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

MRI、选择性剪接和功能能力作为强直性肌营养不良 1 型生物标志物的发展

• 批准号: 10240487
• 负责人: Donovan J Lott
• 金额: $ 19.52万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-17 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240487
• 关键词: 3' Untranslated Regions; Activities of Daily Living; Address; Adult; Affect; Alternative Splicing; Area; Biological Markers; Biopsy; Cessation of life; Clinical; Clinical Trials; Clinical assessments; Data; Data Analyses; Data Collection; Development; Disease; Disease Progression; Equilibrium; Event; Fatty acid glycerol esters; Florida; Functional disorder; Future; Gait; Genes; Goals; Histopathology; Impairment; Incidence; Individual; Inflammation; Infrastructure; Investigation; Lead; Longevity; Lower Extremity; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Messenger RNA; Motor; Muscle; Muscular Dystrophies; Myopathy; Myotonia; Myotonic dystrophy type 1; Neuromuscular Diseases; Nuclear; Outcome; Outcome Measure; Participant; Pathogenicity; Pathologic; Pathology; Patient Outcomes Assessments; Patients; Play; Polynucleotides; Positioning Attribute; Production; Proteins; RNA; RNA Splicing; RNA-Binding Proteins; Relaxation; Research; Resources; Skeletal Muscle; Testing; Time; Tissues; Triplet Multiple Birth; Universities; Upper Extremity; Walking; Work; clinically relevant; disability; experience; fall risk; falls; follow up assessment; functional outcomes; magnetic resonance imaging biomarker; member; mutant; myotonic dystrophy protein kinase; novel; novel therapeutics; preclinical study; premature; recruit; reduced muscle mass; spectroscopic imaging; therapeutic target; tibialis anterior muscle

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.

项目摘要/摘要 肌发育症1型（DM1）是成​​年人最常见的肌肉营养不良形式。它是由 肌营养不良蛋白激酶（DMPK）基因的不稳定三重重复。这些重复会保留 核局灶性突变mRNA，导致许多其他基因的替代剪接异常和结果 多系统病理。 DM1的病理肌肉变化会导致渐进性无力， Myotonia，步态障碍，平衡降低，跌落风险增加，残疾和寿命缩短。很多 通过临床前研究取得了进展，以确定潜在的治疗靶标的来解决 DM1的病理生理学。但是，缺乏敏感，客观的生物标志物是最大的障碍之一 继续进行临床试验。迫切需要重复和临床相关的结果指标 要开发，以便未来的研究可以研究新的治疗剂。 MRI和替代剪接都是 探索是评估DM1中骨骼肌和疾病病理学的生物标志物。而最初的结果来自 初步研究一直很有希望，为了确定 这些措施如何最佳用作DM1的临床意义生物标志物来支持 开发新疗法。因此，这项研究的总体目标是验证定量MRI（QMRI）和 DM1中的替代剪接作为生物标志物。在AIM 1中，将使用QMRI评估30名具有DM1的受试者（来自 下肢和下肢肌肉）和基线和18个月的功能测试。结果将 提供有关随时间变化和QMRI的临床实用性变化的定量信息。为了 AIM 2，这些相同的30 DM1参与者将进行MRI-Infled活检，将RNA隔离为 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个月后添加替代的剪接数据收集和分析，以检查随着时间的流逝的变化 这些事件。我们预计这项研究的结果将提供有关有关的新颖而重要的信息 QMRI和替代剪接的纵向变化以及QMRI之间的关系 剪接和临床评估。这些信息将是将这些结果作为生物标志物的未来使用的关键 在未来的DM1患者的临床试验中。