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: 10224943
• 负责人: JAMES J DOWLING
• 金额: $ 39.14万
• 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/10224943
• 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/antagonist; 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 型兰尼碱受体 (RYR1) 的基因突变会导致多种疾病 肌肉疾病共同构成非营养不良性肌病的最常见原因。最 RYR1相关肌病（RYR1-RM）的严重病例表现出隐性遗传模式并存在于 婴儿期肌肉萎缩、虚弱、呼吸功能不全、身材矮小、智力明显下降 RYR1 蛋白在肌肉中的表达。尽管其严重性，但患病率高且与显着相关 由于 RYR1-RM 可能导致残疾和早期死亡，目前尚无针对 RYR1-RM 的治疗方法或疾病缓解疗法。一个专业 治疗开发的障碍是缺乏反映早期发病和临床的动物模型 隐性 RYR1-RM 的严重程度。为了克服这一障碍，我们开发了两种隐性小鼠模型 RYR1-RM 复制了人类疾病的关键特征，包括肌纤维萎缩、减少 肌肉/体重、肌肉无力、RYR1 表达显着降低和过早死亡。 该提案的科学前提是这些新的 RYR1-RM 小鼠模型提供了独特的 有机会探索 RYR1-RM 的潜在病理机制并测试其治疗效果 基于机制的干预措施。该项目的总体目标是阐明病理机制 负责隐性 RYR1-RM 的肌肉功能障碍，并开发和验证有效的治疗方法。 我们假设突变 RYR1 同四聚体的折叠/稳定性降低导致 RYR1 增加 蛋白质降解显着降低 RYR1 表达，甚至 RYR1 中的任何一个适度增加 表达或功能将改善肌病并延长生存期。此外，我们还假设 RYR1-RM 中肌纤维尺寸的减少是疾病发病机制的一个关键方面，肌纤维萎缩是由于 表观遗传异常，靶向表观基因组或促进肌肉生长的药物可以改善 疾病表型。这些假设的有效性将在三个具体目标中进行严格评估。 目标 1 将描述两种严重隐性遗传小鼠模型中 RYR1 表达、功能和肌病的特征 RYR1-RM 并评估 FDA 批准的药物 ebselen 全身治疗的治疗潜力 和已知的RYR1激活剂。目标 2 将阐明小鼠中 RYR1 表达减少的机制 RYR1-RM小鼠模型并评估化学药物全身治疗的疗效 分子伴侣和 ER 应激抑制剂 (4PBA)。目标 3 将确定导致肌肉萎缩的机制 在 RYR1-RM 小鼠中测试 HDAC 抑制剂或肌纤维调节剂治疗的潜力 尺寸。这些研究的结果将为导致疾病的病理机制提供新的见解。 隐性 RYR1-RM 中 RYR1 表达减少和肌纤维萎缩并确定治疗方案 旨在增强 RYR1 功能、减少 RYR1 的几种基于机制的干预措施的潜力 退化，并限制隐性 RYR1-RM 临床前模型中的肌肉萎缩。