Wellstone Muscular Dystrophy Specialized Research Center (Seattle)

总体总结/摘要：西雅图韦尔斯通中心的主要主题是改善治疗 通过识别和克服新出现的成功障碍来治疗肌营养不良症 肌肉营养不良的临床试验。总体目标是开发试剂、测量、临床 试验方法和临床试验基础设施，以加快Duchene有效疗法的开发 肌营养不良症(DMD)和FSHD，并将肌营养不良症的临床试验和治疗带到 西北地区的家庭。具体的目的和目标是冲破成功的主要障碍 西北地区和全国肌营养不良的临床治疗试验。目标1(项目1)将 开展肌营养不良症基因治疗的转化性和临床前研究。这方面的研究将：(A) 改善微小肌营养不良蛋白基因的功能，重点放在心肌上，并确定治疗方法 采取行动改善微肌营养不良蛋白赋予的功能益处；(B)使这些AAV介导的 在临床前FSHD小鼠模型中实现抑制人DUX4的递送方法；以及 (C)在西雅图建立临床试验准备，以便参与AAV介导的DMD治疗试验。 AIM 2(项目2)将加强面部肩关节骨营养不良(FSHD)的临床试验基础。前一部 资助期在功能评估、MRI特征和分子之间建立了相关性 FSHD中的标记。这一目标的研究将：(A)确定候选人之间的相关性 在之前的资助期中确定的分子生物标志物和MRI特征可以预测功能性 (B)确定候选分子的相关性和预测值 在第一个队列中确定的生物标记物和MRI特征可以在独立的队列中得到验证； 和(C)确定炎症和炎症区浸润性单个核细胞的分子表型。 这是否代表了寡克隆性T细胞反应。目标3(核心A、B、C)将管理、提供 为科学研究提供资源，培养未来的肌营养不良症科学和临床研究人员。这个 中心核心(行政、科研资源和培训核心)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 作为国家资源，为下一代科学和临床提供培训 肌肉营养不良症的研究人员。这些目标加在一起，将实现带来肌肉发达的总体目标 营养不良的临床试验和治疗到西北和全国的家庭。

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 overall goal is to develop the reagents, measurements, clinical trials methods, and clinical trials infrastructures to speed the development of effective therapies for Duchene muscular dystrophy (DMD) and FSHD, and to bring muscular dystrophy clinical trials and therapies to the families of the Northwest. 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) improve the function of the micro-dystrophin gene, with a focus on cardiac muscle, and identify therapies that act to improve the functional benefit conferred by micro-dystrophin; (b) adapt these AAV-mediated delivery methods to achieve the suppression of human DUX4 in a preclinical mouse model of FSHD; and (c) establish a clinical trials readiness in Seattle for participation in AAV-mediated therapeutic trials in DMD. Aim 2 (Project 2) will enhance facioscapulohumeral dystrophy (FSHD) clinical trial foundations. The prior funding period established correlations between functional assessments, MRI characteristics, and molecular markers in FSHD. Studies in this aim will: (a) determine whether the correlation between candidate molecular biomarkers and MRI characteristics identified in the prior funding period predict functional progression; (b) determine whether the correlation and predictive value of the candidate molecular biomarkers and MRI characteristics identified in the first cohort can be validated in an independent cohort; and (c) determine the molecular phenotype of the infiltrating mononuclear cells in areas of inflammation and whether this represents an oligoclonal T-cell response. 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 Resource, and Training Cores) 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, and provide training of the next generation of scientific and clinical researchers in muscular dystrophy. Together, these aims will achieve the overall goal to bring muscular dystrophy clinical trials and therapies to the families of the Northwest and the nation.