Design, Synthesis and Efficacy of New Small Molecule Therapeutics to Impede Myotonic Dystrophy

Summary/Abstract
Many of the growing family of over 40 neuromuscular and neurodegenerative repeat expansion diseases,
including myotonic dystrophy (DM), involve a strong RNA gain-of- function (GOF) mechanism with toxicity
induced by expansion RNAs. In this mechanism, the expanded RNAs sequester RNA binding proteins (RBPs)
leading to the disruption of multiple downstream RNA processing pathways. The reduction of the expanded
RNAs to alleviate disease mechanism and downstream pathogenesis is therefore an attractive therapeutic
approach. We have previously demonstrated promising small molecule efficacy including: (1) actinomycin D
mediated selective reduction of transcription from expanded CTG repeats; (2) microtubule inhibitors mediated
selective modulation of toxic CUG RNA levels; and (3) diamidines mediated reduction of toxic RNAs. While
these results show promise, many of these compounds are toxic and display sub-optimal properties leading us
to develop a new set of modified polycyclic compounds (MPCs). These compounds are based on three
elements: a heterocyclic core; a benzimidazole side group; and functionalized end groups. Modifying each of
these elements provides a large panel of potential compounds to aid in understanding mechanism of action
and develop new drug candidates to address the urgent unmet therapeutic need in DM. Preliminary data for
two of these MPCs shows robust rescue of splicing in both DM1 and DM2 cell lines in the nanomolar range
with little associated toxicity or effects on cell viability as well as rescue of mis-splicing in 2 independent DM
mouse models. In this proposal, we will use parallel in vitro and in vivo design-model-test cycles to
systematically modify and evaluate compounds by focusing on replacement, testing and refinement of the
three MPC elements (core, side and end groups). These data will provide a better understanding of their
mechanism of action and be followed by testing of their therapeutic potential in DM patient-derived cell
lines and animal models. The successful completion of this project will provide a new class of therapeutic
small molecules, a better understanding of their mechanism of action and in vivo data from multiple animal
models supporting their future therapeutic potential. Taken together this information will address the large
unmet need for therapeutic approaches for DM and provide supporting data towards future clinical studies.

Grant Number: 5R01NS120485-04
NIH Institute/Center: NIH
Principal Investigator: Andrew Berglund