Establishing Biomarkers and Clinical Endpoints in Myotonic Dystrophy Type-1 (Renewal)

摘要 强直性肌营养不良1型(DM1)是成人最常见的肌营养不良症。基因 BASE是编码DM蛋白激酶的基因DMPK非编码区CTG重复序列的扩展。 强直性肌营养不良患者会出现进行性肌肉无力、早期白内障、心律失常、 和其他症状。疾病机制涉及突变的DMPK的有害功能获得 信使核糖核酸，这一过程在DM1中首次描述，称为RNA毒性。RNA结合蛋白被困在 重复的RNA，导致剪接调控功能的丧失。剪接变化会导致DM1症状和 也可以作为疾病严重程度的生物标志物。 发现DM1是由一种RNA物种的毒性引发的，其特征是调控不当 其他RNA的剪接已经提供了很好的治疗靶点和候选生物标志物。几种治疗方法 方法正在开发中，有两种方法处于早期临床试验阶段。然而，设计和实施 临床试验的数量受到疾病异质性、自然病史数据的稀缺以及缺乏已证实的临床试验的限制。 药物影响的终点或生物标志物。我们已经开始了一项自然历史研究，以确定临床终点， 用于临床试验的生物标志物和患者特征。这项名为END-DM1的研究招募了277名参与者，但 早期进展因新冠肺炎疫情而受阻。 目前的续展申请旨在完成临床结果评估研究(目标1) 和DM1中的生物标志物(AIM 2)。我们将在肌强直的16个地点完成700名患有DM1的成年人的注册 营养不良临床研究网络，在12个月和24个月进行回访。根据初步数据，我们 选择了一套简明的临床测量方法，显示出可接受的可靠性和对疾病的响应性 进步。建议的研究旨在为不同的患者建立最小的临床重要性差异。 测量这一人群，确定预测未来进展的基线特征，并提供 为分层、选择样本量或在未来试验中丰富提供合理的基础。Aim 2将建立在我们的 以前的努力是开发DM1严重程度和治疗反应的RNA剪接生物标记物。这个目标是 专注于提供直接证据表明靶向参与骨骼肌的组织生物标记物。我们会 使用一种涉及目标高吞吐量的新方法评估一组受DM1影响的剪接事件 测序。这项研究的完成是合乎逻辑的下一步，为在 DM1，并与迅速扩大的临床前努力保持同步，以开发有效的药物治疗。

Abstract Myotonic dystrophy type-1 (DM1) is the most common form of muscular dystrophy in adults. The genetic basis is an expansion of CTG repeats in the non-coding region of DMPK, the gene encoding DM protein kinase. Individuals with myotonic dystrophy develop progressive muscle weakness, early cataracts, cardiac arrhythmias, and other symptoms. The disease mechanism involves a deleterious gain-of-function by the mutant DMPK mRNA, a process first described in DM1, known as RNA toxicity. RNA binding proteins become trapped on repetitive RNA, causing loss of splicing regulatory functions. Splicing changes contribute to DM1 symptoms and also may serve as biomarkers of disease severity. The discovery that DM1 is instigated by toxicity of one RNA species and characterized by misregulated splicing of other RNAs has furnished good therapeutic targets and candidate biomarkers. Several therapeutic approaches are under development and two are in early phase clinical trials. However, the design and conduct of clinical trials is limited by disease heterogeneity, scarcity of natural history data, and the lack of proven clinical endpoints or biomarkers of drug impact. We have begun a natural history study to define clinical endpoints, biomarkers, and patient characteristics for clinical trials. This study, END-DM1, has enrolled 277 participants but early progress was hampered by the COVID-19 pandemic. The current renewal application seeks to complete the study of clinical outcome assessments (Aim 1) and biomarkers (Aim 2) in DM1. We will complete enrollment of 700 adults with DM1 at 16 sites of the Myotonic Dystrophy Clinical Research Network with return visits at 12 and 24 months. Based on preliminary data, we selected a concise set of clinical measures showing acceptable reliability and responsivity to disease progression. The proposed study is designed to establish minimal clinically important differences for different measures in this population, identify baseline characteristics that predict future progression, and provide a rational basis for stratification, selection of sample size, or enrichment in future trials. Aim 2 will build on our previous efforts to develop RNA splicing biomarkers of DM1 severity and therapeutic response. This Aim is focused on tissue biomarkers that provide direct evidence of target engagement in skeletal muscle. We will assess a panel of DM1-affected splice events using a novel method that involves targeted high-throughput sequencing. Completion of this study is the logical next step to lay the groundwork for effective clinical trials in DM1, and keep pace with the rapidly expanding preclinical efforts to develop an effective drug treatment.