Our analysis with zebrafish yields similar predictive performance as previous validation meta-studies performed with dogs, the standard regulatory preclinical model.
Sylvia Dyballa 1, Rafael Miñana 1, Maria Rubio-Brotons 1, Carles Cornet 1, Tiziana Pederzani 1, Georgia Escaramis 2 3, Ricard Garcia-Serna 4, Jordi Mestres 4 5, Javier Terriente 1
1ZeClinics SL, IGTP (German Trias and Pujol Institute), Badalona, Spain.
2CIBER Epidemiology and Public Health. Dpt. of Biomedicine, Faculty of Life Science and Health, University of Barcelona. Barcelona, Spain.
3Research Group on Statistics. Econometrics and Health (GRECS), UdG. Girona, Spain.
4Chemotargets SL, Parc Científic de Barcelona, Baldiri Reixac 4 (TI-05A7), Barcelona, Spain.
5Systems Pharmacology, Research Program on Biomedical Informatics (GRIB), IMIM Hospital del Mar Medical Research Institute and University Pompeu Fabra, PRBB (Barcelona Biomedical Research Park). Barcelona, Spain.
ABSTRACT
Cardiovascular drug toxicity is responsible for 17% of drug withdrawals in clinical phases, half of post-marketed drug withdrawals and remains an important adverse effect of several marketed drugs. Early assessment of drug-induced cardiovascular toxicity is mandatory and typically done in cellular systems and mammals. Current in vitro screening methods allow high-throughput but are biologically reductionist. The use of mammal models, which allow a better translatability for predicting clinical outputs, is low-throughput, highly expensive, and ethically controversial. Given the analogies between the human and the zebrafish cardiovascular systems, we propose the use of zebrafish larvae during early drug discovery phases as a balanced model between biological translatability and screening throughput for addressing potential liabilities. To this end, we have developed a high-throughput screening platform that enables fully automatized in vivo image acquisition and analysis to extract a plethora of relevant cardiovascular parameters: heart rate, arrhythmia, AV blockage, ejection fraction, and blood flow, among others. We have used this platform to address the predictive power of zebrafish larvae for detecting potential cardiovascular liabilities in humans. We tested a chemical library of 92 compounds with known clinical cardiotoxicity profiles. The cross-comparison with clinical data and data acquired from human induced pluripotent stem cell cardiomyocytes calcium imaging showed that zebrafish larvae allow a more reliable prediction of cardiotoxicity than cellular systems. Interestingly, our analysis with zebrafish yields similar predictive performance as previous validation meta-studies performed with dogs, the standard regulatory preclinical model for predicting cardiotoxic liabilities prior to clinical phases.
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