OLIGOMERS

• US 20120108652A1
• Filed: 11/30/2011
• Published: 05/03/2012
• Est. Priority Date: 09/11/2008
• Status: Active Grant

• Current Assignee: Royal Holloway And Bedford New College Royal Holloway, University Of London
• Original Assignee: Royal Holloway University of London
• Inventors: POPPLEWELL, Linda, GRAHAM, Ian, DICKSON, John George
• Granted Patent: US 8,461,325 B2
• Time in Patent Office: Days
• US Class Current: 514/44.A
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• 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 15/115 Aptamers, i.e. nucleic acids binding a target molecule specifically and with high affinity without hybridising therewith ; Nucleic acids binding to non-nucleic acids, e.g. aptamers
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/3233 Morpholino-type ring
• CPC Class Codes: C12N 2310/351 Conjugate
• CPC Class Codes: C12N 2310/3513 Protein; Peptide
• CPC Class Codes: C12N 2320/31 Combination therapy
• CPC Class Codes: C12N 2320/35 based on a specific dosage / administration regimen

Abstract

Molecules are provided for inducing or facilitating exon skipping in forming spliced mRNA products from pre-mRNA molecules in cells. The molecules may be provided directly as oligonucleotides or expression products of vectors that are administered to a subject. High rates of skipping can be achieved. High rates of skipping reduce the severity of a disease like Duchene Muscular Dystrophy so that the disease is more like Becker Muscular Dystrophy. This is a severe reduction in symptom severity and mortality.

Claims

1. An oligomer for ameliorating DMD, the oligomer comprising at least 25 contiguous bases of a base sequence selected from the group consisting of:

2. The oligomer according to claim 1, wherein the exon of the dystrophin gene at which exon skipping is caused is exon 44.

3. The oligomer according to claim 1, wherein the oligomer causes an exon skipping rate of at least 50%.

4. The oligomer according to claim 1, wherein the oligomer is between 25 and 35 bases in length.

5. The oligomer according to claim 1, wherein the oligomer is 30 bases in length.

6. The oligomer according to claim 1, wherein the oligomer is conjugated to or complexed with a distinct chemical entity.

7. The oligomer according to claim 1, wherein the oligomer is a phosphorodiamidate morpholino oligonucleotide (PMO).

8. A vector for ameliorating DMD, the vector encoding an oligomer according to claim 1, wherein when introduced into a human cell the oligomer is expressed.

9. A pharmaceutical composition for ameliorating DMD, the composition comprising an oligomer according to claim 1 or a vector according to claim 8, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

10. A pharmaceutical composition according to claim 9 comprising a plurality of oligomers or vectors encoding oligomers, or a combination of the oligomers and vectors, wherein the oligomers and/or vectors in the pharmaceutical composition cause skipping in a plurality of exons.

11. A method of ameliorating DMD in a human patient, the method comprising:

administering a therapeutically effective amount of an oligomer according to claim 1 or a vector according to claim 8 to the patient such that the DMD is ameliorated.

12. The method according to claim 11 comprising administering a therapeutically effective amount of a plurality of oligomers to the patient, wherein the oligomers cause skipping in a plurality of exons.