Kort Eric J, Sayed Nazish, Liu Chun, Mondéjar-Parreño Gema, Forsberg Jens, Eugster Emily, Wu Sean M, Wu Joseph C, Jovinge Stefan
DeVos Cardiovascular Research Program, Fredrik Meijer Heart and Vascular Institute, Spectrum Health and Van Andel Institute, Grand Rapids, MI (E.J.K., J.F., E.E., S.J.).
Department of Pediatrics and Human Development, Michigan State University, Grand Rapids (E.J.K.).
Circulation. 2025 May 20;151(20):1436-1448. doi: 10.1161/CIRCULATIONAHA.121.058621. Epub 2025 Apr 1.
Gene mutations are responsible for a sizeable proportion of cases of heart failure. However, the number of patients with any specific mutation is small. Repositioning of existing US Food and Drug Administration-approved compounds to target specific mutations is a promising approach to efficient identification of new therapies for these patients.
The National Institutes of Health Library of Integrated Network-Based Cellular Signatures database was interrogated to identify US Food and Drug Administration-approved compounds that demonstrated the ability to reverse the transcriptional effects of knockdown. Top hits from this screening were validated in vitro with patient-specific induced pluripotent stem cell-derived cardiomyocytes combined with force measurement, gene expression profiling, electrophysiology, and protein expression analysis.
Several angiotensin receptor blockers were identified from our in silico screen. Of these, olmesartan significantly elevated the expression of sarcomeric genes and rate and force of contraction and ameliorated arrhythmogenic potential. In addition, olmesartan exhibited the ability to reduce phosphorylation of extracellular signal-regulated kinase 1 in -mutant induced pluripotent stem cell-derived cardiomyocytes.
In silico screening followed by in vitro validation with induced pluripotent stem cell-derived models can be an efficient approach to identifying repositionable therapies for monogenic cardiomyopathies.
基因突变在相当一部分心力衰竭病例中起作用。然而，携带任何特定突变的患者数量较少。重新定位美国食品药品监督管理局（FDA）批准的现有化合物以靶向特定突变，是为这些患者高效识别新疗法的一种有前景的方法。
检索美国国立卫生研究院基于综合网络的细胞特征库，以识别具有逆转基因敲低转录效应能力的FDA批准化合物。通过患者特异性诱导多能干细胞衍生的心肌细胞结合力测量、基因表达谱分析、电生理学和蛋白质表达分析，在体外验证此次筛选的顶级命中化合物。
从我们的计算机模拟筛选中鉴定出几种血管紧张素受体阻滞剂。其中，奥美沙坦显著提高了肌节基因的表达、收缩速率和力量，并改善了致心律失常潜力。此外，奥美沙坦表现出降低突变诱导多能干细胞衍生心肌细胞中细胞外信号调节激酶1磷酸化的能力。
计算机模拟筛选后，用诱导多能干细胞衍生模型进行体外验证，可能是一种识别单基因心肌病可重新定位疗法的有效方法。
