Shared Resource Core

Virginia Commonwealth University, Richmond VA

Investigators

Abstract

Modified Project Summary/Abstract Section The myotonic dystrophies share a common pathogenic mechanism and have similar but non overlapping phenotypes. The discovery of the pathogenic mechanism, along with advances in genetic medicine, have rapidly accelerated the development of potential therapies for these conditions. The investigators are aware of multiple partners with potential disease modifying therapies, some currently in clinical trials. In consultation with the larger research community, we have identified two gaps in resources that this Core will support. First, we are aware that samples, inclusive of muscle tissue, DNA, or cell lines, are not widely available or easily accessible. Further, in many instances these samples are lacking in characterization, including genetic analysis or clinical phenotypes. Second, we are aware that a biomarker that was developed in part by our Center Investigators, the Splice Index, is considered the key biomarker for therapeutic trials in DM1. The Splice Index is a composite measure of 22 different splicing events that are dysregulated in DM1. We have shown it can be performed reliability, is strongly correlated with measures of muscle strength and function, and is predictive of future function. This index requires a specific bioinformatic approach that is not widely disseminated despite interest in the biomarker. The investigators have significant expertise that they will bring to bear with the overall goal of the resource core to support late preclinical therapeutic development and early clinical trial conduct. The resource core will provide the following services to accomplish these goals: 1) We will provide a large biorepository of DNA, tissue, and patient derived cell lines along with providing available phenotypic and genomic data with the sample; 2) We will provide access the Splice Index, either by directly performing the assay or through disseminating the required methods and materials; 3) We will provide a web portal to access and search the biorepository as well as directly perform the Splice Index pipeline by providing sequencing data. The web portal will also provide open access to the protocols or SOPs required to successfully develop and test therapies in DM1. The investigators will bring several preexisting efforts into the Resource core to support these efforts. The investigators at VCU have established a biorepository for myotonic dystrophy tissue and previously created cell lines from individuals with DM. The investigators at University of Albany have significant experience testing therapies in these cell lines. Finally, the investigators validated the Splice Index currently in use in DM1 clinical trials. These efforts have defined the expertise and offerings of the Resource Core, as well as a sense of where the DM research community needs support to accelerate these disease modifying therapies. The website will be used as a portal to access the resources and the Core will create milestones to demonstrate use of the resources as well as the success in moving therapeutics across the DM community forward.