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.

Public Health Relevance

People with Myotonic Dystrophy Type 1 (DM1) experience progressive weakness, walking difficulties, increased fall risk, disability, and a shortened life span. The overall goal of this study is to investigate the potential of two biomarkers that can be used in future clinical trials focused on new therapies for DM1. Specifically, we will examine: 1) muscle changes using magnetic resonance imaging (MRI) and 2) an important regulatory step for protein production (alternative splicing) that is disrupted in DM1.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Arthritis and Musculoskeletal and Skin Diseases Clinical Trials Review Committee (AMSC)
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Carifi, Emily Foran
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University of Florida
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Schools of Public Health
United States
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