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

TL;DR

Scientists developed new compounds that reduce RNA toxicity in myotonic dystrophy type 1, showing potential as a treatment.

Contribution

Modified polycyclic compounds (MPCs) were designed to rescue mis-splicing in DM1 with low toxicity and high efficacy.

Findings

MPC03 and MPC04 rescued mis-splicing in DM1 patient-derived cells at low concentrations.

MPCs reduced CUGexp RNA levels and partially corrected splicing in a DM1 mouse model.

MPCs bind specifically to CUGexp RNA, displacing sequestered MBNL proteins.

Abstract

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 (CUGexp), 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 CUGexp RNA levels and partially
rescued DM1 mis-splicing. Binding data and modeling showed that lead
MPCs bind to CUGexp RNA, and in cells lacking CUG repeats,
MPC activity was absent, suggesting that these compounds displace
sequestered MBNL proteins from CUGexp RNA. Taken together,
MPCs show therapeutic promise across multiple DM1 models.

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