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 Wahbi, Stéphane 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 () and George Dickson ()
Additional contact information
Caroline Le Guiner: Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, IRS2 Nantes Biotech
Laurent Servais: Institute I-Motion, Hôpital Armand Trousseau
Marie Montus: Généthon
Thibaut Larcher: Atlantic Gene Therapies
Bodvaël Fraysse: Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, IRS2 Nantes Biotech
Sophie Moullec: Atlantic Gene Therapies, Centre de Boisbonne, ONIRIS, La Chantrerie
Marine Allais: Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, IRS2 Nantes Biotech
Virginie François: Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, IRS2 Nantes Biotech
Maeva Dutilleul: Atlantic Gene Therapies
Alberto Malerba: School of Biological Sciences, Royal Holloway, University of London
Taeyoung Koo: School of Biological Sciences, Royal Holloway, University of London
Jean-Laurent Thibaut: Institut de Myologie, Laboratoire RMN, AIM & CEA
Béatrice Matot: Institut de Myologie, Laboratoire RMN, AIM & CEA
Marie Devaux: Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, IRS2 Nantes Biotech
Johanne Le Duff: Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, IRS2 Nantes Biotech
Jack-Yves Deschamps: Atlantic Gene Therapies, Centre de Boisbonne, ONIRIS, La Chantrerie
Inès Barthelemy: Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort
Stéphane Blot: Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort
Isabelle Testault: Centre Hospitalier Vétérinaire Atlantia
Karim Wahbi: Service de cardiologie, AP-HP, Cochin Hospital–Université Paris Descartes-Sorbonne Paris Cité–Institut de Myologie, Reference Center for Muscle Diseases
Stéphane Ederhy: Service de cardiologie, hôpital Saint-Antoine, AP-HP
Samia Martin: Généthon
Philippe Veron: Généthon
Christophe Georger: Généthon
Takis Athanasopoulos: School of Biological Sciences, Royal Holloway, University of London
Carole Masurier: Généthon
Federico Mingozzi: Généthon
Pierre Carlier: Institut de Myologie, Laboratoire RMN, AIM & CEA
Bernard Gjata: Généthon
Jean-Yves Hogrel: Institut de Myologie, Neuromuscular Physiology and Evaluation Laboratory
Oumeya Adjali: Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, IRS2 Nantes Biotech
Fulvio Mavilio: Généthon
Thomas Voit: NIHR Biomedical Research Centre, UCL Institute of Child Health/Great Ormond Street Hospital NHS Trust
Philippe Moullier: Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, IRS2 Nantes Biotech
George Dickson: School of Biological Sciences, Royal Holloway, University of London

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms16105

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