Modified Polycyclic Compounds Rescue Mis-splicing in Myotonic Dystrophy Type 1 Disease Models

Myotonic dystrophy type 1 (DM1) is an autosomal dominant multisystemic disorder with no approved therapeutics targeting the disease mechanism. DM1 is caused by the expression of expanded CUG repeat RNA (CUG_exp), which sequester the muscleblind-like (MBNL) family of RNA binding proteins leading to dysregulated alternative splicing and a host of downstream impacts. While previous studies showed that diamidines rescued DM1 dysregulated alternative splicing events, their potential was limited by toxicity and off-target effects. A new class of modified polycyclic compounds (MPCs), based on diamidines, were created and screened in DM1 patient-derived cell lines. This approach identified MPC03 and MPC04 as being capable of rescuing DM1 dysregulated splicing events at low nanomolar concentrations with no obvious toxicity and limited off-target effects. In a DM1 mouse model, treatment with MPC03 and MPC04 reduced CUG_exp RNA levels and partially rescued DM1 mis-splicing. Binding data and modeling showed that lead MPCs bind to CUG_exp RNA, and in cells lacking CUG repeats, MPC activity was absent, suggesting that these compounds displace sequestered MBNL proteins from CUG_exp RNA. Taken together, MPCs show therapeutic promise across multiple DM1 models.