Development of a Human iPSC Cardiomyocyte-Based Scoring System for Cardiac Hazard Identification in Early Drug Safety De-risking
Development of a Human iPSC Cardiomyocyte-Based Scoring System for Cardiac Hazard Identification in Early Drug Safety De-risking
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DOI：
10.1016/j.stemcr.2018.11.007
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发表时间：
2018-12-11
影响因子：
5.9
通讯作者：
Gallacher, David J.
中科院分区：
文献类型：
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作者：
Kopljar, Ivan;Lu, Hua Rong;Gallacher, David J.
人类诱导多能干细胞来源的心肌细胞（hiPSC-CM）已成为一种有前途的心脏安全平台，大量使用已知对人类心脏产生不良影响的药物进行的验证研究证明了这一点。然而，在临床前药物开发过程中将 hiPSC-CM 应用于新化学实体 (NCE) 的心脏风险降低中仍然存在挑战。在这里，我们使用 hiPSC-CM 中的钙瞬态筛选测定来开发心脏电负荷的危险评分系统。耐受区间的计算和不同类别的心脏活性药物的评估使我们能够开发出加权评分矩阵。这种方法可以将 hiPSC-CM 中的各种药理作用转化为单一危险标签（无、低、高或极高危险）。对 587 个内部 NCE 的评估以及这些 NCE 子集向离体和体内模型的良好翻译凸显了心脏危害评分在促进早期药物安全筛选期间化合物选择方面的价值。
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have emerged as a promising cardiac safety platform, demonstrated by numerous validation studies using drugs with known cardiac adverse effects in humans. However, the challenge remains to implement hiPSC-CMs into cardiac de-risking of new chemical entities (NCEs) during preclinical drug development. Here, we used the calcium transient screening assay in hiPSC-CMs to develop a hazard score system for cardiac electrical liabilities. Tolerance interval calculations and evaluation of different classes of cardio-active drugs enabled us to develop a weighted scoring matrix. This approach allowed the translation of various pharmacological effects in hiPSC-CMs into a single hazard label (no, low, high, or very high hazard). Evaluation of 587 internal NCEs and good translation to ex vivo and in vivo models for a subset of these NCEs highlight the value of the cardiac hazard scoring in facilitating the selection of compounds during early drug safety screening.