Key result
TN-401 restores cardiac energetics and rescues electrophysiological function in preclinical ARVC models.
Why the study?
Plakophilin-2 alterations cause compromised contractility and electrical instability in ARVC, but the relationship between PKP2, desmosome function, and energy metabolism required investigation.
PKP2 deficiency intrinsically impairs cardiac energy metabolism, which can be rescued by AAV9:PKP2 gene therapy, suggesting metabolic maintenance is a core component of desmosome function in ARVC.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial cardiac disease associated with ventricular arrhythmias and an increased risk of sudden cardiac death. Alterations in the desmosome gene plakophilin-2 (PKP2) lead to compromised contractility and electrical instability of cardiomyocytes. In this study, we utilized ARVC mouse and human induced pluripotent stem cell-derived cardiomyocyte models to confirm impaired energy metabolism that concorded with the human data. Our results supported an intrinsic cellular link between PKP2 and energy metabolism. TN-401-mediated PKP2 expression improved mitochondrial and glycolytic energetics and rescued cardiomyocyte functions that are dictated by mechanical and structural integrity of desmosome. Therefore, maintaining energy metabolism of cardiomyocytes is an integral part of PKP2 and desmosome functions, adding a new layer of understanding to ARVC disease mechanism.
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Aycinena et al. (2025) studied Arrhythmogenic right ventricular cardiomyopathy (ARVC). TN-401 (AAV9:human PKP2) / AAV9:mouse Pkp2 vs. Vehicle, wild-type (WT), or negative control (siNeg) was evaluated on Restoration of cardiac energy metabolism (glycolysis, fatty acid oxidation) and rescue of structural/electrophysiological functions..
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