期刊
NEUROLOGY INDIA
卷 56, 期 3, 页码 254-262出版社
WOLTERS KLUWER MEDKNOW PUBLICATIONS
DOI: 10.4103/0028-3886.43443
关键词
Becker muscular dystrophy; clinical trials; Duchenne muscular dystrophy; exon skipping; morpholino oligomer; personalized genetic medicines
资金
- Muscular Dystrophy Association (USA) [MDA 4352]
- National Institutes of Health [RO1 NS044146-02]
- Muscular Dystrophy Association Western Australia (Inc)
- Charley's Fund
- Gavriel Mier Trust
- James and Mathew Foundation
- Medical and Health Research Infrastructure Fund
Duchenne muscular dystrophy (DMD), the most common and serious form of childhood muscle wasting is generally caused by protein-truncating mutations in the large DMD gene. Specific removal of an exon from a defective DMD gene transcript has the potential to allow synthesis of a semi-functional dystrophin, thereby reducing the severity and presumably progression of muscle wasting. The efficacy of this treatment will vary greatly between the different mutations that preclude the synthesis of a functional dystrophin. Restoration of the reading frame from a large multi-exon genomic deletion, typically greater than 36 exons, may lead to synthesis of a protein with only partial function and limited clinical benefit, whereas excising a nonsense mutation in a redundant exon should generate a near normal dystrophin. A clinical trial has recently confirmed proof-of-principle that exclusion of Exon 51 from human dystrophin mRNAs, carrying frame-shifting deletions adjacent to this exon, results in dystrophin expression. No major side-effects after local administration of the antisense oligomer were reported. Additional trials are underway, targeting the same exon but using an oligomer of different backbone chemistry. If functional dystrophin synthesis is demonstrated, and safety issues are addressed, subsequent trials will involve systemic delivery. Great challenges are ahead, some technical; establishing an effective delivery regimen, some ethical; choosing subsequent targets for therapy, and others of an administrative and regulatory nature.
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