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

Background Patients with arrhythmogenic cardiomyopathy (ACM) 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 (AAV) transduction of cardiac myocytes. Evidence from experimental systems and patients indicates that ventricular myocytes in PKP2 ACM have greatly reduced electrical coupling at gap junctions and reduced Na + current density. In previous AAV 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 ACM. 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 non-linear 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 appear to pose a major safety concern. However, our models did not incorporate potential effects of fibrosis and immune signaling, both of which will presumably be present in PKP2 ACM patients undergoing gene therapy. Conclusions The extent of successful ventricular myocyte transduction anticipated to be achieved in PKP2 AAV gene therapy trials will likely not restore conduction velocity to levels sufficient to decrease risk of reentrant arrhythmias. What is Known - Patients with arrhythmogenic cardiomyopathy due to pathogenic variants in PKP2 (the gene for the desmosomal protein plakophilin-2) are now being enrolled in gene therapy trials. - Experimental and clinical observations indicate that patients with arrhythmogenic cardiomyopathy have slow ventricular conduction with a propensity to conduction block due to source-sink mismatch. - <50% of ventricular myocytes are usually transduced after adeno-associated viral gene therapy. What the Study Adds - At anticipated levels of successful transduction of ventricular myocytes, little change in conduction velocity will be achieved in patients with arrhythmogenic cardiomyopathy due to variants in PKP2 . - Higher levels of transduction could produce conditions that increase risk of conduction block, especially in the presence of areas of non-conducting fibrofatty scar tissue.