Novel Therapeutics for FSHD

项目摘要 面肩肱型肌营养不良症（FSHD）导致终身严重残疾，是最常见的 流行的肌肉萎缩症，折磨儿童和成人。虽然遗传学的重大进展 强烈暗示了一个强大的转录因子DUX 4及其靶基因的不适当表达 在FSHD的肌纤维变性中，还没有保护性的药理学治疗存在。 疾病马萨诸塞州大学医学院（UMMS） 合作研究中心是一个合作研究人员的网络，其研究和培训计划 专注于开发FSHD的新型有效疗法。长期目标是满足这一需要 通过三个针对药物发现和优化的高度协同项目，由我们的 核心，合作者和顾问。中心的具体目标是：1）通过以下方式识别FSHD疾病修饰因子 在项目1中，对一个大型犹他州FSHD家族进行了扩展的基因组研究，以辨别天然基因变异 和影响FSHD临床表型的调节途径; 2）发现DUX 4的调节剂 使用新型Wellstone FSHD细胞和动物模型以及基于CRISPR的抑制， 确定基因和调控途径治疗靶点的方法; 3）优化我们的前导DUX 4 RNA 项目3中的药物和DUX 4信号化合物，与工业界合作; 4）与 FSHD和患者倡导团体支持和参与FSHD研究和临床试验; 5） 扩大与拥有开发FSHD疗法的工具和经验的行业合作伙伴的合作; 6）培养下一代临床科学家和翻译研究人员，他们将成为推动 我们的Wellstone治疗开发计划的力量。三个中心核心将支持研究， 该Wellstone中心的培训活动以及更大的FSHD研究和患者社区。这些 包括一个管理核心，以促进我们所有研究中心研究者之间的沟通， 研究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 并为FSHD患者及其家人提供教育。教育和培训中心将 继续监督学生和研究员的研究和临床培训。核心资源将扩大 FSHD生物材料的独特储存库，包括DNA，肌肉组织，肌原性原代细胞和肌肉 来源于活组织检查的细胞系和来源于患者成纤维细胞的iPSC细胞，以支持Wellstone和 FSHD社区研究。这些材料可供学术和工业团体使用， 越来越多地被用作生物标志物和临床前治疗研究的FSHD模型。的资源 核心将利用新的诱导DUX 4小鼠和斑马鱼模型和异种移植模型，这将支持我们的研究。 提出了临床前项目，并将与其他FSHD研究小组分享这些模型，以加速 FSHD治疗开发。

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.