Long-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy

Caroline Le Guiner, Laurent Servais, Marie Montus, Thibaut Larcher, Bodvaël Fraysse, Sophie Moullec, Marine Allais, Virginie François, Maeva Dutilleul, Alberto Malerba, Taeyoung Koo, Jean Laurent Thibaut, Béatrice Matot, Marie Devaux, Johanne Le Duff, Jack Yves Deschamps, Inès Barthelemy, Stéphane Blot, Isabelle Testault, Karim WahbiStéphane Ederhy, Samia Martin, Philippe Veron, Christophe Georger, Takis Athanasopoulos, Carole Masurier, Federico Mingozzi, Pierre Carlier, Bernard Gjata, Jean Yves Hogrel, Oumeya Adjali, Fulvio Mavilio, Thomas Voit, Philippe Moullier, George Dickson

Research output: Contribution to journalArticlepeer-review

180 Citations (Scopus)

Abstract

Duchenne muscular dystrophy (DMD) is an incurable X-linked muscle-wasting disease caused by mutations in the dystrophin gene. Gene therapy using highly functional microdystrophin genes and recombinant adeno-associated virus (rAAV) vectors is an attractive strategy to treat DMD. Here we show that locoregional and systemic delivery of a rAAV2/8 vector expressing a canine microdystrophin (cMD1) is effective in restoring dystrophin expression and stabilizing clinical symptoms in studies performed on a total of 12 treated golden retriever muscular dystrophy (GRMD) dogs. Locoregional delivery induces high levels of microdystrophin expression in limb musculature and significant amelioration of histological and functional parameters. Systemic intravenous administration without immunosuppression results in significant and sustained levels of microdystrophin in skeletal muscles and reduces dystrophic symptoms for over 2 years. No toxicity or adverse immune consequences of vector administration are observed. These studies indicate safety and efficacy of systemic rAAV-cMD1 delivery in a large animal model of DMD, and pave the way towards clinical trials of rAAV-microdystrophin gene therapy in DMD patients.

Original languageEnglish
Article number16105
JournalNature Communications
Volume8
DOIs
Publication statusPublished - 25 Jul 2017

Bibliographical note

Publisher Copyright:
© The Author(s) 2017.

Fingerprint

Dive into the research topics of 'Long-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy'. Together they form a unique fingerprint.

Cite this