Arrhythmogenic cardiomyopathy (ACM) is a genetically inherited disease characterized by progressive cardiomyocyte loss and fibro-fatty replacement of the ventricular myocardium. ACM is mostly caused by mutations in genes encoding proteins of the intercalated disc, with PKP2, DSG2, and DSP, encoding for plakophilin-2, desmoglein-2, and desmoplakin, respectively, being most frequently mutated. ACM classically manifests as ventricular arrhythmias and sudden death, which is often the first clinical manifestation of the disease, and are an indication for cardiac transplantation. The heterogeneous landscape of ACM pathogenesis complicates the search for effective therapeutic options. To this day, the molecular mechanisms underlying this disease remain poorly understood and characterized, even for patients with an identified mutation. Our ultimate aim is to gain a better understanding of the molecular mechanisms.
As a first part of the project, we are generating three human induced pluripotent stem cell (hiPSC) lines, which will be derived from ACM patient urine samples. These hiPSC lines will harbor a mutation in DSG2, DSP and CTNNA3 (the latter encoding for αT-catenin). An isogenic control line carrying the corrected gene will be generated for each hiPSC line using CRISPR/Cas9. After differentiation, the resulting induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) will be characterized on electrophysiological, molecular and ultrastructural level. We will focus on morphology and function and analyse the effect of stress on iPS-CMs by mechanical means.