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In preclinical models for Duchenne muscular dystrophy, dystrophin restoration during AAV-U7-mediated exon-skipping therapy was shown to decrease drastically after six months in treated muscles. This decline in efficacy is strongly correlated with loss of the therapeutic AAV genomes, probably due to alterations of the dystrophic myofiber membranes. To improve the membrane integrity of the dystrophic myofibers at the time of AAV-U7 injection, mdx muscles were pre-treated with a single dose of peptide-phosphorodiamidate morpholino (PPMO) antisense oligonucleotides that induced temporary dystrophin expression at the sarcolemma. The PPMO pre-treatment allowed efficient maintenance of AAV genomes in mdx muscles and enhanced the AAV-U7 therapy effect with a ten-fold increase of the protein level after six months. PPMO pre-treatment was also beneficial to AAV-mediated gene therapy with transfer of micro-dystrophin cDNA into muscles. Therefore, avoiding vector genome loss after AAV injection by PPMO pre-treatment would allow efficient long-term restoration of dystrophin and the use of lower and thus safer vector doses for Duchenne patients.

Original publication

DOI

10.1093/hmg/ddw201

Type

Journal article

Journal

Human molecular genetics

Publication Date

04/07/2016

Addresses

Sorbonne Universités UPMC Univ Paris 06, Inserm, CNRS, Institut de Myologie, Centre de Recherche en Myologie (CRM), GH Pitié Salpêtrière, 105 bd de l'Hôpital, Paris 13, France.