Oligomers

• US 9,243,252 B2
• Filed: 10/04/2013
• Issued: 01/26/2016
• Est. Priority Date: 09/11/2008
• Status: Active Grant

• Current Assignee: Royal Holloway University of London
• Original Assignee: Royal Holloway University of London
• Inventors: Popplewell, Linda, Graham, Ian, Dickson, John George
• Primary Examiner(s): Chong, Kimberly
• Application Number:
  US14/045,841
• Publication Number:
  US 20140057964A1
• Time in Patent Office: 844 Days
• Field of Search: None
• US Class Current: 1/1
• 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. A vector for ameliorating Duchenne muscular dystrophy the vector encoding an oligomer comprising at least 25 contiguous bases of a base sequence selected from the group consisting of:

2. A pharmaceutical composition for ameliorating Duchenne muscular dystrophy, the composition comprising the vector according to claim 1 or the oligonucleotide encoded by the vector according to claim 1, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

3. A pharmaceutical composition according to claim 2 comprising a plurality of vectors encoding oligomers including the vector according to claim 1 and/or a plurality of oligomers including the oligomer encoded by the vector according to claim 1 wherein each oligomer encoded by a vector in the plurality of vectors causes skipping of an exon, and each oligomer in the plurality of oligomers causes skipping of an exon.

4. A method of ameliorating Duchenne muscular dystrophy in a human patient, the method comprising:

administering a therapeutically effective amount of the vector according to claim 1 or the oligonucleotide encoded by the vector according to claim 1 to the patient such that the Duchenne muscular dystrophy is ameliorated.

5. The method according to claim 4 comprising administering a therapeutically effective amount of a plurality of vectors encoding oligomers including the vector according to claim 1 and/or a plurality of oligomers including the oligomer encoded by the vector according to claim 1 to the patient, wherein each oligomer encoded by a vector in the plurality of vectors causes skipping of an exon, and each oligomer in the plurality of oligomers causes skipping of an exon.

6. The vector according to claim 1, wherein the oligomer causes exon skipping of exon 46 of the dystrophin gene.

7. The vector according to claim 6, wherein the oligomer causes exon skipping in at least 50% of the total pre-mRNA.

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

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

10. The pharmaceutical composition according to claim 2, wherein the oligomer is conjugated to or complexed with a targeting protein.

11. The pharmaceutical composition according to claim 2, wherein the oligomer is conjugated to or complexed with a drug for treating Duchenne muscular dystrophy.

12. The pharmaceutical composition according to claim 2, wherein the oligomer is conjugated to or complexed with an arginine-rich cell penetrating peptide.

13. The pharmaceutical composition according to claim 3, wherein each oligomer encoded by a vector in the plurality of vectors causes skipping of a different exon, and each oligomer in the plurality of oligomers causes skipping of a different exon.