Author(s) :

Ramkumar Babu.

Volume/Issue :

Abstract :

Arrhythmogenic cardiomyopathy (ACM) is a heritable cardiac disease characterized by progressive myocardial dysfunction, life-threatening arrhythmias, and an elevated risk of sudden cardiac death. Mutations in the PKP2 gene, encoding the desmosomal protein plakophilin-2, represent the most common genetic cause of ACM, accounting for approximately 21–35% of diagnosed cases. Plakophilin-2 is an essential scaffold protein within cardiac desmosomes, maintaining the mechanical and electrical integrity of cardiomyocytes through interactions with desmoplakin, desmogleins, desmocollins, and intermediate filaments. Loss-of-function PKP2 mutations disrupt desmosomal assembly, impair gap junction-mediated electrical conduction, and trigger downstream fibrofatty replacement of myocardium via the TGF-β1/p38 MAPK pathway. Current therapies, including implantable cardioverter defibrillators (ICDs) and antiarrhythmic drugs, manage symptoms but do not address the underlying molecular defect. Adeno associated virus (AAV)-based gene replacement therapy has emerged as a promising disease-modifying strategy, with several Phase 1/2 clinical trials now underway. However, significant obstacles remain, including off-target tissue tropism, immune-related adverse events, and the difficulty of translating preclinical findings from murine models to human patients. This review synthesizes current knowledge on PKP2’s role in cardiac biology, the molecular consequences of its mutation in ACM, the status of ongoing clinical trials, and the key challenges and future directions for gene therapy development.