Development of MRI, Alternative Splicing, and Functional Abilities asBiomarkers in Myotonic Dystrophy Type 1

项目摘要/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。它是由一种 强直性肌营养不良蛋白激酶(DMPK)基因的不稳定三重重复。这些重复创建了 核病灶中突变的mRNA导致许多其他基因的选择性剪接异常及其结果 多系统病理学。DM1的病理性肌肉变化导致进行性虚弱， 肌强直、步态障碍、平衡能力下降、摔倒风险增加、残疾和寿命缩短。大有可为 通过临床前研究确定潜在的治疗靶点以解决 DM1的病理生理学。然而，缺乏敏感、客观的生物标记物是 继续进行临床试验。迫切需要可重复的和临床相关的结果衡量标准。 有待开发，以便未来的研究可以探索新的疗法。核磁共振和选择性剪接都已经被 探索作为生物标志物来评估骨骼肌和DM1的疾病病理。虽然初步结果来自 初步研究一直很有希望，但仍有更详细的工作有待完成，以确定 如何将这些指标最佳地用作DM1的有临床意义的生物标记物，以支持 开发新的治疗方法。因此，本研究的总体目标是验证定量磁共振成像(QMRI)和 选择性剪接作为DM1的生物标志物。在目标1中，30名患有DM1的受试者将接受qMRI(来自 在基线和18个月时进行上肢和下肢肌力)和功能测试。结果将会是 提供有关肌肉病理随时间变化的定量信息以及qMRI的临床应用。为 目标2，同样的30名DM1参与者将接受MRI信息的活检，从中提取RNA以 量化剪接事件。我们将评估替代剪接与qMRI和功能测试的关系。 AIM 3将在18个月后添加替代剪接数据收集和分析，以检查随时间的变化 这些事件。我们期待这项研究的结果将提供有关 定量磁共振成像与选择性剪接的纵向变化及其相互关系 拼接和临床评估。这一信息将是未来将这些结果用作生物标志物的关键 在未来对DM1患者的临床试验中。

Project Summary/Abstract Myotonic Dystrophy Type 1 (DM1) is the most common form of muscular dystrophy in adults. It is caused by an unstable triple repeat of the myotonic dystrophy protein kinase (DMPK) gene. These repeats create retention of mutant mRNA in the nuclear foci causing alternative splicing abnormalities in many other genes and resultant multi-systemic pathology. The pathological muscular changes from DM1 cause progressive weakness, myotonia, gait impairments, decreased balance, increased fall risk, disability, and a shortened life span. Much progress has been made through preclinical studies to identify potential therapeutic targets to address the pathophysiology of DM1. However, the lack of sensitive, objective biomarkers is one of the largest obstacles in moving ahead with clinical trials. There is a dire need for repeatable and clinically relevant outcome measures to be developed so future studies can investigate new therapeutics. Both MRI and alternative splicing have been explored as biomarkers to assess skeletal muscle and disease pathology in DM1. While the initial results from preliminary studies have been promising, far greater detailed work remains to be completed in order to determine how these measures can be optimally used as clinically meaningful biomarkers for DM1 in support of the development of new therapies. Thus, the overall objective of this study is to validate quantitative MRI (qMRI) and alternative splicing as biomarkers in DM1. In Aim 1, 30 subjects with DM1 will be assessed with qMRI (from the upper and lower extremity musculature) and functional tests at baseline and at 18 months. The results will provide quantitative information about muscle pathology change over time and the clinical utility of qMRI. For Aim 2, these same 30 DM1 participants will have an MRI-Informed biopsy from which RNA will be isolated to quantitate splicing events. We will assess how alternative splicing is related to both qMRI and functional tests. Aim 3 will add alternative splicing data collection and analyses after 18 months to examine change over time in these events. We anticipate the results from this study will provide novel and vital information regarding the longitudinal changes in qMRI and alternative splicing as well as the relationships between qMRI, alternative splicing, and clinical assessments. This information will be key to the future use of these outcomes as biomarkers in future clinical trials for patients with DM1.