Establishing endpoints in canine myotubular myopathy for clinical translation

描述(申请人提供)：在患者中，X连锁肌管肌病(XLMTM)是由肌管蛋白(MTM1)突变引起的，导致严重的肌肉无力、呼吸衰竭和过早死亡。大多数患者在出生后12个月内死于呼吸道并发症。目前，这种遗传性疾病还没有治愈方法，这是因为缺乏同时反映人类状况的基因和表型的动物模型。最近，鉴定了一种XLMTM犬模型，并获得了该疾病的遗传携带者。第一个XLMTM犬群的建立现在允许研究人员为临床前试验开发和开发一种新的临床相关动物模型。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，本研究的具体目的是：1.通过对XLMTM犬骨骼肌系列活检的分析，建立其骨骼肌组织病理学的时间进程，明确其特点。具体目的2.建立XLMTM犬进行性临床下降的时间进程。

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.