Toxic RNA Selective Screening to Identify Drugs, Targets & Genetic Modifiers for Myotonic Dystrophy

Presented on September 8th, 2023.

Kaalak Reddy, PhD
State University of New York at Albany’s RNA Institute, New York, United States

Myotonic dystrophy (DM) is caused by DNA repeat expansions that produce toxic repeat expansion RNA. These toxic RNA molecules gain a number of aberrant functions in the cell leading to disease. One major consequence is the sequestration of the MBNL family of RNA processing proteins. By acting as a molecular sponge to the MBNL proteins, toxic RNA production causes widespread RNA processing defects as a result. Thus, when considering development of therapeutic approaches, a cellular system where the toxic RNA abundance can be sensitively and rapidly measured on a large scale can permit screening of large numbers of chemical and biological agents with therapeutic potential. We previously developed a HeLa DM cell line that enables us to simultaneously measure the levels of a toxic RNA and a non-toxic control RNA to rapidly identify treatments that selectively affect the toxic RNA. We previously used this cellular screening system to identify new candidate small molecule therapeutics for DM. We are now expanding our approach to screen the human genome for genetic modifiers of toxic RNA levels in DM. Through genetic screening, we identified new splicing factors that modulate toxic RNA effects in DM patient cells. Identifying genetic modifiers of toxic RNA in DM provides new biological and therapeutic insights and may shed light on new disease modifiers for DM that can help to explain the considerable disease heterogeneity in patients.

Learn more about the 2023 MDF Annual Conference at https://www.myotonic.org/2023-mdf-ann...