G.P.41: Canine X-linked myotubular myopathy: A dose-finding study of systemic AAV8-MTM1 effects on muscle strength, gait, respiration, neuromuscular function and survival

Abstract

Mutations in the myotubularin gene (MTM1) result in X-linked myotubular myopathy (XLMTM), a fatal pediatric disease of skeletal muscle characterized by small centrally nucleated myofibers containing abnormal mitochondrial accumulations. Patients typically present with severe hypotonia and respiratory failure. Previous local studies in Mtm1-mutant mice demonstrated potential efficacy of gene therapy to treat the disease. We recently reported that administration of adeno-associated virus serotype 8 (AAV8) vector expressing myotubularin under the muscle-specific desmin promoter, delivered systemically in myotubularin deficient mice and by regional hind limb perfusion in XLMTM dogs, could prolong life and restore muscle function. Here we report initial results of a larger dose escalation study testing the efficacy of AAV8-MTM1 systemic venous infusion in XLMTM dogs. Four groups were studied in a blinded manner: Wild-type or female carrier controls (N = 6); affected dogs given saline only (N = 4); affected dogs given AAV8-MTM1 (5E12 vg/kg) (N = 3) or (2.5E13 vg/kg) (N = 3). AAV8-MTM1 was administered at 10 weeks of age and dogs were followed for 9 months. Efficacy readouts included limb strength, gait, respiratory and neurological assessments at 13, 15, and 17 weeks-of-age, then monthly to 40 weeks-of-age. Results indicate a dose-dependent response to AAV8-MTM1. At the highest AAV dose, we observed marked improvements to near-normal levels in all physiological and clinical parameters tested along with improved survival, whereas the lowest dose provided only modest improvements. Together, these data indicate a dose-response for AAV8-MTM1 on muscle strength, walking speed, neuromuscular function and survival in dogs with myotubularin deficiency.