Screening Modified Polycyclic Compounds in Myotonic Dystrophy Type 1 Cell Lines

Myotonic dystrophy type 1 (DM1) is an autosomal dominant neuromuscular disease with no treatment options and causes progressive muscular atrophy and weakness. DM1 occurs when the DMPK gene contains an abnormal CTG repeat expansion in the 3’ untranslated region. Transcription of the expansion leads to sequestration of RNA binding proteins and downstream splicing dysregulation. This dysregulation ultimately affects many systems in the body leading to the DM1 phenotype. This project consists of two parts, with one of our goals being to test experimental small molecule (MPC-04) in an immortalized patient-derived DM1 cell model. Using RNA sequencing data from patient-derived DM1 myotubes, 120 skipped-exon events that are dysregulated in DM1 were identified and showed positive changes in alternative splicing behavior after MPC-04 treatment. Future experiments include testing MPC-04 in the immortalized DM1 cell model 1) to determine if splicing events found in the DM1 myotubes are mis-spliced in the immortalized cell model, 2) rescued by MPC-04 treatment and 3) more broadly develop this immortalized DM1 cell model as a screening tool for testing therapeutic approaches for DM1. The second goal is to characterize the activity of these MPCs in fibroblasts and myotubes with splicing rescue, gene expression changes, and protein expression restorations. Our findings identified promising lead compounds, including HM043 and HM058G, that demonstrated significant correction of splicing defects and potential therapeutic benefit. Ongoing efforts aim to further analyze their mechanisms of action, with the ultimate goal of advancing small-molecule therapeutics for the treatment of DM1.