Abstract 242: Drug Repurpose Using Human Stem Cell Models of Cardiac Arrhythmias

Abstract

For translational approach toward drug development, we has investigated the molecular mechanisms underlying various inherited cardiac diseases and identified lead compounds to test the derivatives in iPSC and mouse models. In this study, we focus on a lethal disease, Timothy syndrome (TS), which is characterized as a developmental disorder containing multiple organ dysfunctions including autism and cardiac arrhythmia such as long QT syndrome (type 8, LQTS8) and ventricular tachycardia. TS is caused by de novo gain-of-function mutations in a voltage-gated calcium channel Ca V 1.2, which is essential for cardiac excitation-contraction coupling. Previous reports demonstrated that beta blockers and calcium channel blockers were not sufficient to prevent the lethal arrhythmias in TS patients. In fact, some TS infants died shortly after birth. Therefore, new drug development or FDA drug repurposing is really crucial for the patients. We generated and characterized human iPSC and mouse models of TS. Also, we have used familial LQTS8 and LQTS1 iPSC lines to generate more LQTS iPSC models. Interestingly, our chemical tests identified that an FDA-approved drug, fluvoxamine, rescued cardiac phenotypes in TS (de novo LQTS8), familial LQTS8 and LQTS1 iPSC models. Fluvoxamine has been clinically used for depression and anxiety disorder as a selective serotonin reuptake inhibitor (SSRI). Fluvoxamine is also known to activate Sigma 1 receptor (Sigma-1R). To explore the mechanisms underlying the beneficial effects of fluvoxamine, we tested several Sigma-1R agonists (ex. PRE-084 as a non-SSRI) and antagonists (ex. NE-100) and other SSRIs which do not have any effect on Sigma-1R function (ex. peroxetine) on TS iPSC-derived cardiomyocytes. The results demonstrate that Sigma-1R activation using PRE-084 could rescue the phenotypes in TS models. The molecular mechanism in which Sigma-1R activation rescues cardiac arrhythmic phenotypes is novel. Furthermore, we share our next strategy of chemical synthesis for the development of novel Sigma-1R agonists, which are less permeable to the brain through the blood-brain barrier (BBB), as new therapeutic compounds for LQTS.