美国斯坦福大学Mark Mercola取得最新进展。他们使用患者诱导多能干细胞（hiPSC）心肌细胞重新设计抗心律不齐药物，以提高治疗潜力并降低毒性。相关论文于2020年9月14日发表于《细胞-干细胞》。

他们报告了抗心律不齐药物美西律的化学精制，该技术通过对来自带有SCN5A钠通道变异体的心律失常长QT综合征3（LQT3）患者的hiPSC-CM进行高通量筛选。使用药物化学合成和检测的迭代周期，他们确定了具有更高效力和选择性的药物类似物，可抑制一组7种LQT3钠通道变体中的晚期钠电流，并抑制LQT3的多个遗传和药理学hiPSC-CM模型中具有不同变化的心律失常活性背景。这些美西律类似物可以用作机械探针和用于临床开发。

据介绍，用人hiPSC来源的心肌细胞对心脏疾病进行建模是候选疗法的临床前测试的新方式。但是，与疾病相关的生理测定可能很复杂，目前没有使用先天性疾病表型的hiPSC-心肌细胞模型指导大规模筛查和药物化学的范例。

附：英文原文

Title: Reengineering an Antiarrhythmic Drug Using Patient hiPSC Cardiomyocytes to Improve Therapeutic Potential and Reduce Toxicity

Author: Wesley L. McKeithan, Dries A.M. Feyen, Arne A.N. Bruyneel, Karl J. Okolotowicz, Daniel A. Ryan, Kevin J. Sampson, Franck Potet, Alex Savchenko, Jorge Gómez-Galeno, Michelle Vu, Ricardo Serrano, Alfred L. George, Robert S. Kass, John R. Cashman, Mark Mercola

Issue&Volume: 2020-09-14

Abstract: Modeling cardiac disorders with human induced pluripotent stem cell (hiPSC)-derivedcardiomyocytes is a new paradigm for preclinical testing of candidate therapeutics.However, disease-relevant physiological assays can be complex, and the use of hiPSC-cardiomyocytemodels of congenital disease phenotypes for guiding large-scale screening and medicinalchemistry have not been shown. We report chemical refinement of the antiarrhythmicdrug mexiletine via high-throughput screening of hiPSC-CMs derived from patients withthe cardiac rhythm disorder long QT syndrome 3 (LQT3) carrying SCN5A sodium channelvariants. Using iterative cycles of medicinal chemistry synthesis and testing, weidentified drug analogs with increased potency and selectivity for inhibiting latesodium current across a panel of 7 LQT3 sodium channel variants and suppressing arrhythmicactivity across multiple genetic and pharmacological hiPSC-CM models of LQT3 withdiverse backgrounds. These mexiletine analogs can be exploited as mechanistic probesand for clinical development.

DOI: 10.1016/j.stem.2020.08.003

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30399-4