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. This study aimed 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. At therapeutic doses, rAAV8-cMTM1 was well tolerated and led to expression of myotubularin protein in skeletal muscles, with repaired myofibre pathology. Most importantly, treatment with rAAV8-cMTM1 led to extended survival, recovery of neurological function, and improvements in peak airflow velocity, limb strength, and walking gait without safety concerns. These data provide strong rationale for moving therapeutic doses of rAAV8-MTM1 into clinical studies.
Mack DL, Poulard K, Goddard MA, et al. Systemic AAV8-Mediated Gene Therapy Drives Whole-Body Correction of Myotubular Myopathy in Dogs. Mol Ther. 2017 Apr 5;25(4):839-854.
