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

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.

• Authors: 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, George Dickson
• Journal: Nature communications (Nat Commun) Vol. 8 Pg. 16105 (07 25 2017) ISSN: 2041-1723 [Electronic] England
• PMID: 28742067 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dystrophin

Topics

• Administration, Intravenous
• Animals
• Dependovirus
• Disease Models, Animal
• Dogs
• Dystrophin (genetics)
• Gene Transfer Techniques
• Genetic Therapy
• Genetic Vectors
• Male
• Muscle, Skeletal (metabolism, physiopathology)
• Muscular Dystrophy, Animal (genetics, metabolism, physiopathology, therapy)
• Muscular Dystrophy, Duchenne (genetics, metabolism, physiopathology)
• Transgenes