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

Caroline Le Guiner 1 Laurent Servais 2 Marie Montus 3 Thibaut Thibaut Bodvael Fraysse 4 Sophie Moullec 5 Marine Allais 6 Virginie François 7 Maeva Dutilleul 8 Alberto Malerba 9 Taeyoung Koo 9 Jean-Laurent Thibaut Béatrice Matot 10 Marie Devaux 11 Johanne Le Duff 7 Jack-Yves Deschamps 8 Inès Barthélémy 12 Stéphane Blot 13 Isabelle Testault 14 Karim Wahbi 15 Stéphane Ederhy 16 Samia Martin 17 Philippe Veron 18 George Georger 19 Takis Athanasopoulos 20 Carole Masurier 3 Federico Mingozzi 3 Pierre Carlier 21 Bernard Gjata 3 Jean-Yves Hogrel 22 Oumeya Adjali 23 Fulvio Mavilio 3 Thomas Voit 24 Philippe Moullier 25 George Dickson 9 Thibaut Larcher 8 Laurent Thibaut Christophe Georger 26
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 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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