Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center - Seattle

总体摘要/摘要 西雅图韦尔斯通中心的主要主题是改进肌肉疾病的治疗方法 通过识别和克服肌肉临床试验成功的新障碍来治疗营养不良 营养不良。具体的目的和目标是打破成功治疗的主要障碍。 西北地区和全国肌肉营养不良的临床试验。目标1(项目1)将进行 肌营养不良症基因治疗的转化性和临床前研究。这一目标的研究将(A)确定 优化骨骼肌和心肌的AAV变体，修改微肌营养不良蛋白序列以减少 免疫原性和增强功能，并测试分裂内含子载体策略，以提供更有效的 Dystrophin构建到骨骼肌和心肌；(B)将应用并行AAV介导的方法来实现 在FSHD小鼠模型和大型动物猪FSHD模型中抑制人DUX4， 推广使用类似的载体技术作为优势肌肉的通用传递平台 营养不良和为FSHD打开新的治疗机会。目标2(项目2)将建立 面肩肱骨营养不良的临床试验基础。这一目标的研究将(A)进行临床和核磁共振 对先前西雅图Wellstone FSHD队列的长期扩展进行评估并应用新方法 以生成用于关联的FSHD疾病进展的多年复合数据集 随着疾病的进展；(B)对候选治疗药物进行剂量递增安全性和耐受性研究 这将结合最新的MRI和分子特征来评估他们在 设计未来的临床试验；以及(C)对一种新的猪进行功能、核磁共振和分子表征 FSHD模型，以确定其作为临床前人类研究模型的实用性。目标3(核心A、B、C)将 管理，为科学研究提供资源，并培训未来的肌营养不良症科学和临床 研究人员。中心核心(行政、科学研究和培训)将提供支持和 监督所有活动，提供必要的生物资源，以实现中心的目标和服务 作为国家资源，为下一代肌肉科学和临床研究人员提供培训 营养不良，并开展外展和教育活动。这些目标加在一起，将实现总体目标 开发试剂、测量、临床试验方法和临床试验基础设施，以加快 开发治疗DMD和FSHD的有效疗法，并将肌营养不良症的临床试验和 为西北地区和更远地区的家庭提供治疗。

Overall Summary/Abstract The major theme of the Seattle Wellstone center is to improve therapeutic approaches to muscular dystrophies by identifying and overcoming the emerging new barriers to successful clinical trials in muscular dystrophies. The specific aims and objectives are to breach the major barriers to successful therapeutic clinical trials in muscular dystrophies in the Northwest and nationwide. Aim 1 (Project 1) will conduct translational and pre-clinical studies of muscular dystrophy gene therapy. Studies in this Aim will (a) identify optimized AAV variants for skeletal and cardiac muscle, modify micro-dystrophin sequences to diminish immunogenicity and increase function, and test split intein vector strategies for delivering more potent dystrophin constructs to skeletal and cardiac muscle; (b) will apply parallel AAV-mediated methods to achieve the suppression of human DUX4 in a mouse model of FSHD and in a large animal porcine model of FSHD, extending the use of similar vector technologies as a general delivery platform for dominant muscular dystrophies and opening new therapeutic opportunities for FSHD. Aim 2 (Project 2) will establish facioscapulohumeral dystrophy clinical trial foundations. Studies in this aim will (a) perform clinical and MRI assessment in a long-term extension of the prior Seattle Wellstone FSHD cohorts and apply newer methods of MRI data analysis to generate a multi-year composite dataset of FSHD disease progression for correlations with disease progression; (b) perform a dose-escalation safety and tolerability study of a therapeutic candidate that will incorporate the most current MRI and molecular characteristics to assess their performance for the design of future clinical trials; and (c) perform functional, MRI, and molecular characterization of a new porcine model of FSHD to determine its utility as a preclinical model for human studies. Aim 3 (Cores A, B, C) will administer, provide resources for scientific research, and train future muscular dystrophy scientific and clinical researchers. The Center cores (Administrative, Scientific Research, and Training) will provide support and oversight of all activities, provide necessary biological resources to achieve the goals of the Center and serve as a national resource, provide training of the next generation of scientific and clinical researchers in muscular dystrophy and conduct outreach and educational activities. Together, these aims will achieve the overall goal to develop the reagents, measurements, clinical trials methods, and clinical trials infrastructures to speed the development of effective therapies for DMD and FSHD, and to bring muscular dystrophy clinical trials and therapies to the families of the Northwest and beyond.