Format

Send to

Choose Destination
Toxicol Sci. 2019 Jul 30. pii: kfz165. doi: 10.1093/toxsci/kfz165. [Epub ahead of print]

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

Author information

1
ZeClinics SL, IGTP (German Trias and Pujol Institute), Badalona, Spain.
2
CIBER Epidemiology and Public Health. Dpt. of Biomedicine, Faculty of Life Science and Health, University of Barcelona. Barcelona, Spain.
3
Research Group on Statistics. Econometrics and Health (GRECS), UdG. Girona, Spain.
4
Chemotargets SL, Parc Científic de Barcelona, Baldiri Reixac 4 (TI-05A7), Barcelona, Spain.
5
Systems 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 (hiPSC-CM) 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.

KEYWORDS:

Cardiovascular toxicity; ZeCardio; adverse effect; drug screening; hiPSC; high-throughput; zebrafish

PMID:
31359052
DOI:
10.1093/toxsci/kfz165

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center