Wellstone Muscular Dystrophy Specialized Research Center (Seattle)

总体总结/摘要：西雅图Wellstone中心的主要主题是提高治疗效果， 通过识别和克服新出现的成功治疗肌营养不良症的新障碍 肌肉萎缩症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，以加速开发杜切尼的有效疗法 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 西北的家庭。具体的目的和目标是突破成功的主要障碍， 在西北和全国范围内进行肌营养不良症的治疗性临床试验。目标1（项目1）将 进行肌营养不良症基因治疗的转化和临床前研究。这方面的研究将（a） 改善微肌营养不良蛋白基因的功能，重点是心肌，并确定治疗方法 其用于改善微肌养蛋白赋予的功能益处;（B）使这些AAV介导的 在FSHD的临床前小鼠模型中实现人DUX 4的抑制的递送方法;和 (c)在西雅图建立临床试验准备，以参与DMD中AAV介导的治疗试验。 目标2（项目2）将加强面肩肱营养不良（FSHD）的临床试验基础。现有 基金期间建立了功能评估、MRI特征和分子水平之间的相关性。 FSHD中的标记物。为此目的进行的研究将：（a）确定候选人之间的相关性 在先前资助期间确定的分子生物标志物和MRI特征预测功能性 （B）确定候选分子的相关性和预测值是否 在第一组群中鉴定的生物标志物和MRI特征可以在独立组群中验证; 和（c）确定炎症区域中浸润单核细胞的分子表型， 这是否代表寡克隆T细胞反应。目标3（核心A、B、C）将管理、提供 科研资源，培养未来的肌营养不良症科研和临床研究人员。的 中心核心（行政、科研资源和培训核心）将提供支持， 监督所有活动，提供必要的生物资源，以实现中心的目标， 作为国家资源，并提供下一代科学和临床 肌肉萎缩症的研究人员总之，这些目标将实现总体目标，使肌肉发达的 营养不良的临床试验和治疗的家庭西北和国家。

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.