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.