Antisense oligonucleotides targeting exon 51 of dystrophin gene

Abstract

FIELD: biotechnology; medicine.SUBSTANCE: invention discloses hydroxyalkoxylated antisense oligonucleotides suitable for inducing exon 51 skipping of dystrophin pre-mRNA.EFFECT: treatment and / or slowing the progression of neuromuscular disorders caused by pathological mutations in the dystrophin gene, more particularly in the treatment of Duchenne muscular dystrophy (DMD).12 cl, 8 dwg, 4 tbl, 7 ex

Claims

1. A hydroxyalkoxylated antisense oligonucleotide (hydroxyalkoxylated AON) for inducing skipping of exon 51 of dystrophin pre-mRNA, comprising one antisense oligonucleotide (AON) and one or two triethylene glycol groups (TEG), wherein the AON comprises the nucleotide sequence of SEQ ID NO: 22333 or a nucleotide sequence that has at least 90% identity to SEQ ID NO: 22333.

2. The hydroxyalkoxylated AON of claim 1, wherein the hydroxyalkoxylated AON consists of an AON and one TEG group, and wherein the 5'-terminal monomer or the 3'-terminal monomer of said AON is linked to one TEG group.

3. The hydroxyalkoxylated AON of claim 1, wherein the hydroxyalkoxylated AON is comprised of an AON and two TEG groups, and wherein each of the 5'-terminal monomer and the 3'-terminal monomer of said AON is linked to one TEG group.

4. The hydroxyalkoxylated AON of any one of claims 1 to 3, wherein one or two TEG groups are attached to the AON via a phosphate (PO) linker.

5. The hydroxyalkoxylated AON of any one of claims 1 to 4, wherein one or two TEG groups are attached to the AON via a phosphorothioate (PS) linker.

6. A hydroxyalkoxylated AON according to any one of claims 1 to 5, characterized in that all cytosine bases of the AON are 5-methylcytosine bases.

7. A hydroxyalkoxylated AON according to any one of claims 1 to 5, wherein the AON comprises 4, 5, 6, 7, 8 or 9 monomers that contain a modification of the bicyclic nucleic acid (BNA) backbone.

8. The hydroxyalkoxylated AON of claim 1, wherein the hydroxyalkoxylated AON comprises the nucleotide sequence SEQ ID NO: 22345.

9. The use of a hydroxyalkoxylated AON according to any one of claims 1 to 8 or a pharmaceutical composition comprising a hydroxyalkoxylated AON according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier as a medicine or for the treatment of Duchenne muscular dystrophy (DMD).

10. The use of a hydroxyalkoxylated AON according to any one of claims 1 to 8 or a pharmaceutical composition comprising a hydroxyalkoxylated AON according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier for inducing skipping of exon 51 from dystrophin pre-mRNA.

11. A method of treating Duchenne muscular dystrophy (DMD) in a subject, comprising administering to the subject a hydroxyalkoxylated AON according to any one of claims 1-8 or a pharmaceutical composition comprising a hydroxyalkoxylated AON according to any one of claims 1-8 and a pharmaceutically acceptable carrier.

12. A method for inducing skipping of exon 51 of dystrophin pre-mRNA, comprising contacting dystrophin pre-mRNA with a hydroxyalkoxylated AON according to any one of claims 1-8.

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