In Silico Mining of a System Wide Transcriptional Profiling Database for Clinically Relevant Gene Modulation by FDA Approved or FDA Ready Agents; Validation of a Novel Translational Approach

Abstract

It has been recognized that small molecules can affect a substantial proportion of the human transcriptome in ways that are currently unknown and difficult to predict. Working with the Broad Institute, using their Connectivity Map database, we have worked to identify compounds anticipated to modulate two diseases; myotonic dystrophy (DM1) and Duchenne muscular dystrophy (DMD). DM1 stems from an expanded CTG repeat found in the DMPK gene. The down regulation of DMPK mRNA represents a valid therapeutic avenue. DMD is characterized by degeneration of muscle, caused by mutations in the dystrophin gene. One therapeutic strategy for DMD is to increase the dystrophin homologue utrophin. We have identified a number of compounds capable of decreasing DMPK mRNA and others which increase utrophin mRNA and protein. We hope our success in compound identification not only leads to potential therapeutics for these diseases, but highlights the usefulness of using in silico screens.