Systemic AAV8-Mediated Gene Therapy Drives Whole-Body Correction of Myotubular Myopathy in Dogs

作者：Mack David L; Poulard Karine; Goddard Melissa A; Latoumerie Virginie; Snyder Jessica M; Grange Robert W; Elverman Matthew R; Denard Jerome; Veron Philippe; Buscara Laurine; Le Bec Christine; Hogrel Jean Yves; Brezovec Annie G; Meng Hui; Yang Lin; Liu Fujun; O'Callaghan Michael; Gopal Nikhil; Kelly Valerie E; Smith Barbara K; Strande Jennifer L; Mavilio Fulvio; Beggs Alan H; Mingozzi Federico; Lawlor Michael W; Buj Bello Ana^*; Childers Martin K^*

来源：Molecular Therapy, 2017, 25(4): 839-854.

DOI：10.1016/j.ymthe.2017.02.004

X-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.

• 出版日期2017-4-5
• 单位INSEAD