Ostini Alessio, Kléber André G, Rudy Yoram, Saffitz Jeffrey E, Kucera Jan P
Department of Physiology (A.O., J.P.K.), University of Bern, Switzerland.
Graduate School for Cellular and Biomedical Sciences (A.O.), University of Bern, Switzerland.
Circ Arrhythm Electrophysiol. 2025 May;18(5):e013658. doi: 10.1161/CIRCEP.124.013658. Epub 2025 Apr 9.
Patients with arrhythmogenic cardiomyopathy due to pathogenic variants in , 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 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.
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 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.
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 arrhythmogenic cardiomyopathy patients undergoing gene therapy and could impact arrhythmogenesis.
The extent of successful ventricular myocyte transduction anticipated to be achieved in 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.
由于桥粒蛋白盘状球蛋白-2基因的致病变异导致的致心律失常性心肌病患者正在参与基因治疗试验，该试验旨在通过腺相关病毒转导心肌细胞来替换缺陷等位基因。来自实验系统和患者的证据表明，致心律失常性心肌病中的心室肌细胞在缝隙连接处的电偶联大大减少，钠电流密度降低。在先前的腺相关病毒基因治疗试验中，一般只有不到50%的心室肌细胞被转导。
我们使用已建立的心室细胞电生理计算模型来确定不同水平的成功基因治疗对致心律失常性心肌病患者传导的影响。在由实验研究中观察到的具有不同电偶联水平和钠电流密度的细胞组成的组织构建体中分析传导速度和传导阻滞的发生情况。
我们观察到传导速度与转导细胞比例之间存在非线性关系。当高达40%的心肌细胞被转导时，传导速度仅适度增加。在具有中度去偶联水平（正常水平的0.10或0.15）的组织构建体中未发生传导阻滞，因为这种程度的偶联足以使电紧张电流通过患病细胞。因此，在1期临床试验中可能出现的低水平转导似乎不会带来重大安全问题。然而，我们的模型没有纳入纤维化和炎症的潜在影响，这两者在接受基因治疗的致心律失常性心肌病患者中可能都存在，并且可能影响心律失常的发生。
预计在腺相关病毒基因治疗试验中成功实现的心室肌细胞转导程度可能无法将传导速度恢复到足以降低折返性心律失常风险的水平。需要60%至80%的转导效率才能将传导速度恢复到正常的50%。
