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

建立 1 型强直性肌营养不良的生物标志物和临床终点（更新）

• 批准号: 10574277
• 负责人: Nicholas Elwood Johnson
• 金额: $ 38.7万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10574277
• 关键词: Establishing; Biomarkers; Clinical; Endpoints; Myotonic

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.

摘要 强直性肌营养不良1型（DM 1）是成人中最常见的肌营养不良形式。遗传 基础是在DMPK（编码DM蛋白激酶的基因）的非编码区中CTG重复序列的扩增。 患有强直性肌营养不良的个体发展为进行性肌无力、早期白内障、心律失常， 和其他症状。疾病机制涉及突变体DMPK的有害功能获得 这一过程首先在DM 1中描述，称为RNA毒性。RNA结合蛋白被困在 重复RNA，导致剪接调控功能的丧失。剪接变化导致DM 1症状， 也可以作为疾病严重程度的生物标志物。 发现DM 1是由一种RNA种类的毒性引起的，其特征是被错误调节， 其它RNA的剪接提供了良好的治疗靶标和候选生物标志物。几种治疗 目前正在开发各种方法，其中两种方法正处于早期临床试验阶段。然而，设计和执行 由于疾病异质性、缺乏自然史数据以及缺乏经证实的临床试验， 药物影响的终点或生物标志物。我们已经开始了一项自然史研究来确定临床终点， 生物标志物和用于临床试验的患者特征。这项名为END-DM 1的研究招募了277名参与者， COVID-19疫情阻碍了早期进展。 现时的续期申请旨在完成临床成效评估研究（目的1） 和DM 1中的生物标志物（Aim 2）。我们将在16个肌强直研究中心完成700名1型糖尿病成人的入组。 营养不良临床研究网络，在12个月和24个月时进行回访。根据初步数据，我们 选择了一套简明的临床措施，显示出可接受的可靠性和对疾病的反应性 进展拟定的研究旨在确定不同药物的最小临床重要差异。 在这一人群中进行测量，确定预测未来进展的基线特征，并提供一个 分层的合理依据、样本量的选择或未来试验中的富集。目标2将建立在我们的 先前的努力开发了DM 1严重程度和治疗反应的RNA剪接生物标志物。该目的是 集中于提供骨骼肌中靶点参与的直接证据的组织生物标志物。我们将 使用涉及靶向高通量的新方法评估一组DM 1影响的剪接事件 测序完成这项研究是为有效的临床试验奠定基础的合乎逻辑的下一步， DM 1，并跟上快速扩大的临床前努力，以开发一种有效的药物治疗。