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

描述（由申请人提供）：该Wellstone申请专注于Duchenne型肌营养不良症（DMD）和面肩肱型肌营养不良症（FSHD）的临床前和临床研究，这是两种最常见的营养不良形式。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的重点是通过关注表达盒设计、AAV血清型、物理递送方法和放大来使AAV介导的基因转移方法适应DMD的大型动物模型，以测试表达微肌营养不良蛋白的AAV载体可用于治疗DMD中涉及的所有主要肌肉群的假设。同时，我们将通过将RNAi盒递送到细胞系和小鼠模型中，然后在狗中进行安全性测试，来调整AAV系统以靶向显性疾病FSHD。因此，我们正在进行临床前研究，通过模拟DMD和FSHD来开发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合作研究计划，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。在项目2中开发的临床基础设施将为华盛顿大学未来基因治疗DMD、FSHD和其他MD的临床试验奠定基础。这些研究将得到三个核心的支持。一个行政核心，以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。一个科学研究资源核心，为中心成员和世界各地的肌营养不良症研究人员提供AAV和慢病毒载体库存。该核心还将提供与肌肉萎缩症研究和基因转移相关的培训，咨询和试剂。最后，一个研究者发展和患者外展核心（IDPO），用于基础和临床研究的指导研究计划，以及伦理学，这将使新的研究人员做好准备，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。

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.