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

项目总结/摘要 强直性肌营养不良1型（DM 1）是成人肌营养不良症中最常见的形式。它是由一个 强直性肌营养不良蛋白激酶（DMPK）基因的不稳定三重重复。这些重复创造了 核灶中的突变mRNA导致许多其他基因的选择性剪接异常， 多系统病理学DM 1的病理性肌肉变化导致进行性无力， 肌强直、步态障碍、平衡能力下降、跌倒风险增加、残疾和寿命缩短。多 通过临床前研究已经取得了进展，以确定潜在的治疗靶点， DM 1的病理生理学然而，缺乏敏感的、客观的生物标志物是生物标志物研究的最大障碍之一。 进行临床试验迫切需要可重复的和临床相关的结果措施 以便将来的研究能够探索新的疗法。MRI和选择性剪接都是 探索作为生物标志物来评估DM 1中的骨骼肌和疾病病理学。虽然初步结果从 初步的研究是有希望的，但更详细的工作仍有待完成，以确定 这些指标如何最佳地用作DM 1的临床有意义的生物标志物，以支持 开发新的疗法。因此，本研究的总体目标是验证定量MRI（qMRI）， 选择性剪接作为DM 1的生物标志物。在目标1中，将使用qMRI评估30例DM 1受试者（来自 上肢和下肢肌肉组织）和功能测试。结果将 提供关于肌肉病理学随时间变化的定量信息和qMRI的临床效用。为 目标2，同样的30名DM 1参与者将进行MRI知情活检，从中分离RNA， 定量剪接事件。我们将评估选择性剪接如何与qMRI和功能测试相关。 Aim 3将在18个月后增加选择性剪接数据收集和分析，以检查随着时间的推移而发生的变化 这些事件。我们预计，这项研究的结果将提供有关 qMRI和选择性剪接的纵向变化以及qMRI、选择性剪接之间的关系 剪接和临床评估。这些信息将是未来使用这些结果作为生物标志物的关键 在未来的1型糖尿病患者的临床试验中。

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.