Plakophilin-2 (PKP2) (PKP2)

Plakophilin-2 (PKP2) is a member of the armadillo-repeat protein family and a core component of the cardiac desmosome, which provides mechanical coupling between cardiomyocytes (UniProt P78337). It plays a crucial role in desmosome assembly, cell-to-cell signaling, and the regulation of sodium channel (Nav1.5) activity (PubMed: 24561156). Mutations in the PKP2 gene are the leading cause of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), a genetic heart disease characterized by fibrofatty replacement of the myocardium and high risk of sudden cardiac death (PubMed: 15489853). In the context of PKP2 deficiency, the loss of desmosomal integrity leads to electrical instability and structural remodeling of the heart. Current therapeutic approaches involve AAV-mediated gene replacement, such as LX2020 (AAVrh74.PKP2) and TN-401 (AAV9.PKP2), which aim to restore PKP2 levels in the heart to stabilize desmosomal structures and prevent arrhythmias (Lexeo Therapeutics; Tenaya Therapeutics). These gene therapies target the underlying deficiency to halt or reverse disease progression in patients with PKP2-associated cardiomyopathy. Clinical trials are currently evaluating the safety and efficacy of these AAV-delivered transgenes in patients with confirmed PKP2 mutations.

Other names

Plakophilin 2PKP2ARVD9

Gene replacement therapy designed to restore functional Plakophilin-2 protein expression in cardiomyocytes to stabilize desmosomes and prevent disease progression.