Ostini Alessio, Kléber André G, Rudy Yoram, Saffitz Jeffrey E, Kucera Jan P
bioRxiv. 2024 Dec 17:2024.12.12.628155. doi: 10.1101/2024.12.12.628155.
Patients with arrhythmogenic cardiomyopathy (ACM) 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 (AAV) transduction of cardiac myocytes. Evidence from experimental systems and patients indicates that ventricular myocytes in 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.
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 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.
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 ACM patients undergoing gene therapy.
The extent of successful ventricular myocyte transduction anticipated to be achieved in AAV gene therapy trials will likely not restore conduction velocity to levels sufficient to decrease risk of reentrant arrhythmias.
Patients with arrhythmogenic cardiomyopathy due to pathogenic variants in (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.
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 . 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.
由于桥粒蛋白盘状球蛋白2基因（ ）的致病变异而患有致心律失常性心肌病（ACM）的患者，正被纳入旨在通过腺相关病毒（AAV）转导心肌细胞来替代缺陷等位基因的基因治疗试验。来自实验系统和患者的证据表明， ACM患者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AAV基因治疗试验中，通常只有不到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学计算模型，来确定不同水平的成功基因治疗对 ACM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展情况。
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。在具有中度解偶联水平（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免疫信号的潜在影响，而在接受基因治疗的 ACM患者中，这两者可能都存在。
预计在AAV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。
由于桥粒蛋白盘状球蛋白2基因（ ，桥粒蛋白盘状球蛋白2的基因）的致病变异而患有致心律失常性心肌病的患者，目前正被纳入基因治疗试验。实验和临床观察表明，致心律失常性心肌病患者由于源-汇不匹配，心室传导缓慢且有传导阻滞倾向。腺相关病毒基因治疗后，通常只有不到50%的心室肌细胞被转导。
在预期的心室肌细胞成功转导水平下，由于 基因变异而患有致心律失常性心肌病的患者，其传导速度几乎不会改变。更高水平的转导可能会产生增加传导阻滞风险的情况，尤其是在存在非传导性纤维脂肪瘢痕组织区域的情况下。
