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.

抽象的杜氏肌营养不良症 (DMD) 通常由 DMD 基因突变引起，破坏开放阅读框，导致没有肌营养不良蛋白，而较温和的贝克尔肌营养不良症 (BMD) 通常是由突变导致的，这些突变允许部分表达这一观察结果导致了预期疗法的开发。导致内部缺失的 BMD 样肌营养不良蛋白的表达。针对一小部分患者的四种此类商业疗法，以及变革性的前景微抗肌营养不良蛋白基因疗法即将出现，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效果、为家庭提供预后以及除其他问题外，指导基因替代疗法中的再治疗方法。此外，理解内生性、终身性之间的区别也至关重要。部分功能性肌营养不良蛋白和出生后递送的治疗性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：肌营养不良蛋白的含量是多少？什么样的部分功能性肌营养不良蛋白，在什么时间表达就足够了？这个项目有两个方面：首先，我们寻求更详细地了解分子参数。其次，我们寻求开发导致表型改善的肌营养不良蛋白表达。内源性 DMD 基因表达全长肌营养不良蛋白的方法，该基因是可能适用于一部分患者，并且有可能改善结果与微抗肌营养不良蛋白相比，我们的中心假设是存在多种机制。解释疾病严重程度的变化，并且了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持久性和长期益处。我们的理由是，对这些机制的详细探索将有助于更好地理解 DMD 新型基因疗法预期的长期结果。