Establishing Biomarkers and Clinical Endpoints in Myotonic Dystrophy Type-1

摘要 强直性肌营养不良1型（DM 1）是肌肉萎缩症中最常见的形式， 成年人了强直性肌营养不良的个体发展为进行性肌无力， 白内障心律不齐和其他症状遗传基础是CTG的扩展 在DMPK的非编码区重复，这会导致有害的功能获得性， DMPK mRNA。RNA结合蛋白被捕获在重复RNA上，导致RNA的丢失。 剪接调节功能。 发现DM 1是由RNA毒性和错误调节的剪接引起的， 治疗靶点和候选生物标志物。目前有几种治疗方法 包括早期临床试验。然而，临床的设计和实施 试验受到疾病异质性、缺乏自然史数据和缺乏已证实的 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资源的范围来克服这些限制。 历史数据（目标1）和完成生物标志物鉴定步骤（目标2）。我们计划 在肌强直性营养不良临床研究网络的八个站点招募了500名患有DM 1的成年人。 研究评估将在1年和2年后重复进行。我们建议的入选标准是非- 限制性地捕获各种DM 1严重性的数据。根据初步 从我们目前对113例患者的多中心研究中，我们选择了一组简明的临床资料， 显示出可接受的可靠性和对进展的反应性的测量。拟定研究 旨在确定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依据， 未来的审判目标2将建立在我们以前的努力，开发DM 1的RNA剪接生物标志物 严重程度和治疗反应。该目标的重点是提供直接的组织生物标志物， 骨骼肌中靶点参与的证据。我们将评估一组受DM 1影响的 剪接事件使用一种新的方法，涉及有针对性的高通量测序。我们 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， 的拼接测量，并正式建立拼接数据存档，以便 生物标志物数据在各实验室之间具有可比性，并与参考数据具有可比性。完成本 这项研究是为DM 1的有效临床试验奠定基础的合乎逻辑的下一步， 与快速扩展的临床前努力同步，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. 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.