Sen Paul D. Wellstone Muscular Dystrophy Cooperative Research Center: Seattle

参议员 Paul D. Wellstone 肌营养不良症合作研究中心：西雅图

• 批准号: 8735212
• 负责人: JEFFREY S CHAMBERLAIN
• 金额: $ 163.4万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-07 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8735212
• 关键词: Address; Advanced Development; Animal Model; Area; Basic Science; Biological Markers; Blood Vessels; Canis familiaris; Capsid Proteins; Catchment Area; Cell Line; Characteristics; Clinical; Clinical Research; Clinical Trials; Code; Collaborations; Communication; Communities; Consult; Development; Disease; Dose; Duchenne muscular dystrophy; Dystrophin; Event; Facioscapulohumeral; Facioscapulohumeral Muscular Dystrophy; Foundations; Fred Hutchinson Cancer Research Center; Funding; Future; Gene Delivery; Gene Transfer; Genes; Goals; Health; Heart; Human; Immune; Immune response; Individual; Inherited; Lead; Lentivirus Vector; Link; Magnetic Resonance Imaging; Measurement; Mediating; Medical center; Mentors; Messenger RNA; Methods; Modeling; Molecular; Mus; Muscle; Muscular Dystrophies; Neurologist; Patients; Pediatric Hospitals; Proteins; RNA Interference; Reagent; Regimen; Research; Research Ethics; Research Infrastructure; Research Personnel; Research Support; Resources; Respiratory Diaphragm; Scientist; Serotyping; Skeletal Muscle; Surrogate Endpoint; System; Testing; Therapeutic; Therapeutic Clinical Trial; Therapy Clinical Trials; Training; Universities; Washington; Work; adeno-associated viral vector; base; clinical infrastructure; data management; design; gene therapy; member; micro-dystrophin; mouse model; outreach; outreach program; preclinical study; programs; radiologist; safety testing; scale up; therapy development; vector

DESCRIPTION (provided by applicant): This Wellstone application is focused on preclinical and clinical studies of Duchenne muscular dystrophy (DMD) and facioscapulohumeral muscular dystrophy (FSHD), the two most common forms of dystrophy. This is a collaborative venture between scientists and clinicians at the University of Washington, Fred Hutchinson Cancer Research Center, Seattle Children's Hospital and The University of Rochester. Project 1 focuses on adapting methods for AAV-mediated gene transfer to large animal models for DMD by focusing on expression cassette design, AAV serotypes, physical delivery methods and scale-up to test the hypothesis that AAV vectors expressing microdystrophin can be used to treat all the major muscle groups involved in DMD. In parallel, we will adapt AAV systems for targeting the dominant disorder FSHD by delivering RNAi cassettes to cell lines and mouse models followed by safety testing in dogs. Thus, we are performing preclinical studies to develop clinical trials for dominant and recessively inherited dystrophies by modeling DMD and FSHD. This latter work provides a link to project 2, which will leverage the collaborative research programs on FSHD in Seattle and Rochester for studies of advanced biomarker assessments of disease, and to explore immune mediated events in FSHD. The clinical infrastructure to be developed in Project 2 will lay a foundation for future clinical trials of gen therapy for DMD, FSHD and other MDs at the University of Washington. These studies will be supported by three Cores. An Administrative Core to facilitate communication and coordination between the components of the Center and for overseeing data management and distribution. A Scientific Research Resource Core to provide stocks of AAV and lentiviral vectors to members of the Center and to muscular dystrophy researchers worldwide. This Core will also provide training, consulting and reagents related to muscular dystrophy research and gene transfer. Lastly, an Investigator Development and Patient Outreach Core (IDPO) for a mentored research program in basic and clinical research, and ethics that will prepare new investigators to address the critical needs of individuals with dystrophy. The IDPO will also provide outreach programs to the public and patient communities.

描述（由申请人提供）：该 Wellstone 申请重点关注杜氏肌营养不良症 (DMD) 和面肩肱型肌营养不良症 (FSHD) 这两种最常见的营养不良形式的临床前和临床研究。这是华盛顿大学、弗雷德哈钦森癌症研究中心、西雅图儿童医院和罗切斯特大学的科学家和临床医生之间的合作项目。项目 1 侧重于将 AAV 介导的基因转移方法应用于 DMD 的大型动物模型，重点关注表达盒设计、AAV 血清型、物理递送方法和放大，以检验表达微肌营养不良蛋白的 AAV 载体可用于治疗 DMD 涉及的所有主要肌肉群的假设。与此同时，我们将通过向细胞系和小鼠模型提供 RNAi 盒，然后在狗身上进行安全性测试，调整 AAV 系统，以针对显性疾病 FSHD。因此，我们正在进行临床前研究，通过 DMD 和 FSHD 建模来开展显性和隐性遗传性营养不良的临床试验。后一项工作提供了与项目 2 的链接，该项目将利用西雅图和罗切斯特的 FSHD 合作研究项目来研究疾病的高级生物标志物评估，并探索 FSHD 中的免疫介导事件。项目2将开发的临床基础设施将为华盛顿大学未来针对DMD、FSHD和其他MD的基因治疗临床试验奠定基础。这些研究将得到三个核心的支持。行政核心，促进中心各组成部分之间的沟通和协调，并监督数据管理和分发。科学研究资源核心，为中心成员和世界各地的肌营养不良研究人员提供 AAV 和慢病毒载体库存。该核心还将提供与肌营养不良症研究和基因转移相关的培训、咨询和试剂。最后，研究者发展和患者外展核心（IDPO），用于基础和临床研究以及伦理方面的指导研究项目，为新的研究者做好准备，以满足营养不良患者的关键需​​求。 IDPO 还将向公众和患者社区提供外展计划。