Establishing endpoints in canine myotubular myopathy for clinical translation

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DESCRIPTION (provided by applicant): In patients, X-linked myotubular myopathy (XLMTM) is caused by mutation in myotubularin (MTM1) and results in profound muscular weakness, respiratory failure and premature death. Most patients succumb to respiratory complications within 12 months of birth. Currently, there is no cure for this inherited disease, stemming, in par, from the lack of animal models that reflect both the genotype and phenotype of the human condition. Recently, a canine model of XLMTM was identified, and a genetic carrier of the disease was acquired. The establishment of the first XLMTM canine colony now allows investigators to develop and exploit a novel clinically-relevant animal model for pre-clinical trias. As a prerequisite to future preclinical trials, the onset, progression and pathophysiologic characteristics of the canine model will first require careful baseline studies. As such, the specific aims are: Specific Aim 1. Establish the time course and define the characteristics of skeletal muscle histopathology in XLMTM dogs through analysis of serial biopsies. Specific Aim 2. Establish the time course of progressive clinical decline in XLMTM dogs. PUBLIC HEALTH RELEVANCE: X-linked myotubular myopathy (XLMTM) is caused by mutation in myotubularin (MTM1) and results in profound muscular weakness, respiratory failure and premature death. Herein we propose to develop and exploit a novel canine model of XLMTM.