Abstract

High Content Screening for Physiological Endpoints in the Development of an RNA Therapeutic for Heart Failure

Mark Mercola, Professor, Sanford Burnham Medical Research Institute

A debilitating loss of contractility characterizes heart failure, which remains a major cause of morbidity and mortality worldwide.  In order to expand the target space for drugs to treat heart failure, we developed kinetic imaging cytometry, a new high content screening technology capable of measuring cardiomyocyte contractile calcium transients and voltage action potential kinetics and morphology. Using this technology, we functionally screened human microRNAs for the ability to suppress cardiomyocyte contractility.   microRNAs are endogenous short non-coding RNAs that have been found to modulate most biological processes.  Of over a hundred microRNAs found to suppress proteins involved in calcium handling, a small number were found to be upregulated in heart failure.  A chemically modified antisense RNA (anti-miR) to one of the most potent microRNAs was developed and found to halt established heart failure in a mouse model, and statistically improve cardiac function. Functional screening of microRNAs can be an entry point into systems-level understanding of networks that control complex biological processes, as well as identify microRNAs that themselves might be valuable therapeutic targets.