Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA; email:
Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Annu Rev Pharmacol Toxicol. 2018 Jan 6;58:83-103. doi: 10.1146/annurev-pharmtox-010617-053110. Epub 2017 Oct 6.
Billions of US dollars are invested every year by the pharmaceutical industry in drug development, with the aim of introducing new drugs that are effective and have minimal side effects. Thirty percent of in-pipeline drugs are excluded in an early phase of preclinical and clinical screening owing to cardiovascular safety concerns, and several lead molecules that pass the early safety screening make it to market but are later withdrawn owing to severe cardiac side effects. Although the current drug safety screening methodologies can identify some cardiotoxic drug candidates, they cannot accurately represent the human heart in many aspects, including genomics, transcriptomics, and patient- or population-specific cardiotoxicity. Despite some limitations, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a powerful and evolving technology that has been shown to recapitulate many attributes of human cardiomyocytes and their drug responses. In this review, we discuss the potential impact of the inclusion of the hiPSC-CM platform in premarket candidate drug screening.
制药行业每年投入数十亿美元用于药物开发，旨在推出有效且副作用最小的新药。由于心血管安全性问题，有 30%的在研药物在临床前和临床筛选的早期阶段被排除在外，有几个通过早期安全筛选的先导分子进入市场，但后来由于严重的心脏副作用而被撤回。尽管目前的药物安全筛选方法可以识别一些具有心脏毒性的候选药物，但它们在许多方面不能准确代表人类心脏，包括基因组学、转录组学以及患者或人群特异性的心脏毒性。尽管存在一些局限性，但人诱导多能干细胞衍生的心肌细胞（hiPSC-CMs）是一种强大且不断发展的技术，已被证明可以重现人类心肌细胞及其药物反应的许多特征。在这篇综述中，我们讨论了将 hiPSC-CM 平台纳入候选药物上市前筛选的潜在影响。
