Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center

我们的Wellstone中心的使命是促进研究，导致变革性的治疗， 常染色体显性形式的肌营养不良症。主要集中在强直性肌营养不良1型和2型 (DM1 DM2）。该中心联合了两组研究人员， 营养不良二十年来，即临床和翻译研究人员谁研究糖尿病在 罗切斯特大学的RNA科学家和遗传学家组成的研究小组， 佛罗里达。总之，这种伙伴关系被认为是建立RNA获得功能作为一种遗传机制， 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， 第一个显示RNA毒性和MBNL不足的DM1动物模型，完成了第一个治疗性的 在动物模型中拯救DM1，开发临床方法，自然史数据和生物标志物， 需要进行临床试验，并将第一种靶向治疗带到DM1的早期试验中。 延续这一思路，拟议的研究设计有三个平行的目标： 机制，以加强临床前治疗剂的管道，并产生工具和 进行高信息量临床试验的知识。中心的每一个项目都涉及到密切的 罗切斯特和佛罗里达研究中心的研究者合作。项目1侧重于DM 1，并将描述 第一个等位基因系列的小鼠在鼠DM1基因座具有高度扩增的重复序列的靶向插入。它 还将确定剪接生物标志物如何响应毒性RNA的增加，MBNL1的减少， 蛋白质和治疗干预。使用一套通用的模型和方法，研究人员将 比较两种主要的减轻RNA毒性的策略：使用反义核酸的转录后敲低 寡核苷酸（ASO）和使用小分子的转录抑制。阿索战略将侧重于 改善药物向肌纤维递送的方法。虽然在“审判准备就绪”方面取得了实质性进展， DM1已经完成，DM2落后了。项目2将启动自然史和临床终点的研究 关于DM2将比较DM 1和DM 2中的转录组变化，并将生物标志物的临床步骤 发展将完成。重复相关的非AUG（RAN）翻译将作为潜在的 DM2中肌病的机制。项目3涉及DM2的动物模型和机制。第一 DM2的转基因小鼠模型将被表征，并且通过内含子与外显子的RNA毒性机制， 重复，或CUG与CCUG重复，将进行比较。新模型将用于开发阿索和小型 DM2的分子治疗共享资源核心包含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人员谁研究主导社区 各种形式的营养不良。总之，该中心将继续促进和支持世界范围的努力， 为DM1、DM2和FSHD开发有效的治疗方法。

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.