Pathophysiology and Treatment of Recessive RYR1 Related Myopathy

隐性 RYR1 相关肌病的病理生理学和治疗

• 批准号: 10405495
• 负责人: JAMES J DOWLING
• 金额: $ 39.94万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-29 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10405495
• 关键词: Acute; Alleles; Animal Model; Cessation of life; Characteristics; Chemicals; Chronic; Clinical; Coupling; Data; Disease; Drug Targeting; Epigenetic Process; Exhibits; Exons; FDA approved; Functional disorder; GDF8 gene; Genes; Goals; Growth; High Prevalence; Histone Deacetylase; Histone Deacetylase Inhibitor; Human Characteristics; Inheritance Patterns; Inherited; Intervention; Messenger RNA; Modeling; Molecular Chaperones; Mus; Muscle; Muscle Fibers; Muscle Weakness; Mutate; Mutation; Myopathy; Outcome; Outcome Measure; Output; Pathogenesis; Patients; Pharmaceutical Preparations; Phenocopy; Point Mutation; Pre-Clinical Model; Preclinical Testing; Receptor Gene; Respiratory Insufficiency; Ryanodine Receptor Calcium Release Channel; Sampling; Sarcoplasmic Reticulum; Severities; Severity of illness; Skeletal Muscle; Sodium; Testing; Therapeutic; Therapeutic Intervention; Treatment Efficacy; base; disability; disease phenotype; early onset; ebselen; effective therapy; efficacy evaluation; endoplasmic reticulum stress; epigenome; infancy; inhibitor; inhibitor therapy; insertion/deletion mutation; insight; mortality; mouse model; mutant; novel; premature; primary outcome; protein degradation; protein expression; protein folding; protein function; receptor; receptor expression; receptor function; secondary outcome; therapeutic evaluation; therapy design; therapy development

Mutations in the gene that encodes the skeletal muscle type I ryanodine receptor (RYR1) result in a wide range of muscle disorders that collectively comprise the most common cause of non-dystrophic myopathy. The most severe cases of RYR1-related myopathy (RYR1-RM) exhibit a recessive pattern of inheritance and present in infancy with muscle hypotrophy, weakness, respiratory insufficiency, short stature, and a marked reduction in RYR1 protein expression in muscle. Despite their severity, high prevalence and association with significant disability and early mortality, there are no treatments or disease-modifying therapies for RYR1-RM. A major barrier to therapy development has been the lack of an animal model that mirrors the early onset and clinical severity of recessive RYR1-RM. To overcome this barrier, we developed two mouse models of recessive RYR1-RM that pheno-copy key characteristics of the human disorder including myofiber hypotrophy, reduced muscle/body mass, muscle weakness, markedly reduced RYR1 expression, and premature death. The scientific premise of this proposal is that these new mouse models of RYR1-RM provide a unique opportunity to explore the underlying patho-mechanisms of RYR1-RM and test the therapeutic efficacy of mechanism-based interventions. The overall goal of the project is to elucidate the patho-mechanisms responsible for muscle dysfunction in recessive RYR1-RM and to develop and validate effective treatments. We hypothesize that reduced folding/stability of mutated RYR1 homotetramers results in increased RYR1 protein degradation that markedly reduces RYR1 expression, and that even a modest increase in either RYR1 expression or function will ameliorate the myopathy and prolong survival. Furthermore, we also hypothesize that reduced myofiber size in RYR1-RM is a key aspect of disease pathogenesis, that hypotrophy is due to epigenetic abnormalities, and that drugs that target the epigenome or promote muscle growth can ameliorate the disease phenotype. The validity of these hypotheses will rigorously evaluated in three specific aims. Aim 1 will characterize RYR1 expression, function and myopathy in two mouse models of severe, recessive RYR1-RM and assess the therapeutic potential of systemic treatment with ebselen, an FDA-approved drug and known RYR1 activator. Aim 2 will elucidate the mechanism(s) for reduced RYR1 expression in our mouse models of RYR1-RM mice and evaluate the therapeutic efficacy of systemic treatment with a chemical chaperone and ER stress inhibitor (4PBA). Aim 3 will determine the mechanisms leading to muscle hypotrophy in RYR1-RM mice and test the potential of treatment with either HDAC inhibitors or modulators of myofiber size. The results of these studies will provide novel insights into the patho-mechanisms responsible for reduced RYR1 expression and muscle fiber hypotrophy in recessive RYR1-RM and determine the therapeutic potential of several mechanism-based interventions designed to enhance RYR1 function, reduce RYR1 degradation, and limit muscle hypotrophy in pre-clinical models of recessive RYR1-RM.

编码骨骼肌I型ryanodine受体（RYR1）的基因突变导致范围广泛