iPS derived cardiomyocytes as a tool to test the clinical significance and drug effectiveness in a novel mutation linked to CPVT

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disease that is associated with sudden cardiac death and often lethal in young adults. Several different mutations affecting cellular Ca2+ release upon stress have been associated with the disease. Treatment options include betablockers and class Ic antiarrhythmic substances (known to also decrease ryanodine receptor (RyR) mediated Ca2+ leak). We recently identified a female 43 years old patient with polymorph ventricular premature excitation and syncope upon stressful events. The family history unveiled several instances of sudden cardiac death in close relatives. Genetic testing showed a novel mutation in the TECRL gene (serin309), a gene that codes for trans-2,3-enoyl-CoA-reducase like protein which impacts ryanodine receptor mediated Ca2+ release. A different mutation in the same protein has only recently been linked to CPVT1. Within the scope of this project, human induced pluripotent stem cells (iPSc) are generated from this patient, human cardiomyocytes (iPSc-CMs) subsequently tested for pro-arrhythmic Ca2+ release, arrhythmic contractions (partner site Berlin) and altered action potential characteristics as well as ion channel current (partner site Mannheim). The applicants are also going to test different antiarrhythmic drugs in the iPSc-CMs to find the most effect drug in this setting. Additionally, we are going to use the CRISPR/Cas9 (CRISPR-associated protein 9) system to modify the suspected causative TECRL variant in CPVT-cells to a wild-type sequence (mutation correction) or knockout TECRL variant in a WT cell line. Ultimately the data gathered within the scope of this application might allow to effectively reduce the risk of arrhythmia in patients with this novel CPVT related mutation.