This is a revised application (formerly called a competing supplement) to request support for a significant expansion of 1R01NS094387-01 Longitudinal Assessment of Brain Structure and Function in Myotonic Dystrophy Type 1 (DM1), from here on referred to as the `parent brain study'. Myotonic dystrophy type 1 (DM1) is a genetic disease caused by a trinucleotide (CTG) repeat expansion in the dystrophia myotonica protein kinase (DMPK) gene. It is a multisystem disorder however the hallmark symptoms are that of myotonia (prolonged contraction/poor relaxation after contraction), and muscle weakness. In DM1, muscle function may be affected by several components: pure muscle weakness, myotonia, muscle fatigue. Importantly, DM1 is progressive with worsening function over time and a pattern in which peripheral musculature is affected first, followed by proximal muscles being affected. In addition to the muscle symptoms, there has been recent focus on the need to better understand CNS involvement in DM1 as families have reported that some of the most disabling symptoms of the disease are cognitive and behavioral changes. As a single-gene disorder, DM1 has the distinct advantage of the opportunity for `root-cause' treatment or prevention via gene therapy. The effectiveness of gene therapy using Antisense Oligonucleotides (ASOs) in treatment of an animal model of DM1 has been shown, and the Phase I human trials have already begun. This has highlighted an urgent need to identify biomarkers that are: 1) disease-specific and clinically relevant; and 2) can track disease progression. The parent brain imaging grant is focused on evaluating biomarkers for DM1 effects on brain while the revised application will be focused on evaluating biomarkers for DM1 effects on muscle. The revised muscle application will directly `piggy-back' onto the parent brain study by utilizing the same patients, controls, and longitudinal design. Given that the parent brain study is early in its course, this provides a unique opportunity to expand the assessments of these rare patients, leveraging their participation and significantly enhancing the potential for important findings.
The aims of the revised muscle application are essentially parallel to the parent brain study and outline the goals of a study designed for biomarker discovery: 1. Evaluation of muscle structure using MRI and muscle function using electrophysiology and quantitative functional measures. 2. Correlation of muscle structure with muscle function, and with other disease-specific measures. 3. Longitudinal assessment to detect change over time.
This is a revised application (formerly called a competing supplement) to request support for a significant expansion of 1R01NS094387-01 Longitudinal Assessment of Brain Structure and Function in Myotonic Dystrophy Type 1 (DM1), from here on referred to as the `parent brain study'. The parent grant was funded in September of 2015 and has the overall aim to investigate the use of Magnetic Resonance Imaging (MRI) measures of white matter health as biomarkers of DM1 brain disease. The revised application will expand the scope of the study by adding an overall aim to investigate biomarkers of peripheral muscle structure using MRI and muscle function using quantitative measures of muscle physiology. This will be linked with the ongoing brain structure and function data, providing unique correlations.
