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Recent advances in in vivo screening for antiarrhythmic drugs
1Harvard Medical School, Brigham and Women's Hospital, Cardiovascular Division, 75 Francis Street, Boston, MA 02115, USA. camacrae@bics.bwh.harvard.edu
Introduction:
Our understanding of the complexity of arrhythmogenesis has grown progressively over the last two decades. The range of established arrhythmia mechanisms now includes numerous pathways including ion channels, membrane adaptor proteins, transcription factors and cytoplasmic signaling cascades.
Areas Covered:
This review outlines the emerging biology underlying potentially lethal rhythm disturbances, and highlights the problems that these novel mechanisms present for rational target identification in the traditional framework of drug discovery. The article describes the fundamental rationale for in vivo screening and highlights the utility of the zebrafish for this approach. The article also outlines initial efforts exploiting in vivo antiarrhythmic discovery and the potential for this approach to be disruptive even in the setting of disease mechanisms that operate across multiple timescales in multiple tissues.
Expert Opinion:
In vivo screening in genetically faithful model organisms offers access to existing and unimagined arrhythmia pathways. Rate limiting steps are the rigor of the modeling of specific arrhythmias and the downstream identification of the molecular targets once specific disease suppressors have been identified.
Insights
Emerging arrhythmia mechanisms challenge traditional drug discovery. In vivo screening in zebrafish offers a novel approach to identify antiarrhythmic targets for complex heart rhythm disorders.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Genetics
Background:
- Understanding of arrhythmogenesis has expanded significantly over the past 20 years.
- Established arrhythmia mechanisms now encompass ion channels, membrane adaptor proteins, transcription factors, and signaling cascades.
Purpose of the Study:
- To review emerging biological mechanisms of lethal heart rhythm disturbances.
- To highlight challenges in rational drug target identification within traditional discovery frameworks.
- To explore the utility of in vivo screening, particularly in zebrafish, for antiarrhythmic drug discovery.
Main Methods:
- Review of current literature on arrhythmia mechanisms and drug discovery.
- Discussion of the rationale and application of in vivo screening.
- Highlighting the use of zebrafish as a model organism for antiarrhythmic screening.
Main Results:
- Novel biological pathways contribute to complex arrhythmias.
- Traditional drug discovery faces challenges with these new mechanisms.
- In vivo screening in zebrafish demonstrates potential for identifying novel antiarrhythmic strategies.
Conclusions:
- In vivo screening in model organisms provides access to known and novel arrhythmia pathways.
- Key challenges include rigorous arrhythmia modeling and downstream molecular target identification.
- This approach holds potential for disruptive innovation in antiarrhythmic drug discovery.
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