In partnership with the Myotonic Dystrophy Foundation US, the Myotonic Dystrophy Foundation UK made the following Research Fellowship grants in 2019:

Carl Shotwell
University of Florida, Gainesville, Florida, US

The goal of Mr. Shotwell’s project “Engineering Synthetic RNA Binding Proteins to Probe the Mechanisms of Myotonic Dystrophy and Development of Potential New Therapeutics” is to design and identify synthetic proteins that displace endogenous Muscleblind (MBNL) from binding to expanded CUG (DM1) and CCUG (DM2) repeats and thereby rescue splicing without off-target effects of some other putative treatment strategies. The specific aims of the project are to: (1) determine the minimal domains required for a functional MBNL1 protein for splicing regulation and (2) create synthetic MBNL1 proteins with enhanced binding to toxic CUG/CCUG-expanded RNA. The first aim is designed to better understand the functional regions (domains) of MBNL protein, while the second aim exploits that knowledge to design synthetic proteins with potential therapeutic value.

Shruti Choudhary, PhD
Scripps Research Institute Florida, US

In Dr. Choudhary’s project “Selective and non-toxic small molecules that cleave r(CUG) repeats in DM1—optimization and evaluation as a therapeutic approach” she proposes straightforward studies to develop small molecules that recognize long, pathogenic CUG repeats in DMPK over smaller, non-pathogenic lengths. The rationale is that small molecules targeted in this fashion may be more selective than oligonucleotide drugs currently in development which may or may not be able to distinguish between short and disease causing repeats. The work focuses on optimizing and testing a small molecule drug based on the bleomycin scaffold. The specific aims are to: (1) optimize the bleomycin-cleavage module, (2) study compound potency and selectivity in DM1 patient-derived cell lines, and (3) evaluate the efficacy of the best compounds in a mouse model of DM1.