Screening drugs for myocardial disease in vivo with zebrafish: an expert update

ABSTRACT

Introduction: Our understanding of the complexity of cardiovascular disease pathophysiology remains very incomplete and has hampered cardiovascular drug development over recent decades. The prevalence of cardiovascular diseases and their increasing global burden call for novel strategies to address disease biology and drug discovery.

Areas covered: This review describes the recent history of cardiovascular drug discovery using in vivo phenotype-based screening in zebrafish. The rationale for the use of this model is highlighted and the initial efforts in the fields of disease modeling and high-throughput screening are illustrated. Finally, the advantages and limitations of in vivo zebrafish screening are discussed, highlighting newer approaches, such as genome editing technologies, to accelerate our understanding of disease biology and the development of precise disease models.

Expert opinion: Full understanding and faithful modeling of specific cardiovascular disease is a rate-limiting step for cardiovascular drug discovery. The resurgence of in vivo phenotype screening together with the advancement of systems biology approaches allows for the identification of lead compounds which show efficacy on integrative disease biology in the absence of validated targets. This strategy bypasses current gaps in knowledge of disease biology and paves the way for successful drug discovery and downstream molecular target identification.

KEYWORDS:

• Zebrafish
• phenotype
• screening
• cardiovascular

Article Highlights

• Modern cardiovascular drug discovery has lagged recently due to limited understanding of complex disease pathophysiology;

• Target-based in vitro screening cannot model the complexity of biological and pathological processes in a whole organism or mimic the pharmacokinetic behaviors of bioactive molecules;

• The resurgence of phenotype-based screening, as represented by zebrafish embryo models, has emerged as an area of increasing success;

• Using new approaches, such as genome editing technologies, has accelerated the understanding of disease biology and development of zebrafish disease models;

• New molecular entities initially identified in zebrafish screens are expected to represent an increasing proportion of the drug candidates that will enter clinical testing in the near future.

This box summarizes key points contained in the article.

Acknowledgments

The authors thank Aaron Kithcart (Harvard Medical School and Brigham and Women’s Hospital, MA) for critically reading the manuscript and making valuable suggestions.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

Yanbin Zhao and Kun Zhang are funded by the Starting Research Fund from the Shanghai Jiao Tong University. Patrick Sips has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 794365. Calum Macrae was supported by the NIH (the National Heart, Lung, and Blood Institute, the National Institute of Neurological Disorders and Stroke and the Office of the Director), the Burroughs Welcome Fund, the American Heart Association, AstraZeneca and Verily Life Sciences.