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Cell Culture


approved drug with a FDA black box warning used to treat life-threatening arrhythmia, was added to 2D and 3D primary human hepatocyte cultures. Dose response curves were generated,


measuring cell viability via an ATP assay. The IC50 reported for the 3D cell cultures (26µM) was sig- nificantly lower than that from the 2D cultures (209µM). To validate this approach, a 100-compound


screen was performed using DILI and control compounds selected based on recent publications to examine the response of 2D monolayer versus 3D spheroid hepatocytes1. A two-week hepato- toxicity assay with three repeated doses of testing compounds was carried out with 3D primary human hepatocyte spheroids made from cryopre- served primary human hepatocytes in Corning® 96-well spheroid microplates. For comparison, 2D monolayer cultures from the same primary human hepatocytes were used in a single-dose, short-term cytotoxicity assay. Bioluminescent ATP assays


were performed, and eight-point dose response


curves were generated. IC50 values for each com- pound were calculated. Using clinical Cmax values as drug exposure references and the margin of


safety (MOS) approach, quantitative analysis of assay specificity and sensitivity were performed1. Results indicated that 3D primary human hepato- cyte spheroids are two to three times more sensi- tive to DILI compound treatment than 2D cultures (Table 1). Use of this 3D approach enables earlier and


more accurate screening of compounds for poten- tial toxicity in the drug development workflow and allows for derisking of compounds selected to advance in the pipeline. DILI assessments conduct- ed in 2D culture systems may provide misleading results and allow compounds with potentially seri- ous toxicity flags to progress to further develop- ment only to fail at a much later, more costly point. A recently-published study assessed the predic- tive accuracy of primary human hepatocytes in 3D


New Easi-CRISPR Technology


The latest evolution in the CRISPR revolution.


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With Easi-CRISPR, our genetic engineers deliver more complex models, faster.


 Simplify large genetic insertions, such as conditional knockouts.  Produce viable models up to six months faster than traditional large insertion methods.


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Drug Discovery World Winter 2018/19


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