Stem cells for drug screening
Before entering the market, drugs must be screened for safety and efficacy. The majority of these research and development drug-screening tests are performed on animals and incur high costs. In vitro testing can also take place in certain cell lines, but it hardly recapitulates the human physiological situation. Hundreds of animals are needed to test simply one compound and they often undergo a series of complex analytical procedures for prolonged periods of time. Especially when it comes to reproductive toxicity, evaluation covers the fertilisation process, spermatogenesis and oogenesis, but also embryo–foetal development. As a result, faster and more reliable drug screening tests are urgently required. To address this issue, scientists on the EU-funded 'Embryonic stem cell-based novel alternative testing strategies' (ESNATS) project proposed to use embryonic stem cells (ESCs) as a platform for evaluating drug toxicity. The consortium consisted of leading European experts in the field of ESC biology and toxicology alongside representatives from regulatory bodies and the pharmaceutical industry. After extensive optimisation, ESCs differentiated towards the neuronal lineage were used to develop a battery of ESC-based tests with special focus on neurotoxicity and prenatal development toxicity. Pharmacokinetic models helped scientists define the target tissue concentrations and correlate them with their in vitro concentrations. Validation assays clearly demonstrated the capacity of the ESNATS system to respond to toxic challenges posed by various compounds. Five test systems recapitulating different time points of human early neuronal development were chosen for further exploitation. For metabolic toxicity and to predict adverse liver responses in humans, hepatocyte cells were used. To ensure practical usage in the pharmaceutical industry, concepts for automated ESC culture were also developed. Although the ESNATS tests have not received official regulatory acceptance through the EURL ECVAM validation process, they are already being used in-house by many pharmaceutical companies. The future directions of this system include the elucidation of gene expression alterations and the identification target molecules implicated in compound toxicity.
Keywords
Stem cells, drug screening, toxic compounds, reproductive toxicity, embryonic stem cell, drug toxicity, neurotoxicity, prenatal development, gene expression, compound toxicity
