Optimization of the TeraTox Assay for Preclinical Teratogenicity Assessment.
Optimization of the TeraTox Assay for Preclinical Teratogenicity Assessment.
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DOI：
10.1093/toxsci/kfac046
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发表时间：
2022-06-28
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目前用于评估开发中药物致畸性的无动物方法仍存在大量假阴性。为了提高人类致畸性预测的灵敏度，我们表征了TeraTox测试，这是一种使用3D人类诱导多能干细胞的新开发的多谱系分化测定。TeraTox产生主要输出浓度依赖性细胞毒性和由每种测试化合物诱导的改变的基因表达。这些数据被输入到一个可解释的机器学习模型中进行预测，这与候选药物的浓度依赖性人类致畸潜力有关。我们应用TeraTox分析了33种已批准的药物和12种具有已知体内数据的专利候选药物。将TeraTox预测与已知的人类或动物毒性进行比较，我们报告的准确性为69%（特异性：53%，灵敏度：79%）。TeraTox的性能优于2个定量结构-活性关系模型，并且具有比在同一实验室中运行的小鼠胚胎干细胞测试更高的灵敏度（准确性：58%，特异性：76%，灵敏度：46%）。通过结合TeraTox和小鼠胚胎干细胞测试结果，可以进一步提高整体预测准确性。此外，TeraTox揭示的基因表达改变模式可能有助于将毒理学相似的化合物分组，并可能推断出共同的作用模式。因此，TeraTox检测和此处描述的数据集代表了药物致畸性评估的新工具和宝贵资源。
Current animal-free methods to assess teratogenicity of drugs under development still deliver high numbers of false negatives. To improve the sensitivity of human teratogenicity prediction, we characterized the TeraTox test, a newly developed multilineage differentiation assay using 3D human-induced pluripotent stem cells. TeraTox produces primary output concentration-dependent cytotoxicity and altered gene expression induced by each test compound. These data are fed into an interpretable machine-learning model to perform prediction, which relates to the concentration-dependent human teratogenicity potential of drug candidates. We applied TeraTox to profile 33 approved pharmaceuticals and 12 proprietary drug candidates with known in vivo data. Comparing TeraTox predictions with known human or animal toxicity, we report an accuracy of 69% (specificity: 53%, sensitivity: 79%). TeraTox performed better than 2 quantitative structure-activity relationship models and had a higher sensitivity than the murine embryonic stem cell test (accuracy: 58%, specificity: 76%, and sensitivity: 46%) run in the same laboratory. The overall prediction accuracy could be further improved by combining TeraTox and mouse embryonic stem cell test results. Furthermore, patterns of altered gene expression revealed by TeraTox may help grouping toxicologically similar compounds and possibly deducing common modes of action. The TeraTox assay and the dataset described here therefore represent a new tool and a valuable resource for drug teratogenicity assessment.
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影响因子：
--
作者：
Cassano A;Manganaro A;Martin T;Young D;Piclin N;Pintore M;Bigoni D;Benfenati E
通讯作者：
Benfenati E
影响因子：
10
作者：
Blundell C;Yi YS;Ma L;Tess ER;Farrell MJ;Georgescu A;Aleksunes LM;Huh D
通讯作者：
Huh D
影响因子：
46.2
作者：
Sakata T;Chen JK
通讯作者：
Chen JK
影响因子：
3.8
作者：
ADAMS, SS;BOUGH, RG;MILLS, RFN
通讯作者：
MILLS, RFN
影响因子：
3.2
作者：
Adler, Sarah;Pellizzer, Cristian;Bremer, Susanne
通讯作者：
Bremer, Susanne