Novel therapeutics for FSHD

项目总结 面肩肱骨肌营养不良症(FSHD)会导致终生严重残疾，是最常见的 普遍存在的肌肉营养不良症，儿童和成人都有。虽然遗传学方面的重大进展 与强大的转录因子DUX4及其靶标的不适当表达有关 FSHD肌纤维变性的基因，目前还没有保护性的药物治疗 这种病。马萨诸塞大学医学院(UMMS)Wellstone肌营养不良症 合作研究中心是一个合作研究人员的网络，其研究和培训 项目的重点是开发治疗FSHD的新的有效疗法。长期目标是 通过三个针对药物发现和优化的高度协同的项目来满足这一需求， 由我们的核心、合作者和顾问提供支持。中心的具体目标是：1)确定FSHD 通过对项目1中一个犹他州FSHD大型家系进行扩展基因组研究的疾病修饰者 识别影响FSHD临床表型的天然基因变异和调控途径；2) 利用新型Wellstone FSHD细胞和动物在项目2中发现DUX4毒性的调节剂 识别基因和调控通路治疗的模型和基于CRISPR的抑制方法 目标；3)在项目3中优化我们的领先DUX4 RNA疗法和DUX4信号化合物 与业界合作；4)与FSHD和患者倡导团体合作，支持和 参与FSHD研究和临床试验；5)扩大与以下行业合作伙伴的合作 拥有开发FSHD疗法的工具和经验；以及6)培训新一代临床医生- 科学家和翻译研究人员，他们将是我们韦尔斯通治疗的推动力 发展计划。三个中心核心将支持该中心的研究和培训活动 韦尔斯通中心以及更大的FSHD研究和患者社区。其中包括一个 管理核心，以促进我们所有站点的调查人员之间的沟通并连接 调查人员与患者倡导团体，特别是FSH协会，以便我们可以继续 参与并向患有FSHD的个人及其家人提供教育。教育与培训 CORE将继续监督学生和研究员的研究和临床培训。资源 CORE将扩展一个独特的FSHD生物材料库，包括DNA、肌肉组织、肌源性 来自活检组织的原代细胞和肌肉细胞系，以及来自患者成纤维细胞的IPSC细胞 以支持Wellstone和更大的FSHD社区研究。这些材料可供学术人士使用 和行业组织，并越来越多地被用作生物标志物和临床前的FSHD模型 治疗性研究。Resources Core将利用新的可诱导DUX4小鼠和斑马鱼模型 和异种移植模型，它将支持我们提出的临床前项目，并将共享这些模型 与其他FSHD研究小组一起加快FSHD治疗的开发。

PROJECT SUMMARY Facioscapulohumeral muscular dystrophy (FSHD) causes lifelong severe disability and is one of the most prevalent muscular dystrophies, afflicting both children and adults. While major advances in genetics have strongly implicated the inappropriate expression of a powerful transcription factor, DUX4, and its target genes in the degeneration of muscle fibers in FSHD, no protective pharmacologic treatments yet exist for this disease. The University of Massachusetts School of Medicine (UMMS) Wellstone Muscular Dystrophy Cooperative Research Center is a network of collaborative investigators whose research and training programs focus on developing novel and effective therapeutics for FSHD. The long-term objectives are to meet this need through three highly synergistic projects directed toward drug discovery and optimization, supported by our Cores, collaborators and advisors. Specific Center goals are: 1) identifying FSHD disease modifiers through expanded genomic investigations of a large Utah FSHD kindred in Project 1 to discern native gene variants and regulatory pathways that influence the FSHD clinical phenotype; 2) discovering modulators of DUX4 toxicity in Project 2 using the novel Wellstone FSHD cell and animal models and CRISPR-based inhibition approaches to identify gene and regulatory pathway therapeutic targets; 3) optimizing our lead DUX4 RNA therapeutics and DUX4 signaling compounds in Project 3, in collaboration with industry; 4) partnering with FSHD and patient advocacy groups to support and participate in FSHD research and clinical trials; 5) expanding collaborations with industry partners who have tools and experience to develop FSHD therapeutics; and 6) training the next generation of clinician- scientists and translational researchers, who will be the driving force of our Wellstone therapeutic development program. Three Center Cores will support the research and training activities of this Wellstone Center and also the greater FSHD research and patient communities. These include an Administrative Core to facilitate communication between our investigators at all sites and to connect investigators with patient advocacy groups, particularly the FSH Society, so that we may continue to engage and provide education to individuals with FSHD and their families. The Education and Training Core will continue to oversee the research and clinical training of students and fellows. The Resources Core will expand a unique repository of FSHD biomaterials, including DNA, muscle tissues, myogenic primary cells and muscle cell lines derived from biopsies, and iPSC cells derived from patient fibroblasts to support Wellstone and greater FSHD community research. These materials are available to academic and industry groups and have increasingly been used as FSHD models for biomarker and preclinical therapeutic studies. The Resources Core will utilize novel inducible DUX4 mouse and zebrafish models and a xenograft model that will support our proposed preclinical projects and also will share these models with other FSHD research groups to accelerate FSHD therapeutic development.