# US 10,246,707 B2 · Method for efficient exon (44) skipping in duchenne muscular dystrophy and associated means

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- Number: US 10,246,707 B2
- Document ID: US10246707B2
- Status: Granted
- Kind: B2
- Application number: 14/859,598
- Filed: 2015-09-21
- Published: 2016-02-25
- Granted: 2019-04-02
- Earliest claimed: 2008-05-14
- Assignees: BioMarin Technologies B.V.; Academisch Ziekenhuis Leiden
- Applicants: BioMarin Technologies B.V.; Academisch Ziekenhuis Leiden
- Inventors: Gerard Johannes Platenburg; Josephus Johannes de Kimpe; Judith Christina Theodora van Deutekom; Garrit-Jan Boudewijn van Ommen; Annemieke Aartsma-Rus
- Web page: https://patentgrep.com/patent/US10246707B2

## CPC

- 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)}
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/04: for myasthenia gravis
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61K 48/00: Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- C12N 2310/11: Antisense
- C12N 2310/111: spanning the whole gene, or a large part of it
- C12N 2310/314: Phosphoramidates
- C12N 2310/315: Phosphorothioates
- C12N 2310/321: 2'-O-R Modification
- C12N 2310/3233: Morpholino-type ring
- C12N 2310/346: having a combination of backbone and sugar modifications
- C12N 2310/3513: Protein; Peptide
- C12N 2310/3517: Marker; Tag
- C12N 2320/33: Alteration of splicing
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

The invention relates to a nucleic acid molecule that binds and/or is complementary to the nucleotide molecule having sequence 5′-GUGGCUAACAGAAGCU (SEQ ID NO 1) and to its use in a method for inducing skipping of exon 44 of the DMD gene in a DMD patient.

## Claims

### Claim 1

A single stranded antisense oligonucleotide 16 to 25 nucleotides in length that comprises a base sequence of the sequence selected from the group consisting of SEQ ID NO: 5 to SEQ ID NO: 16, SEQ ID NO: 20 to SEQ ID NO: 28, SEQ ID NO: 30 to SEQ ID NO: 34, SEQ ID NO: 41, and SEQ ID NO: 46, wherein the antisense oligonucleotide induces skipping of exon 44 of human dystrophin pre-mRNA, and comprises a modification.

### Claim 2 (depends on 1)

The antisense oligonucleotide according to claim 1, wherein said antisense oligonucleotide comprises the base sequence of the sequence SEQ ID NO: 5.

### Claim 3 (depends on 1)

The antisense oligonucleotide according to claim 1, comprising a 2′-O-alkyl phosphorothioate antisense oligonucleotide.

### Claim 4 (depends on 3)

The antisense oligonucleotide according to claim 3, wherein said antisense oligonucleotide comprises a 2′-O-methyl phosphorothioate ribose.

### Claim 5 (depends on 1)

A viral-based vector, comprising a Pol III-promoter driven expression cassette for expression of an antisense oligonucleotide according to claim 1.

### Claim 6 (depends on 1)

The antisense oligonucleotide of claim 1, wherein said modification comprises a modified backbone.

### Claim 7 (depends on 6)

The antisense oligonucleotide according to claim 6, 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.

### Claim 8 (depends on 1)

The antisense oligonucleotide according to claim 1, wherein said modification is selected from the group consisting of: phosphorodiamidate morpholino oligomer (PMO), peptide nucleic acid, and locked nucleic acid.

### Claim 9 (depends on 2)

The antisense oligonucleotide according to claim 2, wherein the antisense oligonucleotide is a PMO.

### Claim 10 (depends on 1)

The oligonucleotide of claim 1, wherein said oligonucleotide is conjugated to a ligand.

### Claim 11 (depends on 10)

The oligonucleotide of claim 10, wherein said ligand is a peptide.

### Claim 12 (depends on 1)

The antisense oligonucleotide according to claim 1, wherein said modification comprises a locked nucleic acid (LNA).