Novel Therapeutics for Timothy Syndrome and Related Cardiac Channelopathy

Project Summary: Calcium channel dysfunction in heart muscle cells induces cardiac arrhythmias such as Timothy syndrome, a severe form of genetic long QT syndrome type 8. In preliminary experiments using pharmaceutical approach, we found that activation of Sigma 1 receptor using its agonists could alleviate the cellular phenotypes in human induced pluripotent stem cell (iPSC) and mouse models of the genetic disease. The goal of this study is to design, synthesize and characterize new small molecules to develop novel Sigma 1 receptor agonists that are more suitable for the cardiac phenotypes in the genetic disease. To accomplish this goal, we will take advantage of our experience and expertise in pharmaceutical science and medicinal chemistry using human iPSC and rodent models to address our hypotheses. In addition, we will examine whether our approach using the new small molecules can be applicable for common forms of genetic long QT syndrome such as type 1 and 2. Therefore, our translational study will provide new opportunity of drug development for genetic cardiac arrhythmias.