Oligomers

• US 10,421,969 B2
• Filed: 09/12/2018
• Issued: 09/24/2019
• Est. Priority Date: 10/04/2011
• Status: Active Grant

• Current Assignee: Royal Holloway And Bedford New College
• Original Assignee: Royal Holloway And Bedford New College
• Inventors: Dickson, John George, Kang, Jagjeet Kaur
• Primary Examiner(s): Chong, Kimberly
• Application Number:
  US16/129,680
• Publication Number:
  US 20190048350A1
• Time in Patent Office: 377 Days
• CPC Class Codes: A61K 47/54 the modifying agent being an organic compound
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: C07H 21/04 with deoxyribosyl as saccharide radical
• CPC Class Codes: C12N 15/1136 against growth factors, growth regulators, cytokines, lymphokines or hormones
• CPC Class Codes: C12N 15/1138 against receptors or cell surface proteins
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/314 Phosphoramidates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/3233 Morpholino-type ring
• CPC Class Codes: C12N 2320/30 Special therapeutic applications
• CPC Class Codes: C12N 2320/31 Combination therapy
• CPC Class Codes: C12N 2320/33 Alteration of splicing

Abstract

Certain disclosed oligomers induce exon skipping during processing of myostatin pre-mRNA. The oligomers may be in a vector or encoded by the vector. The vector is used for inducing exon skipping during processing of myostatin pre-mRNA. A therapeutically effective amount of the oligomer may be administered to a subject patient such that exon skipping during processing of myostatin pre-mRNA is induced. The administration to a subject may be used in order to increase or maintain muscle mass, or slowing degeneration of muscle mass in the subject. The administration to a subject may ameliorate muscle wasting conditions, such as muscular dystrophy. Examples of such muscular dystrophies which may be so treated include Becker'"'"'s muscular dystrophy, congenital muscular dystrophy, Duchenne muscular dystrophy, distal muscular dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy (FSHD), limb-girdle muscular dystrophy, myotonic muscular dystrophy, and oculopharyngeal muscular dystrophy.

Claims

1. An oligomer for inducing exon skipping during processing of myostatin pre-mRNA, the oligomer comprising at least 20 contiguous bases of a base sequence selected from:

2. The oligomer of claim 1, wherein the oligomer causes an exon skipping rate of at least 40%.

3. The oligomer of claim 1, wherein the oligomer causes an exon skipping rate of at least 90%.

4. The oligomer of claim 1, wherein the oligomer is a phosphorodiamidate morpholino oligonucleotide (PMO).

5. The oligomer of claim 1, wherein the oligomer is between 20 and 40 bases in length.

6. The oligomer of claim 1, wherein the oligomer is about 30 bases in length.

7. The oligomer of claim 1, wherein the base sequence is selected from SEQ ID NOS. 4, 17, and 18.

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

9. A vector for inducing exon skipping during processing of myostatin pre-mRNA, the vector encoding an oligomer of claim 1, wherein when the vector is introduced into a cell, the oligomer is expressed.

10. A method of inducing exon skipping during processing of myostatin pre-mRNA in a patient, the method comprising administering a therapeutically effective amount of the oligomer of claim 1 or the vector of claim 9 to the patient such that exon skipping during processing of myostatin pre-mRNA is induced.

11. The method of claim 10, wherein the method is for increasing or maintaining muscle mass, or slowing degeneration of muscle mass in the patient.

12. The method of claim 10, wherein the method is for ameliorating muscle wasting conditions.

13. The method of claim 10, wherein the method is for ameliorating a muscular dystrophy such as Becker'"'"'s muscular dystrophy, congenital muscular dystrophy, Duchenne muscular dystrophy, distal muscular dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy (FSHD), limb-girdle muscular dystrophy, myotonic muscular dystrophy and oculopharyngeal muscular dystrophy.

14. The method of claim 10, wherein the method is for ameliorating Duchenne muscular dystrophy.

15. The method of claim 14, wherein the exon skipping occurs in the dystrophin gene and which ameliorates Duchenne muscular dystrophy.

16. The oligomer of claim 2, wherein the exon skipping rate is measured in C2C12 mouse myoblast cells after treatment with an oligomer by comparing gene expression levels of the exon in the cells to total gene expression levels in the cells.

17. The oligomer of claim 3, wherein he exon skipping rate is measured in C2C12 mouse myoblast cells after treatment with an oligomer by comparing gene expression levels of the exon in the cells to total gene expression levels in the cells.