Molecular and Cellular Therapies for Muscular Dystrophy

肌营养不良症的分子和细胞疗法

• 批准号: 6770701
• 负责人: STANLEY C FROEHNER
• 金额: $ 137.07万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-15 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6770701
• 关键词: muscular dystrophy

Duchenne muscular dystrophy, caused by mutations in the gene encoding dystrophin, is one of the most prevalent and devastating human genetic diseases. The goal of this application is to enhance and improve therapeutic strategies and to develop the basic biology for new innovative approaches. Jeff Chamberlain will build on his expertise in DMD gene therapy by developing novel vectors able to deliver mini-dystrophins and/or myogenic regulatory genes either to muscle cells or via hematopoietic and mesenchymal stem cells. A related goal will be exploring methods for the efficient conversion of somatic stem cells into skeletal muscle. Stan Froehner will study the role of alpha-dystrobrevin, a dystrophin-associated protein, in the degeneration process. Mice lacking alpha-dystrobrevin develop muscular dystrophy through a mechanism that involves alteration in cellular signaling. The key functional domains of alpha-dystrobrevin and proteins that interact with these domains will be identified. alpha-dystrobrevin, modified to target to the membrane, will be tested for its ability to alleviate the dystrophic pathology in mdx muscle. Finally, changes in gene expression induced in muscle cells per se by the absence of alpha-dystrobrevin will be analyzed. Steve Hausehka will test the in vivo tissue specificity and long-term expression of regulatory gene cassettes designed to be optimal for packaging different therapeutic cDNAs into AAV, Lentiviral, and Adenoviral vectors. These vectors will then be used to deliver micro-, mini-, and full-length dystrophin and a variety of compensatory proteins to the dystrophic muscles of mdx4cv mice. The Administrative Core will provide general support and organize the biannual Seattle Muscular Dystrophy Conference. The Mouse Biology Core will provide assistance with functional and pathological analyses of mouse models to each project. The results derived from this integrated program project will lead to new therapeutic approaches for DMD and other diseases of muscle degeneration.

杜氏肌营养不良症是由编码肌营养不良蛋白的基因突变引起的，是最普遍和最具破坏性的人类遗传疾病之一。该应用的目标是增强和改进治疗策略并开发新创新方法的基础生物学。 Jeff Chamberlain 将利用他在 DMD 基因治疗方面的专业知识，开发能够将微型肌营养不良蛋白和/或生肌调节基因传递到肌肉细胞或通过造血干细胞和间充质干细胞传递的新型载体。一个相关的目标是探索将成体干细胞有效转化为骨骼肌的方法。斯坦·弗勒纳将 研究α-肌营养不良蛋白（一种肌营养不良蛋白相关蛋白）在变性过程中的作用。缺乏α-抗肌营养不良蛋白的小鼠通过涉及细胞信号传导改变的机制发展为肌营养不良症。 α-dystrobrevin 的关键功能域以及与这些域相互作用的蛋白质将被识别。 α-dystrobrevin 经过修饰以靶向膜，将测试其缓解 mdx 肌肉营养不良病理的能力。最后，将分析由于缺乏α-dystrobrevin而在肌肉细胞本身中诱导的基因表达的变化。 Steve Hausehka 将测试调节基因盒的体内组织特异性和长期表达，这些基因盒旨在将不同的治疗性 cDNA 包装到 AAV、慢病毒和腺病毒载体中。然后，这些载体将用于向 mdx4cv 小鼠的营养不良肌肉递送微型、迷你和全长肌营养不良蛋白以及各种补偿蛋白。 行政核心将提供全面支持并组织一年两次的西雅图肌营养不良症会议。小鼠生物学核心将为每个项目提供小鼠模型功能和病理分析的帮助。该综合计划项目的结果将为 DMD 和其他肌肉退化疾病带来新的治疗方法。