Molecular Mechanisms and Therapeutic Opportunities in Genetic Cardiomyopathies

Genetic cardiomyopathies are important contributors to cardiomyopathy-related morbidity and a recognized cause of sudden cardiac death, particularly in younger individuals. Among the well-characterized inherited forms are arrhythmogenic cardiomyopathy (ACM) and hypertrophic cardiomyopathy (HCM), commonly associated with pathogenic or likely pathogenic variants in genes encoding proteins essential for cardiomyocyte structural and functional integrity, including intercalated disc components in ACM and sarcomeric proteins in HCM. Despite advances in genetic diagnostics, the molecular mechanisms underlying disease development remain incompletely understood and disease-modifying therapies are limited. This thesis aimed to elucidate pathogenic mechanisms and explore new therapeutic strategies using cellular and animal models.
Chapter 2 focused on ACM caused by plakophilin-2 (PKP2) variants, the most frequently mutated gene in this disease. Using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), genetically engineered mouse models, and human explanted tissue, we demonstrate that PKP2 deficiency enhances ubiquitination and degradation of intercalated disc proteins. Inhibition of the ubiquitin–proteasome system increased protein levels and improved cardiomyocyte function, identifying aberrant protein degradation as a potential therapeutic target.
Chapter 3 examined the impact of PKP2 variants on cellular metabolism. Molecular analyses of hiPSC-CMs and human ACM myocardium revealed downregulation of oxidative phosphorylation pathways. Functional studies showed impaired mitochondrial respiration and reduced expression of PGC1α in PKP2 mutant hiPSC-CMs. Increasing PGC1α expression improved mitochondrial gene expression and contractile function, implicating mitochondrial dysfunction in ACM pathogenesis and suggesting a mechanism underlying exercise-induced disease progression. These findings identify impaired mitochondrial function as a potential target for treatment.
The final part of this thesis explored gene correction as a therapeutic strategy for HCM caused by a Dutch founder nonsense variant in myosin binding protein C3 (MYBPC3). We evaluated compact adenine base editors capable of correcting the pathogenic mutation in patient-derived hiPSC-CMs. Base editing enabled precise correction of the disease-causing variant and improved cardiomyocyte function. These findings provide proof-of-concept for the therapeutic potential of base editing in inherited cardiomyopathies and support further development of gene-editing approaches for cardiovascular disease.
Together, these studies provide insight into mechanisms driving genetic cardiomyopathies and identify therapeutic opportunities, including modulation of protein homeostasis, mitochondrial pathways, and direct genetic correction.