Gene Therapy Prolongs Survival and Restores Function in Murine and Canine Models of Myotubular Myopathy

Abstract

Loss-of-function mutations in the myotubularin gene (MTM1) cause X-linked myotubular myopathy (XLMTM), a fatal, congenital pediatric disease that affects the entire skeletal musculature. Systemic administration of a single dose of a recombinant serotype-8 adeno-associated virus (AAV8) vector expressing murine myotubularin to Mtm1-deficient knockout mice at the onset or at late stages of the disease resulted in robust improvement in motor activity and contractile force, corrected muscle pathology and prolonged survival throughout a 6-month study. Similarly, single-dose intravascular delivery of a canine AAV8-MTM1 vector in XLMTM dogs markedly improved severe muscle weakness and respiratory impairment, and prolonged lifespan to more than one year in the absence of toxicity, humoral and cell-mediated immune response. These results demonstrate the therapeutic efficacy of AAV-mediated gene therapy for myotubular myopathy in small and large animal models, and provide proof of concept for future clinical trials in XLMTM patients.

Duchenne muscular dystrophy gene therapy in the canine model

“…131 Since then, several groups have tested AAV-8 in normal 132 and affected dogs. 100,133,134 In contrast to the initial report by Ohshima et al, these later studies did not detect cellular immune reaction. Koo et al expressed a canine-microdystrophin in a 9-week-old affected dog without immune suppression.…”

Triadopathies: An Emerging Class of Skeletal Muscle Diseases

“…By far the most promising is related to myotubular myopathy. An international collaborative group demonstrated that gene therapy with MTM1 not only prevents, but also reverses, the phenotype of Mtm1 knockout mice [64]. This same group also demonstrated the efficacy of local adenoassociated virus-Mtm1 infusion as a treatment for dogs with Mtm1 mutations.…”

Validity of a Neurological Scoring System for Canine X-Linked Myotubular Myopathy

“…9 A missense mutation in the MTM gene (c.465C > A; p.N155K) was discovered and a breeding colony subsequently was established. 9,11 Recently, we reported response to gene therapy in canine and rodent models of XLMTM 12 ; however, in this report a clinical evaluation strategy was not in place to assess dogs. A reliable method to monitor clinical response to therapy would strengthen further evaluation of this disease model.…”

“…For example, we recently reported that gene therapy markedly improved muscle weakness and respiratory impairment and prolonged life span to more than 1 year in treated XLMTM dogs. 12 Further analysis would be required to evaluate the utility of the described neurological severity scoring system in predicting response to treatment in this spontaneous animal model of XLMTM.…”

“…The only measure of disease severity that correlated moderately well with the neurological severity score at 10 weeks of age (i.e., baseline) was hind limb torque flexion, an established technique in this animal model and in other models of neuromuscular disease. 12,[20][21][22] There was a difference between XLMTM and wild-type dogs in neurological severity scores at the earliest age tested (10 weeks), although dogs were relatively mildly affected at this age. Clinical signs at this age included an inability to hold the jaw in a closed position and an abnormal gait characterized by a tendency to push off with both hind limbs (''hopping'') when trotting and running and occasionally a short stride or stilted gait.…”