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

1 U1089
2 Service of Clinical Trials and Databases
3 Généthon
4 Centre de recherche en Myologie – U974 SU-INSERM
5 Inserm UMR 1089 - Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques
6 Centre de Boisbonne, Atlantic Gene Therapies
7 Thérapie génique translationnelle pour les maladies neuromusculaires et de la rétine
8 PAnTher - Physiopathologie Animale et bioThérapie du muscle et du système nerveux
9 Royal Holloway
10 LRMN - Laboratoire de Résonance Magnétique Nucléaire
11 INSERM - Institut National de la Santé et de la Recherche Médicale
12 Modélisation thérapeutique en neurologie: myologie et biothérapies des myopathies canines
13 Chercheur indépendant
14 Centre Hospitalier Vétérinaire Atlantia
15 Service de Cardiologie [CHU Cochin]
16 Service de Cardiologie [CHU Saint-Antoine]
17 LSIS - Laboratoire des Sciences de l'Information et des Systèmes
18 INTEGRARE - Approches génétiques intégrées et nouvelles thérapies pour les maladies rares
19 University of Wolverhampton
20 Laboratoire RMN, Institut de Myologie
21 Thérapie des maladies du muscle strié
22 UMR1089, Laboratoire de Thérapie Génique

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.

Domains: Life Sciences [q-bio]; Biochemistry, Molecular Biology; Molecular biology

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⟩