Long-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy - Archive ouverte HAL Access content directly
Journal Articles Nature Communications Year : 2017

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

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Caroline C. Le Guiner
  • Function : Author
Marie Montus
  • Function : Author
Alberto Malerba
  • Function : Author
Taeyoung Koo
  • Function : Author
Jean-Laurent Thibaut
  • Function : Author
Stéphane Blot
Samia Martin
  • Function : Author
  • PersonId : 938057
Carole Masurier
  • Function : Author
Federico Mingozzi
Bernard Gjata
  • Function : Author
Jean-Yves Hogrel
  • Function : Author
  • PersonId : 901910
Fulvio Mavilio
  • Function : Author
George Dickson
  • Function : Author
Laurent Thibaut
  • Function : Author
Christophe Georger

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.
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hal-02179396 , version 1 (26-05-2020)

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Caroline C. Le Guiner, Laurent Servais, Marie Montus, Thibaut Thibaut, Bodvael Fraysse, et al.. Long-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy. Nature Communications, 2017, 8 (1), pp.16105. ⟨10.1038/ncomms16105⟩. ⟨hal-02179396⟩
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