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 强直性肌营养不良 1 型 (DM1) 是最常见的肌营养不良形式 成年人。强直性肌营养不良症患者早期会出现进行性肌无力 白内障、心律失常和其他症状。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获得 DMPK mRNA。 RNA 结合蛋白被困在重复的 RNA 上，导致丢失 拼接调节功能。 DM1 是由 RNA 毒性和剪接错误调控引起的这一发现导致 治疗靶点和候选生物标志物。多种治疗方法正在研究中 开发，包括早期临床试验。然而，临床试验的设计和实施 试验受到疾病异质性、自然史数据稀缺以及缺乏经过证实的证据的限制 药物影响的临床终点或生物标志物。 我们建议通过扩大自然保护范围来克服这些限制 历史数据（目标 1）并完成生物标志物鉴定步骤（目标 2）。我们计划 在强直性肌营养不良临床研究网络的八个地点招募了 500 名患有 DM1 的成年人。 研究评估将在 1 年后和 2 年后重复进行。我们建议的进入标准是非 限制捕获广泛的 DM1 严重性数据。根据初步 根据我们目前对 113 名患者进行的多中心研究的数据，我们选择了一组简明的临床数据 显示可接受的可靠性和对进展的反应的测量。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基础 未来的考验。目标 2 将建立在我们之前开发 DM1 RNA 剪接生物标志物的努力的基础上 严重程度和治疗反应。该目标专注于提供直接信息的组织生物标志物 骨骼肌目标参与的证据。我们将评估一组受 DM1 影响的人 使用涉及靶向高通量测序的新方法来研究剪接事件。我们的 目标是优化样本收集和处理的方法，扩展我们的参考数据集 拼接测量，并正式确定拼接数据是存档的，以便 生物标志物数据在各个实验室和参考数据之间具有可比性。完成此 研究是合乎逻辑的下一步，为 DM1 的有效临床试验奠定基础，并保持 与快速扩大的临床前工作一起开发有效的药物治疗。