From mechanism to therapy: understanding and targeting genetic cardiomyopathy

Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disorder characterized by the progressive loss of cardiomyocytes, fibrofatty replacement of the myocardium, and an increased risk of life-threatening ventricular arrhythmias and sudden cardiac death, particularly in young individuals and athletes. The disease exhibits substantial genetic and clinical heterogeneity and is most commonly caused by mutations in desmosomal proteins, which disrupt the mechanical and electrical integrity of the heart. Despite its severe clinical consequences, the molecular basis of ACM remains incompletely understood, and current treatment strategies are largely limited to symptom management. This underscores the need to more precisely define disease mechanisms and to develop targeted therapeutic approaches.
To address this, Chapter 1B provides a comprehensive overview of genome editing technologies and their relevance to cardiomyopathy research. It discusses CRISPR-Cas9, base editing, and prime editing, with emphasis on their applicability for generating accurate disease models and enabling mutation-specific therapeutic strategies. In addition, key limitations that currently hinder clinical translation are highlighted, particularly challenges related to delivery efficiency, tissue specificity, and the long-term safety of genome editing systems in the heart.
Building on this conceptual and technological framework, the experimental chapters focus on both mechanistic insights and therapeutic development. Chapter 2 investigates the molecular drivers of ACM using spatial transcriptomics on cardiac tissue from a patient with desmoplakin (DSP)-related cardiomyopathy. In combination with patient-specific in vitro models, this work identifies endothelial PAS domain-containing protein 1 (EPAS1) as a novel regulator of disease progression. The findings demonstrate that EPAS1 contributes to cardiomyocyte death, implicating hypoxia-related signaling pathways as key factors in ACM pathogenesis and providing new insight into how genetic mutations lead to cellular dysfunction.
In Chapter 3, gene therapy via gene replacement is explored, with a focus on plakophilin-2 (PKP2), the most frequently mutated gene in ACM. Using both in vitro and in vivo models of PKP2 haploinsufficiency, it is demonstrated that restoration of PKP2 expression can partially rescue disease-associated phenotypes. These results support the feasibility of gene supplementation as a therapeutic strategy and highlight its potential to address the underlying genetic cause of ACM.
Chapter 4 further advances therapeutic development by applying prime editing, a next-generation genome editing technology, to correct PKP2 mutations. This approach enables precise genetic correction without introducing double-strand DNA breaks, thereby improving specificity and safety compared to earlier techniques. The successful implementation of prime editing in relevant models underscores its potential as a strategy for treating inherited cardiomyopathies, particularly in postmitotic tissues such as the heart.
Finally, Chapter 5 integrates the findings of the thesis and discusses future perspectives. It emphasizes the potential of combining mechanistic insights with gene-based therapeutic approaches to advance toward precision medicine for ACM. Although challenges remain—particularly in terms of efficient delivery and safety-this work provides a strong foundation for the development of targeted and potentially curative treatments for this life-threatening disease.