Systemic Treatment of Duchenne Muscular Dystrophy by Antisense Oligomer Induced Exon Skipping

Qi Long Lu and Bo Wu

Abstract Duchenne muscular dystrophy (DMD), caused by nonsense or frame-shift mutations in the dystrophin gene, is a progressive degenerative disease involving all the muscles body-wide. Antisense oligomer-mediated exon skipping has recently emerged as an effective approach for the restoration of dystrophin. A clinical trial by intramuscular delivery of antisense oligonucleotide demonstrates efficacy in principle in DMD patients, providing optimism for its clinical application as an effective treatment. However, DMD is a systemic disease and requires life-long treatment systemically with antisense therapy for the restoration and maintenance of dystrophin expression in body-wide muscles, especially cardiac muscle. Unmodified antisense oligomers are able to induce effective exon skipping systemically but with significant variation between and within muscles and failure of dystrophin induction in the cardiac muscle. Modifying phosphorodiamidate morpholino oligomer (PMO) with cell-penetrating peptide and polymers greatly improves the efficiency of the delivery and leads to the restoration of near normal levels of dystrophin in both skeletal and cardiac muscles with improved functions. Clinical trials of systemic treatment with antisense oligomers for DMD are well under way and could represent the first realization of gene therapy to muscular dystrophies.

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