Establishing endpoints in canine myotubular myopathy for clinical translation

描述（由申请方提供）：在患者中，X连锁肌管性肌病（XLM TM）由肌管蛋白（MTM1）突变引起，并导致严重肌无力、呼吸衰竭和过早死亡。大多数患者在出生后12个月内死于呼吸系统并发症。目前，还没有治愈这种遗传性疾病的方法，原因是缺乏反映人类疾病基因型和表型的动物模型。最近，XLMTM的犬模型被鉴定，并且获得了该疾病的遗传携带者。第一个XLMTM犬群的建立使研究人员能够开发和利用一种新的临床相关动物模型进行临床前试验。作为未来临床前试验的先决条件，犬模型的发病、进展和病理生理学特征将首先需要仔细的基线研究。因此，具体目标是：具体目标1。通过对系列活检的分析，确定XLMTM犬骨骼肌组织病理学的时间进程并确定其特征。具体目标2。建立XLMTM犬进行性临床下降的时间过程。 公共卫生相关性：X连锁肌管性肌病（XLM TM）是由肌管蛋白（MTM1）突变引起的，可导致严重的肌无力、呼吸衰竭和过早死亡。在此，我们建议开发和利用一种新的XLMTM犬模型。

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.