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Summary: This proposal will identify novel therapies for MTMopathies suitable for rapid clinical translation, test the concept of unified treatment for all MTMopathies, and lay the ground work for therapy development for the broader group of phosphoinoisitide (PIs) metabolism disorders.
Background: MTMopathies are rare neuromuscular genetic conditions caused by mutations in members of the myotubularin (MTMR) gene family. Specifically, mutations in MTM1 cause X-linked myotubular myopathy, and mutations in MTMR2, MTMR5 and MTMR13 are causes of autosomal recessive Charcot-Marie-Tooth Disease Type 4B. MTMopathies are characterized by severe muscle weakness and progressive disabilities (including wheelchair and ventilator dependence), as well as early mortality in some cases. Despite this high burden of morbidity and mortality, no therapies exist for this group of childhood disorders. Of note, MTMopathies are one subtype of an emerging group of neurogenetic diseases due to abnormalities in PIs metabolism that include forms of epilepsy, brain malformation syndrome, neurodevelopmental disease and neuropathies. MTMRs are phosphatases that function to dephosphorylate PIs at the 3-position. Mutations in MTMR genes result in abnormal levels of several PIs. Using the strategy of genetic inhibition of the kinases that regulate the PIs acted upon by MTMRs, we have shown in preclinical disease models that rebalancing PIs is a treatment strategy for MTMopathies. In this proposal, we will test the hypothesis that pharmacologic inhibition of these kinases can provide effective treatment for the diseases associated with MTM1 and MTMR2 mutations.
Objective: To develop and translate therapies for MTMopathies based on the principle of PIs rebalancing via kinase inhibition.
Methods: The goal of this proposal is to develop, validate and translate inhibitors to the PIs kinases PIK3C2B and PIKfyve. We will accomplish this using a pipeline of in vitro drug discovery, cell culture validation of target engagement, zebrafish model testing for efficacy and toxicity, and interventional pre-clinical trials in establishment mouse models. The proposed research pipeline integrates the synergistic expertise of the collaborative team.