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A team led by Dr Amer Jamalpoor at Toxys B.V. will further develop and qualify stem cell-based assays to reduce the reliance on in vivo embryo-fetal development studies and provide insights into species-specific effects to improve translation and human relevancy. Embryo-fetal development studies are conducted in pregnant animals in two species (typically rat and rabbit) to evaluate the potential for a drug to cause harm to a developing embryo or fetus (teratogenicity) for drugs that are intended for use in women of child-bearing potential.
The CrossDART Challenge aims to replace some of these in vivo studies through developing improved in vitro assays for both human and animal species.
In the first proof-of-concept phase of the Challenge, the team at Toxys B.V. miniaturised their existing human ReproTracker® assay, achieving higher throughput with a 96 well plate format, reducing the amount of test compound required (from 100mg to 5-20mg per test) and improving turnaround times to between six to eight weeks, making the assay more amenable to the early screening of pharmaceuticals. The ReproTracker® assay uses human induced pluripotent stem cells differentiated towards cardiomyocytes, hepatocytes and neural rosettes to study the effect of compounds on early development through assessing changes in morphology, function and tissue-specific biomarkers. Additionally, the team started to establish and develop rat and rabbit stem cell lines and assays to allow multi-species comparison.
“I am extremely honoured to lead the CrossDART project, a pioneering initiative fostering the adoption of New Approach Methodologies to predict species-specific in vivo developmental toxicity and driving progress toward animal-free toxicity testing”.
Dr Amer Jamalpoor, Toxys B.V.
The NC3Rs has awarded the team further funding of £1M for phase 2 of the Challenge, to continue development of the multi-species assays and extensively characterise their use to predict the teratogenicity of new drug candidates. Supported by in-kind contributions from eight international Sponsors from the pharmaceutical and not-for-profit sectors* the team will qualify the panel of in vitro assays with positive and negative reference compounds to assess predictivity and compare assay predictions across species. The data from the in vitro assays will be incorporated into computational models to provide species-specific predictions of compound exposure concentrations and teratogenicity in vivo.
Read more about the CrossDART Challenge and our other DART Challenges PREDART and DARTpaths.
*This Challenge is Sponsored by AbbVie, AstraZeneca, Bayer AG, Boehringer Ingelheim, Merck Healthcare KGaA, MMV Medicines for Malaria Venture, Novartis and Roche.