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Antisense pre-treatment increases gene therapy efficacy in dystrophic muscles

Peccate, C; Mollard, A; Le Hir, M; Julien, L; McClorey, G; Jarmin, S; Le Heron, A; ... Lorain, S; + view all (2016) Antisense pre-treatment increases gene therapy efficacy in dystrophic muscles. Human Molecular Genetics , 25 (16) pp. 3555-3563. 10.1093/hmg/ddw201. Green open access

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Abstract

In preclinical models for Duchenne muscular dystrophy, dystrophin restoration during adeno-associated virus (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 the 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 the 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 6 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.

Type: Article
Title: Antisense pre-treatment increases gene therapy efficacy in dystrophic muscles
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/hmg/ddw201
Publisher version: https://doi.org/10.1093/hmg/ddw201
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: gene therapy, antisense oligonucleotides, duchenne's muscular dystrophy, DNA, complementary, dystrophin, exons, genome, tissue membrane, paptides, sarcolemma, microbiology procedures, adeno-associated virus, transfer technique, single-dose regimen, personal integrity
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10061775
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