Molecular Mechanisms of Dystrophin Expression in Ameliorated Phenotypes

改善表型中肌营养不良蛋白表达的分子机制

• 批准号: 10660396
• 负责人: KEVIN M FLANIGAN
• 金额: $ 45.44万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-18 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660396
• 关键词: Address; Age; Alleles; Becker Muscular Dystrophy; Biopsy; Cell Line; Characteristics; Clinical; Data; Dependovirus; Development; Disease; Duchenne muscular dystrophy; Dystrophin; Exons; Family; Gene Delivery; Genes; Genetic; Genotype; Goals; Length; Link; Longevity; Messenger RNA; Methods; Molecular; Muscle; Muscular Dystrophies; Mutation; Mutation Analysis; Myoblasts; Needles; Open Reading Frames; Outcome; Patients; Phenotype; Principal Investigator; Privatization; Prognosis; Protein Isoforms; Proteins; RNA Splicing; Reading Frames; Retreatment; Rod; Severities; Severity of illness; Spectrin; Techniques; Testing; Therapeutic; Time; Transgenes; Variant; Viral Packaging; Work; boys; clinical phenotype; cohort; dystrophinopathy; exon skipping; functional outcomes; gene replacement therapy; gene therapy; genomic predictors; improved outcome; insight; micro-dystrophin; novel; patient population; patient subsets; postnatal; protective effect; restoration; sample archive; therapy development; transcriptome sequencing; vector

Abstract Duchenne muscular dystrophy (DMD) typically results from mutations in the DMD gene that disrupt the open reading frame, resulting in no dystrophin protein, whereas the milder Becker muscular dystrophy (BMD) typically results from mutations that allow expression of a partially functional dystrophin protein. This observation has led to the development of therapies intended to result in expression of internally-deleted, BMD-like dystrophin proteins. Despite the availability of four such commercial therapies for a subset of patients, and the transformative promise of microdystrophin gene therapies that are on the horizon, there are fundamental unanswered questions about the relationship of partial dystrophin expression to patient function—questions that bear on our ability to assess the benefits of therapies, to offer prognosis to families, and to guide approaches to retreatment in gene replacement therapies, among other issues. Furthermore, it will be critical to understand the distinctions between endogenous, lifelong expression of partially functional dystrophins, and therapeutic dystrophins delivered postnatally. Our long-term goal is to understand a fundamental question: How much dystrophin protein—and what kind of partially functional dystrophin, expressed at what time—is enough? Our objective in this project is two-fold. First, we seek to understand in finer detail the molecular parameters of dystrophin expression that result in phenotype amelioration. Second, we seek to develop methods for full-length dystrophin expression from the endogenous DMD gene, which is a possibility for a for a subset of patients, and has the potential for improved outcomes in comparison to microdystrophin. Our central hypothesis is that multiple mechanisms exist to account for variations in disease severity, and that understanding these mechanisms will lead to a better understanding of the durability and long-term benefits of dystrophin restoration therapies. Our rationale is that a detailed exploration of these mechanisms will lead to a better understanding of the long-term outcomes expected from novel gene therapies for DMD.

摘要 Duchenne肌营养不良症(DMD)通常是由DMD基因突变引起的 破坏开放阅读框架，导致没有营养不良蛋白，而较温和的Becker 肌营养不良症(BMD)通常是由允许部分表达的突变引起的 功能性营养不良蛋白。这一观察结果导致了预期治疗方法的发展 导致内部缺失的BMD样肌营养不良蛋白的表达。尽管有空闲时间 为部分患者提供四种这样的商业疗法，以及 微肌营养不良蛋白基因疗法即将问世，但根本上还没有答案 关于部分肌营养不良蛋白表达与患者功能关系的问题--问题 这关系到我们评估治疗的益处，为家庭提供预后的能力，以及 指导基因替代疗法中的再治疗方法，以及其他问题。 此外，理解内源性、终身性和终身性之间的区别是至关重要的 部分功能性肌营养不良蛋白的表达，以及治疗性肌营养不良蛋白在出生后的表达。 我们的长期目标是了解一个基本的问题：有多少Dstrophin蛋白-和 什么样的部分功能的肌营养不良蛋白，在什么时候表达就足够了？我们的目标是 这个项目是双重的。首先，我们试图更详细地了解分子参数 导致表型改善的肌营养不良蛋白的表达。第二，我们谋求发展 从内源性DMD基因全长表达Dstrophin的方法 有可能对部分患者进行治疗，并有可能改善患者的预后 与微肌营养不良蛋白进行比较。我们的中心假设是，存在多种机制来 解释了疾病严重程度的差异，了解这些机制将导致 更好地了解抗肌营养不良蛋白修复疗法的耐用性和长期益处。 我们的理论基础是，对这些机制的详细探索将导致更好的理解 DMD的新基因疗法预期的长期结果。