Establishing endpoints in canine myotubular myopathy for clinical translation

建立犬肌管肌病的临床转化终点

• 批准号: 8543634
• 负责人: Martin K Childers
• 金额: $ 19.77万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-12 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8543634
• 关键词: Address; Affect; Age; Age-Years; Amino Acid Substitution; Animal Model; Atrophic; Benchmarking; Biological; Biological Assay; Biopsy; Birth; Canis familiaris; Centronuclear myopathy; Cessation of life; Characteristics; Clinical; Clinical Research; Clinical Trials; Clinical assessments; Consultations; Contracture; DNA Sequence; Data; Development; Disease; Disease Progression; Dose; Female; Future; Genes; Genetic Carriers; Genotype; Hindlimb; Histopathology; Human; Inherited; Joints; Knock-out; Laboratories; Labrador; Life; Limb structure; Maintenance; Measurement; Measures; Methods; Modeling; Molecular; Mus; Muscle; Muscle Weakness; Muscle function; Muscular Atrophy; Mutation; Myopathy; Neuromuscular Diseases; Pathology; Patients; Performance Status; Phenotype; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Physiological; Point Mutation; Progressive Clinical Course; Protein Tyrosine Phosphatase; Proteins; Research Design; Research Personnel; Respiratory Failure; Respiratory Insufficiency; Respiratory physiology; Rest; Skeletal Muscle; Supportive care; System; Tarsal Joints; Testing; Therapeutic Studies; Tidal Volume; Time; TimeLine; Transgenes; Translating; Translational Research; Translations; Treatment Efficacy; X-linked myotubular myopathy; base; boys; clinically relevant; design; disease phenotype; effective therapy; gene replacement; gene therapy; genetic pedigree; male; multicatalytic endopeptidase complex; muscle strength; mutant; myotubularin; novel; outcome forecast; pre-clinical; preclinical study; premature; pressure; public health relevance; respiratory; response; stem; success

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.

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。

项目成果

Gene therapy in monogenic congenital myopathies.

单基因先天性肌病的基因治疗。

• DOI: 10.1016/j.ymeth.2015.10.004
• 发表时间: 2016
• 期刊: Methods (San Diego, Calif.)
• 作者: Guan,Xuan;Goddard,MelissaA;Mack,DavidL;Childers,MartinK
• 通讯作者: Childers,MartinK

Respiratory assessment in centronuclear myopathies.

中心核肌病的呼吸评估。

• DOI: 10.1002/mus.24249
• 发表时间: 2014
• 期刊: Muscle & nerve
• 影响因子: 3.4
• 作者: Smith,BarbaraK;Goddard,Melissa;Childers,MartinK
• 通讯作者: Childers,MartinK

Regenerative rehabilitation: a new future?

• DOI: 10.1097/phm.0000000000000211
• 发表时间: 2014-11
• 期刊: American journal of physical medicine & rehabilitation
• 影响因子: 3
• 作者: Perez-Terzic C;Childers MK
• 通讯作者: Childers MK

Validity of a Neurological Scoring System for Canine X-Linked Myotubular Myopathy.

犬 X 连锁肌管肌病神经评分系统的有效性。

• DOI: 10.1089/humc.2015.049
• 发表时间: 2015
• 期刊: Human gene therapy. Clinical development
• 作者: Snyder,JessicaM;Meisner,Allison;Mack,David;Goddard,Melissa;Coulter,IanT;Grange,Robert;Childers,MartinK
• 通讯作者: Childers,MartinK