The long term goals of this research proposal are to evaluate the efficacy of myostatin inhibition as a treatment for myotubularin deficiency, which is responsible for X-linked myotubular myopathy (XLMTM) in human children. Children with XLMTM have severe weakness at an early age, and display small muscle fibers on muscle biopsy. While the function of myotubularin remains unclear, two murine models of myotubularin deficiency, the Mtm144 and Mtm1R69C models, have been developed to study this disease. We hypothesize that treatment strategies that increase muscle fiber size will cause symptomatic improvement in myotubularin deficient animals. One strategy to promote myofiber hypertrophy is through the inhibition of myostatin. Myostatin is a negative regulator of muscle growth, which can be knocked out or inhibited genetically or pharmacologically to produce mice with very large muscles and increased muscle strength. This proposal involves the use of a myostatin inhibitor called RAP-031 in the treatment of both strains of myotubularin- deficient mice, with subsequent studies designed to identify the mechanisms by which hypertrophy occurs or is limited in these animals. We will treat myotubularin deficient mice with RAP-031 and evaluate disease progression behaviorally, physiologically, and pathologically. Preliminary studies have shown that treatment of the more severe, Mtm144 mice causes an transient increase in weight, forelimb grip strength, and lifespan. Gene expression assays, microarrays, and Western blots will then be used to determine the activation of pathways involved in myofiber hypertrophy in treated and untreated mice, which can then be compared to the processes activated with RAP-031 in wild type animals. Using this information, further optimization of RAP- 031 treatment in myotubularin deficient animals will be attempted by combining it with other agents that promote myofiber hypertrophy. Based on our mechanistic studies and the results of multi-agent therapy in vitro, we will choose the two most promising combination therapies and test their efficacy in our myotubularin deficient mice. Success in this project would identify the optimal treatment regimen for patients with XLMTM using this therapeutic strategy, and provide the first treatment for this disease. Throughout my training, I have been fortunate enough to be mentored by exceptional scientists and physicians, which has culminated in my desire to pursue a career that incorporates what I have learned as a scientist and neuropathologist. My graduate work in the field of peripheral neuropathy, my current studies in congenital myopathy, and the loss of a childhood friend to muscular dystrophy have all contributed to my intense interest in developing novel treatment strategies for neuromuscular disease. My current full-time research position in the Beggs Lab at Children's Hospital Boston offers the ideal opportunity to pursue these goals, due to the collaborative environment, superb mentorship, and excellent technical resources that are available to me. Now that I have completed my clinical training, the funding provided by this K08 award would allow me to continue pursuing research as my major career focus as I continue to develop into an independent investigator, and the project described in this proposal provides a superb opportunity to pursue a new strategy for the treatment of congenital muscle disease.
This proposal focuses on assessing a novel therapeutic strategy as a treatment for children with XLMTM. Patients with XLMTM have no current therapeutic options, and the relationship between this disease and small myofibers provides a justification for the use of myostatin inhibitors as therapeutic agents. Additionally, because the therapeutic strategy here is unrelated to the genetic defect in myotubularin deficient mice, the treatments proposed in these studies could also be effective in other patients with myopathic disorders.
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|Pierson, Christopher R; Dulin-Smith, Ashley N; Durban, Ashley N et al. (2012) Modeling the human MTM1 p.R69C mutation in murine Mtm1 results in exon 4 skipping and a less severe myotubular myopathy phenotype. Hum Mol Genet 21:811-25|
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