Mack, David L.Poulard, KarineGoddard, Melissa A.Latoumerie, VirginieSnyder, Jessica M.Grange, Robert W.Elverman, Matthew R.Denard, JeromeVeron, PhilippeBuscara, LaurineLe Bec, ChristineHogrel, Jean-YvesBrezovec, Annie G.Meng, HuiYang, LinLiu, FujunO'Callaghan, MichaelGopal, NikhilKelly, Valerie E.Smith, Barbara K.Strande, Jennifer L.Mavilio, FulvioBeggs, Alan H.Mingozzi, FedericoLawlor, Michael W.Buj-Bello, AnaChilders, Martin K.2019-10-072019-10-072017-04-051525-0016http://hdl.handle.net/10919/94380X-linked myotubular myopathy (XLMTM) results from MTM1 gene mutations and myotubularin deficiency. Most XLMTM patients develop severe muscle weakness leading to respiratory failure and death, typically within 2 years of age. Our objective was to evaluate the efficacy and safety of systemic gene therapy in the p.N155K canine model of XLMTM by performing a dose escalation study. A recombinant adeno-associated virus serotype 8 (rAAV8) vector expressing canine myotubularin (cMTM1) under the muscle-speCific desmin promoter (rAAV8-cMTM1) was administered by simple peripheral venous infusion in XLMTM dogs at 10 weeks of age, when signs of the disease are already present. A comprehensive analysis of survival, limb strength, gait, respiratory function, neurological assessment, histology, vector biodistribution, transgene expression, and immune response was performed over a 9-month study period. Results indicate that systemic gene therapy was well tolerated, prolonged lifespan, and corrected the skeletal musculature throughout the body in a dose-dependent manner, defining an efficacious dose in this large-animal model of the disease. These results support the development of gene therapy clinical trials for XLMTM.application/pdfenCreative Commons Attribution-NonCommercial-NoDerivatives 4.0 InternationalArticle - Refereedhttps://doi.org/10.1016/j.ymthe.2017.02.004254282378391525-0024