Novel therapies for neuromuscular diseases with altered phosphoinositide metabolism

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Phosphoinositides (PIs) are small lipid molecules found on different compartments inside of the cell. Their amounts and location in cells are tightly regulated and balanced by proteins called kinases and phosphatases. Mutations in the genes that make several of these proteins have been described in an emerging group of rare childhood genetic diseases including forms of epilepsy, brain malformations, neuropathy, and muscle disease. As a group, these diseases are associated with severe symptoms and, in many cases, early death, and none have treatments. Our goal is find therapies for these devastating disorders. We are particularly focused on diseases associated with mutations in myotubularins, termed MTMopathies. Myotubularins are PIs phosphatases, and mutations in the genes that encode them are associated with severe forms of childhood muscle and nerve disorders. Specifically, mutations in myotubularin (or MTM1) cause X-linked myotubular myopathy (XLMTM) and mutations in myotubular related protein 2 (or MTMR2) cause a form of Charcot-Marie-Tooth neuropathy (CMT4B1). We have shown using both cell and animal models of these diseases that not having either MTM1 or MTMR2 cause accumulation of certain phosphoinositide lipids and that, in turn, cause disease. We then discovered that normalizing the levels of these phosphoinositide lipids by genetically removing the kinases that act opposite myotubularins can dramatically improve features of animals models of these diseases, including even completely reversing them. Based on these results, we hypothesized that chemicals that inhibit these kinases can treat these disorders. In this proposal, we will test this hypothesis by identifying drugs that act against these kinases and then investigating them in well defined models of XLMTM and CMT4B1. We will use 3 different strategies for developing such inhibitors (medicinal chemistry, industrial partnership, and drug repurposing screen), and will test and validate them using a pipeline that includes both cell culture and zebrafish models. Promising kinase inhibitors will then be examined to see whether they can rescue/reverse the abnormalities we observe in our mouse models of human MTMopathies; such models have previously been developed by members of the consortium. Successful drugs will be amenable to rapid translation to patients to be potentially tested in clinical trials, and could provide the first meaningful therapy for these severe diseases of childhood. In addition, our work will lay the groundwork for considering similar approaches for the other neurogenetic diseases associated with abnormalities in how PIs are made or broken down, and will greatly advance the understanding of these conditions.