Using an activator of hERG (RPR-260245) in a model of acquired and inherited Long QT syndrome type 2

The human ether-a-go-go related gene (hERG) channel is the molecular correlate of the rapid delayed rectifier current (IKr); its dysfunction causes Long QT syndrome type II (LQT II). RPR-260245 (RPR) is an activator of hERG that increases hERG current by slowing deactivation. Thus, it represents a potential treatment strategy for LQT. However, only few studies have addressed its impact on cardiac physiology. We used electrophysiology techniques in Xenopus Laevis oocytes and optical mapping in induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs) to test the effects of RPR on hERG and on the cardiac action potential. We show that RPR has little effect on the cardiac AP in WT iPSC-CMs but demonstrate a partial rescue in our model of acquired LQT (aLQT) under dofetilide block and a partial rescue in our model of LQT II. Finally, RPR significantly increases protective hERG current, especially in instances of the R56Q mutation.