Metabolically Competent Stem Cell Systems: Novel Means to Implement 3Rs in Better Drug Safety Assessment

将新药推向市场是一个需要10-15年的过程，耗资4亿美元。每年有超过10000种化合物进入大型制药公司的临床前药物发现和开发管道。这些主要依赖于动物实验的临床前阶段的任务是预测对人体的预期和不良影响。这一点很重要，在临床阶段的新药被用于人类研究之前。因此，许多动物和人类的生命是在这些临床前阶段决定的。开发动物源性体外试验是为了满足商业压力和实施3r。其中一项测试，称为小鼠胚胎干细胞毒性测试（mEST），能够识别导致胎儿畸形和其他毒性的化合物。然而，mEST仅是中等可靠，从而阻碍了其被工业界接受，同时也阻碍了3r的实施。在这里，我们将通过“人性化”来增强这个平台的预测能力。这将通过使用人类脐带干细胞（不是人类胚胎干细胞）和同时将人类药物代谢引入这些系统来实现。预计这些新型平台将减少动物实验的数量，同时提高药物安全性。

Bringing novel drugs onto the market is a process that takes 10-15 years and consummates # 400,000,000. More than 10000 compounds enter the preclinical drug discovery and development pipeline of large pharmaceutical companies per annum. The task of these preclinical stages, which rely heavily on animal experimentation, is to predict desired and adverse effects in man. This importantly before investigational new drugs are given to humans in the clinical stages. Thus the life of many animals and of humans is decided in these pre-clinical stages. Animal-derived in vitro tests have been developed to meet commercial pressures and to implement the 3Rs. One of these tests, termed mouse embryonal stem cell toxicity test (mEST) is able to identify compounds that lead to fetal malformations and other toxicities. However, the mEST is only moderately reliable, thus hampering its acceptance by industry and simultaneously the implementation of the 3Rs. Here we will enhance the predictive power of this platform by its ?humanisation?. This will be achieved by employing human umbilical cord stems cells (not human embryonal stem cells) and at the same time by introducing human drug metabolism into these systems. It is anticipated that these novel platforms will reduce the number of animal experimentation, while at the same time improving drug safety.