Phenotypic screening has been one of the most effective approaches to drug discovery, but only a subset of disease-associated phenotypes can be modelled in cultured cells. Zebrafish exhibit a much broader range of disease-associated phenotypes, including disorders of physiology, metabolism and behaviour, while retaining the ability to be used for high-throughput applications.
Zebrafish are phylogenetically more distant from humans than rodents are, but they possess orthologues of 82% of human disease-associated genes. In many cases, they exhibit physiological and pharmacological conservation that approaches (and occasionally surpasses) that of rodents.
Zebrafish screens have discovered a few compounds that have made it to advanced preclinical and clinical trials, including new compound classes and repurposed drugs.
Zebrafish have been used in several toxicology applications, including the screening of large compound collections for potential liabilities.
Although target identification remains a challenge for phenotype-based small-molecule discovery, rich databases of zebrafish phenotypes have facilitated the identification of targets for several small molecules.
Rapid advances in genome editing and high-throughput phenotyping point to promising new applications for zebrafish in drug discovery over the coming years, including the discovery of compounds that suppress disease phenotypes associated with specific human mutations.
The zebrafish has become a prominent vertebrate model for disease and has already contributed to several examples of successful phenotype-based drug discovery. For the zebrafish to become useful in drug development more broadly, key hurdles must be overcome, including a more comprehensive elucidation of the similarities and differences between human and zebrafish biology. Recent studies have begun to establish the capabilities and limitations of zebrafish for disease modelling, drug screening, target identification, pharmacology, and toxicology. As our understanding increases and as the technologies for manipulating zebrafish improve, it is hoped that the zebrafish will have a key role in accelerating the emergence of precision medicine.
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The authors thank A. Rennekamp for his help compiling Table 1. R.T.P acknowledges support from the Charles Addison and Elizabeth Ann Sanders Professorship. The toxicology work of C.A.M. has been funded by an Innovation in Regulatory Science Award from the Burroughs Wellcome Fund.
The authors' laboratories receive funding from Hoffmann-La Roche (R.P.), Sanofi (C.M.) and Merck (C.M. and R.P.). R.P. holds equity in Teleos Therapeutics. The authors hold patents on a variety of compounds discovered in zebrafish screens.
- Phenotype-based screening
A screen in which the assay output is a complex cellular or organismal phenotype that integrates multiple biochemical pathways and often captures much of the native biological context.
- Target-based screening
A screen in which the assay output is the activity of a specific molecular target in a well-defined but often heterologous context.
To screen in parallel for secondary end points that might condition the final output of the primary screen. Together, such screens enable the incorporation of simple logic; for example, a counter-screen might identify compounds with a specific form of toxicity, allowing the hits from the primary screen to be weighted appropriately for subsequent evaluation.
- Toxicity reporter lines
Genetically modified zebrafish lines expressing specific tissue damage reporters under an organ-specific promoter. These lines will release heterologous reporter peptides that can then be detected using a range of high-throughput detection methods.
- Fibrodysplasia ossificans progressiva
(FOP). A rare autosomal dominant condition caused by gain-of-function mutations in the gene encoding activin receptor-like kinase 2 (ALK2). These mutations result in chronic activation of the bone morphogenetic protein (BMP) pathway with resultant formation of ectopic bone in muscle tissue. Restriction of the thoracic skeleton then leads to respiratory failure, usually in childhood.
- Anaemia of inflammation
A form of anaemia that is characterized by a block in iron availability for haematopoiesis and is observed in many chronic inflammatory diseases.
- Long QT syndrome
A disorder in which restoration of the membrane potential to equilibrium after a cardiac action potential is delayed as a result of abnormal ion fluxes. This delay can be detected from the simple measurement, on a surface electrocardiogram (ECG), of the time from depolarization onset until the return to baseline membrane potential (the QT interval).
- 2:1 atrioventricular heart block
A cardiac rhythm disorder characterized by the failure of every second electrical impulse to propagate from the atrium to the ventricle. This can result from extreme forms of the long QT syndrome in which the delay in restoration of the membrane potential in the ventricle is such that it is refractory to the next electrical impulse from the atrium.
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MacRae, C., Peterson, R. Zebrafish as tools for drug discovery. Nat Rev Drug Discov 14, 721–731 (2015). https://doi.org/10.1038/nrd4627
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