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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的 Duchenne肌肉营养不良（DMD）通常是由于DMD基因中的突变引起的破坏开放的阅读框肌肉营养不良（BMD）通常是由于突变引起的，允许部分表达功能性肌营养不良蛋白。该观察结果导致了预期的疗法的发展导致表达内部缺失的BMD样肌营养不良蛋白。尽管有可用性在一部分患者的四种此类商业疗法中，以及即将到来的微肺炎基因疗法，有基本的未解决关于部分肌营养不良蛋白表达与患者功能的关系 - 问题这对我们评估疗法益处，为家庭提供预后的能力以及指南方法在基因替代疗法中撤退以及其他问题。此外，了解内源性，终生之间的区别至关重要产后传递的部分功能性肌营养不良蛋白和热肌营养不良蛋白的表达。我们的长期目标是了解一个基本问题：多少肌营养不良蛋白和什么样的部分功能性肌营养不良蛋白在什么时间表示？我们的目标这个项目是两个方面。首先，我们寻求更细节地了解分子参数肌营养不良蛋白的表达，导致表型改善。第二，我们试图发展来自内源性DMD基因的全长肌营养不良蛋白表达的方法，这是一个一部分患者的可能性，并且有可能改善结果与微肺炎的比较。我们的核心假设是存在多种机制解释疾病严重程度的差异，理解这些机制将导致更好地了解肌营养不良蛋白恢复疗法的耐用性和长期益处。我们的理由是，对这些机制的详细探索将导致更好的理解 DMD的新基因疗法期望的长期结果。