Work

Computational Modeling of Effects of PKP2 Gene Therapy on Ventricular Conduction Properties in Arrhythmogenic Cardiomyopathy

Year: 2025

Type: article

Abstract: BACKGROUND: Patients with arrhythmogenic cardiomyopathy due to pathogenic variants in PKP2 , the gene for the desmosomal protein plakophilin-2, are being enrolled in gene therapy trials designed to replace the defective allele via adeno-associated viral transduction of cardiac myocytes. Evidence from experimental systems and patients indicates that ventricular myocytes in PKP2 arrhythmogenic cardiomyopathy have greatly reduced electrical coupling at gap junctions and reduced Na + current density. In previous adeno-associated viral gene therapy trials, <50% of ventricular myocytes have generally been transduced. METHODS: We used established computational models of ventricular cell electrophysiology to define the effects of varying levels of successful gene therapy on conduction in patients with PKP2 arrhythmogenic cardiomyopathy. Conduction velocity and development of conduction block were analyzed in tissue constructs composed of cells with levels of electrical coupling and Na + current density observed in experimental studies. RESULTS: We observed a nonlinear relationship between conduction velocity and the proportion of transduced cells. Conduction velocity increased only modestly when up to 40% of myocytes were transduced. Conduction block did not occur in tissue constructs with moderate levels of uncoupling (0.10 or 0.15 of normal) as this degree of coupling was sufficient to allow electrotonic current to pass through diseased cells. Thus, low levels of transduction, likely to occur in phase 1 clinical trials, do not seem to pose a major safety concern. However, our models did not incorporate the potential effects of fibrosis and inflammation, both of which are presumably present in PKP2 arrhythmogenic cardiomyopathy patients undergoing gene therapy and could impact arrhythmogenesis. CONCLUSIONS: The extent of successful ventricular myocyte transduction anticipated to be achieved in PKP2 adeno-associated viral gene therapy trials will likely not restore conduction velocity to levels sufficient to decrease the risk of reentrant arrhythmias. Transduction efficiency of 60% to 80% would be required to restore conduction velocity to 50% of normal.

Source: Circulation Arrhythmia and Electrophysiology

DOI: 10.1161/circep.124.013658

Authors: Alessio Ostini, André G. Kléber, Yoram Rudy, Jeffrey E. Saffitz, Jan P. Kucera

Institutions: University of Bern, Harvard University, Washington University in St. Louis, Beth Israel Deaconess Medical Center

Language: English

Topic: Cardiac electrophysiology and arrhythmias

Subfield: Cardiology and Cardiovascular Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funders: Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, National Heart, Lung, and Blood Institute