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

摘要/Abstract 西雅图威尔斯通中心的主要主题是改善肌肉萎缩症的治疗方法。 通过识别和克服新出现的新障碍，在肌肉萎缩症的临床试验取得成功， 营养不良具体的目的和目标是突破成功治疗的主要障碍 在西北部和全国范围内进行肌营养不良症的临床试验。目标1（项目1）将开展 肌营养不良症基因治疗的转化和临床前研究。为此目的进行的研究将（a）查明 针对骨骼肌和心肌优化的AAV变体，修饰微肌营养不良蛋白序列以减少 免疫原性和增加功能，并测试用于递送更有效 （B）将应用平行的AAV介导的方法来实现 在FSHD的小鼠模型和FSHD的大型动物猪模型中人DUX 4的抑制， 将类似载体技术的使用扩展为优势肌肉的一般递送平台， 并为FSHD开辟新的治疗机会。目标2（项目2）将建立 面肩肱营养不良临床试验基金会。这方面的研究将（a）进行临床和MRI检查 在先前西雅图Wellstone FSHD队列的长期扩展中进行评估，并应用更新的方法 MRI数据分析，以生成FSHD疾病进展的多年复合数据集， （B）进行治疗候选物的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，以评估其性能， 设计未来的临床试验;以及（c）对新的猪模型进行功能、MRI和分子表征。 FSHD模型，以确定其作为人类研究的临床前模型的实用性。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， 监督所有活动，提供必要的生物资源，以实现中心的目标， 作为一个国家资源，提供下一代的科学和临床研究人员在肌肉训练， 并开展外展和教育活动。这些目标将共同实现总体目标 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DMD和FSHD的有效疗法，并将肌营养不良症临床试验和 为西北地区及其他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.