Abstract
Numerous drug treatments that have recently entered the clinic or clinical trials have their genesis in zebrafish. Zebrafish are well established for their contribution to developmental biology and have now emerged as a powerful preclinical model for human disease, as their disease characteristics, aetiology and progression, and molecular mechanisms are clinically relevant and highly conserved. Zebrafish respond to small molecules and drug treatments at physiologically relevant dose ranges and, when combined with cell-specific or tissue-specific reporters and gene editing technologies, drug activity can be studied at single-cell resolution within the complexity of a whole animal, across tissues and over an extended timescale. These features enable high-throughput and high-content phenotypic drug screening, repurposing of available drugs for personalized and compassionate use, and even the development of new drug classes. Often, drugs and drug leads explored in zebrafish have an inter-organ mechanism of action and would otherwise not be identified through targeted screening approaches. Here, we discuss how zebrafish is an important model for drug discovery, the process of how these discoveries emerge and future opportunities for maximizing zebrafish potential in medical discoveries.
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Acknowledgements
The authors thank R. Peterson, D. Raible, S. Baraban, C. MacRae and G. Hanna for helpful discussions, and their funders for support for this work. E.E.P. is funded by a MRC HGU Programme (MC_UU_00007/9), the European Research Council (ZF-MEL-CHEMBIO-648489) and Melanoma Research Alliance (687306). L.I.Z. is funded by Cancer Biology R01 CA103846, NIH Melanoma PPG, P01CA63222, Melanoma Research Alliance, Starr Cancer Consortium grant. D.M.L. is funded by NIH grants R01CA211734, R01CA154923, R01CA215118, RO1CA226926, R24OD016761 and the MGH Research Scholar Award.
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L.I.Z. is a founder and stockholder of Fate Therapeutics, CAMP4 Therapeutics, Amagma Therapeutics and Scholar Rock. He is a consultant for Celularity and Cellarity. D.M.L. has a sponsored research agreement with NextCure and patents issued/pending on immune-deficient zebrafish. E.E.P. declares no competing interests.
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Patton, E.E., Zon, L.I. & Langenau, D.M. Zebrafish disease models in drug discovery: from preclinical modelling to clinical trials. Nat Rev Drug Discov 20, 611–628 (2021). https://doi.org/10.1038/s41573-021-00210-8
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DOI: https://doi.org/10.1038/s41573-021-00210-8
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