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Comparison of zebrafish larvae and hiPSC cardiomyocytes for predicting drug-induced cardiotoxicity in humans

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dc.contributor.author Dyballa, Sylvia, 1982-
dc.contributor.author Miñana, Rafael
dc.contributor.author Rubio-Brotons, Maria
dc.contributor.author Cornet Bartolomé, Carles, 1991-
dc.contributor.author Pederzani, Tiziana
dc.contributor.author Escaramis, Geòrgia
dc.contributor.author Garcia-Serna, Ricard
dc.contributor.author Mestres i López, Jordi
dc.contributor.author Terriente, Javier
dc.date.accessioned 2023-01-24T07:17:28Z
dc.date.available 2023-01-24T07:17:28Z
dc.date.issued 2019
dc.identifier.citation Dyballa S, Miñana R, Rubio-Brotons M, Cornet C, Pederzani T, Escaramis G, et al. Comparison of zebrafish larvae and hiPSC cardiomyocytes for predicting drug-induced cardiotoxicity in humans. Toxicological Sciences. 2019 Oct;171(2):283-95. DOI: 10.1093/toxsci/kfz165
dc.identifier.issn 1096-6080
dc.identifier.uri http://hdl.handle.net/10230/55408
dc.description.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.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Oxford University Press
dc.relation.ispartof Toxicological Sciences. 2019 Oct;171(2):283-95
dc.rights © The Author(s) 2019. Published by Oxford University Press on behalf of the Society of Toxicology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.title Comparison of zebrafish larvae and hiPSC cardiomyocytes for predicting drug-induced cardiotoxicity in humans
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1093/toxsci/kfz165
dc.subject.keyword Cardiovascular toxicity
dc.subject.keyword Adverse effect
dc.subject.keyword High-throughput
dc.subject.keyword Drug screening
dc.subject.keyword Zebrafish
dc.subject.keyword hiPSC
dc.subject.keyword ZeCardio
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/755988
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion


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