Establishing Biomarkers and Clinical Endpoints in Myotonic Dystrophy Type-1

建立 1 型强直性肌营养不良的生物标志物和临床终点

• 批准号: 10496809
• 负责人: Nicholas Elwood Johnson
• 金额: $ 9.8万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10496809
• 关键词: Establishing; Biomarkers; Clinical; Endpoints; Myotonic

Abstract Myotonic dystrophy type-1 (DM1) is the most common form of muscular dystrophy in adults. Individuals with myotonic dystrophy develop progressive muscle weakness, early cataracts, cardiac arrhythmias, and other symptoms. The genetic basis is an expansion of CTG repeats in the non-coding region of DMPK, which causes a deleterious gain-of-function by DMPK mRNA. RNA binding proteins become trapped on repetitive RNA, causing loss of splicing regulatory functions. The discovery that DM1 is instigated by RNA toxicity and misregulated splicing has led to therapeutic targets and candidate biomarkers. Several therapeutic approaches are under development, including 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 are proposing to overcome these limitations by expanding the scope of natural history data (Aim 1) and completing the steps of biomarker qualification (Aim 2). We plan to enroll 500 adults with DM1 at eight sites of the Myotonic Dystrophy Clinical Research Network. Study assessments will be repeated after 1 and 2 years. Our proposed entry criteria are non- restrictive to capture data across the broad spectrum of DM1 severity. Based on preliminary data from our current multicenter study of 113 patients, we selected a concise set of clinical measures showing acceptable reliability and responsivity to progression. The proposed study is designed to establish minimal clinically important differences, identify baseline characteristics to predict future progression, and provide a basis for stratification, or sample size selection 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. Our goal is to optimize methods for sample collection and processing, extend our reference dataset of splicing measurements, and formally establish that splicing data are archival, so that biomarker data are comparable across laboratories and to reference data. 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.

抽象的 Myotonic肌营养不良型1（DM1）是最常见的肌肉营养不良的形式 成年人。肌发育症的人会发育性肌肉无力，早期 白内障，心律不齐和其他症状。遗传基础是CTG的扩展 在DMPK的非编码区域中重复，这会导致有害的功能 DMPK mRNA。 RNA结合蛋白被困在重复的RNA上，导致 剪接调节功能。 发现DM1是通过RNA毒性和剪接不良调节的发现的发现 用于治疗靶标和候选生物标志物。几种治疗方法正在 开发，包括早期临床试验。但是，临床的设计和行为 试验受疾病异质性，自然史数据的稀缺性以及缺乏可靠的限制 药物撞击的临床终点或生物标志物。 我们建议通过扩大自然范围来克服这些限制 历史数据（AIM 1）并完成生物标志物资格的步骤（AIM 2）。我们计划 在Myotonic营养不良临床研究网络的八个地点注册500名DM1成年人。 研究评估将在1年和2年后重复。我们提出的进入标准是非 - 限制捕获跨DM1严重程度的数据。基于初步 我们目前对113名患者的多中心研究的数据，我们选择了一套简洁的临床 措施显示可接受的可靠性和对进展的反应。拟议的研究是 旨在建立最小的临床重要差异，确定基线特征 预测未来的进展，并为分层或样本量选择提供了基础 未来的试验。 AIM 2将以我们以前开发DM1的RNA剪接生物标志物的努力为基础 严重性和治疗反应。该目标的重点是提供直接的组织生物标志物 目标参与骨骼肌的证据。我们将评估一组受DM1影响的面板 使用一种涉及针对性高通量测序的新方法的剪接事件。我们的 目标是优化用于示例收集和处理的方法，扩展我们的参考数据集 剪接测量值，并正式确定剪接数据是档案，以便 生物标志物数据在实验室之间相当并参考数据。完成此操作 研究是在DM1中进行有效临床试验的基础的逻辑下一步，并保持 随着迅速扩大的临床前努力的速度，以开发有效的药物治疗。