Enzyme replacement therapy rescues weakness and improves muscle pathology in mice with X-linked myotubular myopathy

Abstract

No effective treatment exists for patients with X-linked myotubular myopathy (XLMTM), a fatal congenital muscle disease caused by deficiency of the lipid phosphatase, myotubularin. The Mtm1δ4 and Mtm1 p.R69C mice model severely and moderately symptomatic XLMTM, respectively, due to differences in the degree of myotubularin deficiency. Contractile function of intact extensor digitorum longus (EDL) and soleus muscles from Mtm1δ4 mice, which produce no myotubularin, is markedly impaired. Contractile forces generated by chemically skinned single fiber preparations from Mtm1δ4 muscle were largely preserved, indicating that weakness was largely due to impaired excitation contraction coupling. Mtm1 p.R69C mice, which produce small amounts of myotubularin, showed impaired contractile function only in EDL muscles. Short-term replacement of myotubularin with a prototypical targeted protein replacement agent (3E10Fv-MTM1) in Mtm1δ4 mice improved contractile function and muscle pathology. These promising findings suggest that even low levels of myotubularin protein replacement can improve the muscle weakness and reverse the pathology that characterizes XLMTM.

Current and future therapeutic approaches to the congenital myopathies

“…Delivery of functional myotubularin applying an AAV8-based vector has now been demonstrated to improve the clinical and histopathological phenotype in Mtm1-deficient mice, and to increase muscle strength, reduce respiratory impairment and prolong survival in a canine model of XLMTM [61], the Labrador retriever [62]. Similar improvements of contractile function and histopathological features have been observed following short term myotubularin enzyme replacement in Mtm1d4 mice [63]. Results from these animal studies have been promising and have provided the basis for human enzyme replacement and gene therapy trials currently in preparation.…”

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

“…In Mtm1 knockout mice, administration of low levels of an engineered myotubularin protein were sufficient to improve both muscle function and pathology (35). In other studies, mice carrying an engineered Mtm1 missense mutation that affects RNA splicing and leaves just traces of myotubularin activity survive 8 times longer than constitutive Mtm1 knockout mutants (36).…”

Triadopathies: An Emerging Class of Skeletal Muscle Diseases

“…This same group also demonstrated the efficacy of local adenoassociated virus-Mtm1 infusion as a treatment for dogs with Mtm1 mutations. Another parallel advance has been the use of enzyme replacement therapy with MTM1 protein, where a pilot study using locally administered MTM1 improved the disease phenotype in Mtm1 knockout mice [65]. Both MTM1 gene and protein therapies are poised for testing in patients via clinical trials.…”