Preparing for Therapeutics across the Spectrum of Myotonic Dystrophy

Virginia Commonwealth University, Richmond VA

Investigators

Abstract

Myotonic Dystrophy Type 1 (DM1) is a progressive, multisystemic disorder caused by a toxic CUG repeat expansion in the 3’UTR of the DMPK gene that leads to dysregulated RNA splicing. Therapies targeting knockdown of the DMPK transcript have gained traction with multiple Phase I/II studies releasing positive results. Related approaches that interfere with the interaction between toxic repeat and RNA splicing proteins have entered clinical trials. Notably, all of these trials currently include a fairly homogenous population of adults with DM1. This leaves clear gaps in the ability for the entire community to access these promising therapies. The Center is designed to bring these therapies to the entire community. We have identified a sparsity of natural history and biomarker data in children with DM1 as one clear gaps in trial readiness. We also have identified that genetic modifiers of disease severity and therapeutic efficacy may also be a gap in the investigation of these therapies. The projects will benefit from the significant ongoing and prior efforts by the Center Investigators, the Myotonic Dystrophy Clinical Research Network (DMCRN) and the international community to achieve successful completion. Project 1 will enroll 150 children with congenital myotonic dystrophy or childhood onset into a two-year observational study. Participants will be followed with measures of motor function, cognition, and quality of life. In a subset of children with childhood myotonic dystrophy we will expand prior efforts to validate a composite measure of RNA splicing, the Splice Index, into this population. In Project 2, we will leverage six prior or nearly completed studies to perform a genome wide association study (GWAS) with over 1600 DM1 participants. We will identify genetic variants that contribute to variation from the predicted relationship between selected phenotypes and the repeat length. In parallel we will identify genetic variants that influence the efficacy of therapeutics currently in clinical trials. We will confirm identified variants in animal models of DM1. The combined projects, including prior efforts within the Center will be deposited into a biorepository that will be disseminated through the resource core along with supportive phenotypic and genomic data. The resource core will also provide access to the Splice Index, the biomarker of choice for ongoing therapeutic trials. The training core will focus on developing a pipeline of myotonic dystrophy scientists through summer didactic courses in bioinformatics and clinical trial design and will support a 1-year clinical research fellowship in myotonic dystrophy. The administrative core will provide the website that will serve as the portal into the Center, provide resources to execute these multinational projects, and will use virtual platforms to link the investigator teams. Combined, these cores and projects are linked synergistically to achieve the shared goal to prepare the entire DM community for these advancing therapies, including populations that currently have access to disease modifying therapeutic trials. Given the absence of available therapies and high unmet need in myotonic dystrophy, there is urgency to move these objectives forward.