Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center

我们韦尔斯通中心的使命是促进导致变革性治疗的研究 常染色体显性遗传性肌营养不良。主要集中在1型和2型强直性肌营养不良。 (DM1和DM2)。该中心联合了两组曾共同研究强直性肌张力的研究人员 营养不良20年，即在纽约大学研究糖尿病的临床和翻译研究人员团队 罗切斯特大学和研究糖尿病的核糖核酸科学家和遗传学家组成的团队 佛罗里达。总之，这种伙伴关系被归功于建立了作为遗传机制的RNA获得功能， 阐明MBNL蛋白和CUG重复序列作为RNA毒性的基本驱动因素的作用，开发 第一个显示出RNA毒性和MBNL不足的DM1动物模型，完成了第一个治疗 在动物模型中拯救DM1，开发临床方法，自然病史数据，以及符合以下条件的生物标志物 需要进行临床试验，并将第一个靶向治疗带入DM1的早期试验。 继续这一脉络，拟议的研究设计了三个平行的目标：澄清疾病 机制，以加强临床前治疗药物的流水线，并产生工具和 具有进行高信息量临床试验的知识。中心的每个项目都涉及CLOSE 罗切斯特和佛罗里达两地的调查人员合作。项目1的重点是DM1，并将描述 第一个等位基因系列的小鼠在小鼠的DM1基因座上定向插入了高度扩展的重复序列。它 也将决定剪接生物标志物如何对有毒RNA的增加、MBNL1的减少做出反应 蛋白质和治疗干预。使用一套通用的模型和方法，调查人员将 比较两种主要的减轻RNA毒性的策略：使用反义转录后敲除 寡核苷酸(ASO)和使用小分子的转录抑制。ASO战略将重点放在 方法改善药物对肌纤维的转运。虽然在“审判准备”方面取得了实质性进展 已经为DM1做好了，DM2落后了。项目2将启动对自然病史和临床终点的研究 对于DM2。比较DM1和DM2的转录组变化，以及生物标志物的临床步骤 开发工作将完成。重复关联的非8月(RAN)翻译将被视为潜在的 DM2肌病的发病机制。项目3涉及DM2的动物模型和机制。第一 将描述DM2转基因小鼠模型的特征，以及内含子与外显子对RNA毒性的机制 将比较重复次数或CUG与CCUG重复次数。新型号将用于开发ASO和Small DM2的分子治疗。共享资源核心包括DM和FSHD国家登记处。它 支持我们中心的项目，但也服务于更广泛的研究优势的研究人员社区 营养不良的形式。综上所述，该中心将继续鼓励和支持世界范围内的努力 开发治疗DM1、DM2和FSHD的有效方法。

The mission of our Wellstone Center is to promote research that leads to transformative treatments for autosomal dominant forms of muscular dystrophy. The main focus is on myotonic dystrophy type 1 and type 2 (DM1 and DM2). The Center unites two groups of investigators who have worked together on myotonic dystrophy for two decades, namely, the team of clinical and translational researchers who study DM at the University of Rochester, and the team of RNA scientists and geneticists who study DM at the University of Florida. Together, this partnership is credited with establishing RNA gain of function as a genetic mechanism, elucidating the role of MBNL proteins and CUG repeats as fundamental drivers of RNA toxicity, developing the first DM1 animal models showing RNA toxicity and MBNL insufficiency, accomplishing the first therapeutic rescue of DM1 in animal models, developing clinical methods, natural history data, and biomarkers that are needed to conduct clinical trials, and bringing the first targeted treatment to early-phase trials for DM1. Continuing is this vein, the proposed studies are designed with three parallel objectives: to clarify disease mechanisms, to strengthen the pipeline of preclinical therapeutic agents, and to generate the tools and knowledge for conducting highly informative clinical trials. Each Project of the center involves close collaboration of investigators at Rochester and Florida sites. Project 1 is focused on DM1, and will characterize the first allelic series of mice having targeted insertion of highly expanded repeats at the murine DM1 locus. It will also determine how splicing biomarkers respond to increments of toxic RNA, decrements of MBNL1 protein, and therapeutic interventions. Using a common set of models and methods, the investigators will compare two leading strategies to mitigate RNA toxicity: post-transcriptional knockdown using antisense oligonucleotides (ASOs), and transcriptional inhibition using small molecules. The ASO strategy will focus on methods to improve drug delivery to muscle fibers. While substantial progress towards “trial readiness” has been made for DM1, DM2 lags behind. Project 2 will initiate studies of natural history and clinical endpoints for DM2. The transcriptome changes in DM1 and DM2 will be compared, and clinical steps of biomarker development will be completed. Repeat-associated non-AUG (RAN) translation will be examined as a potential mechanism for myopathy in DM2. Project 3 addresses animal models and mechanisms for DM2. The first transgenic mouse model of DM2 will be characterized, and mechanisms for RNA toxicity by intronic vs. exonic repeats, or CUG vs. CCUG repeats, will be compared. The new models will be used to develop ASO and small molecule treatments for DM2. The Shared Resource core contains the National Registry for DM and FSHD. It supports Projects of our Center but also serves the broader community of researchers who study dominant forms of dystrophy. Taken together, the Center will continue to stimulate and support world-wide efforts to develop effective treatments for DM1, DM2, and FSHD.