a nucleic acid vector.

8. The method according to claim 1, wherein the oligonucleotide is in a pharmaceutical composition comprising an excipient and/or a targeting ligand.

10. The method according to claim 1, wherein the oligonucleotide has a length selected from the group consisting of about 12 to about 30 nucleotides, about 12 to about 45 nucleotides and about 12 to about 25 nucleotides.

11. The method of claim 1, wherein the oligonucleotide has a phosphorothioate-containing backbone.

12. The method according to claim 1, where the oligonucleotide comprises a morpholino phosphorodiamidate oligonucleotide, a phosphorothioate oligonucleotide, a locked nucleic acid (LNA), a peptide nucleic acid (PNA) and/or an ethylene-bridged nucleic acid.

13. The method of claim 1, wherein the oligonucleotide binds only to the sequence of consecutive trinucleotide repeats.

14. The method of claim 1, wherein the oligonucleotide reduces the amount of an aberrant protein.

15. The method of claim 12, wherein the oligonucleotide is a 2′

-O-methyl phosphorothioate.

16. The method of claim 15, wherein the oligonucleotide comprises the base sequence of:

SEQ ID NO;

6.

9. A method for reducing the number of repeat-containing gene transcripts in a cell comprising providing to said cell an oligonucleotide comprising 10 to 50 nucleotides that is complementary to a repetitive nucleotide unit of a pre-mRNA transcript, wherein said repetitive nucleotide unit is a CUG repetitive nucleotide unit;

and wherein the oligonucleotide has a phosphorothioate-containing backbone.