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

Caroline C. Le Guiner 1 Laurent Servais 2 Marie Montus 3 Thibaut Thibaut Bodvael Fraysse 4 Sophie Moullec 5 Marine Allais 6 Virginie François 4 Maeva Dutilleul 7 Alberto Malerba 8 Taeyoung Koo 8 Jean-Laurent Thibaut Béatrice Matot 9 Marie Devaux 10 Johanne Le Duff 4 Jack-Yves Deschamps 7 Inès Barthélémy 11 Stéphane Blot 12 Isabelle Testault 13 Karim Wahbi 14 Stéphane Ederhy 15 Samia Martin 3 Philippe Veron 16 George Georger 17 Takis Athanasopoulos 18 Carole Masurier 3 Federico Mingozzi 3 Pierre Carlier 19 Bernard Gjata 3 Jean-Yves Hogrel 20 Oumeya Adjali 3, 4 Fulvio Mavilio 3 Thomas Voit 21 Philippe Moullier 22 George Dickson 8 Thibaut Larcher 7 Laurent Thibaut Christophe Georger 3 
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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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, Nature Publishing Group, 2017, 8 (1), pp.16105. ⟨10.1038/ncomms16105⟩. ⟨hal-02179396⟩



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