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Cardiotoxicity High-throughput screening (HTS) with zebrafish embryo

Periodic Reporting for period 2 - ZECARDIO (Cardiotoxicity High-throughput screening (HTS) with zebrafish embryo)

Reporting period: 2018-04-01 to 2019-03-31

The complex nature of pharmaceutical new molecules generation, both in terms of R&D process and regulatory requirements, indicates a huge need for innovative tools/services for optimal delivery to patients of novel medicines in the fastest and cheapest manner. The pharmaceutical industry strives continuously to produce new, safer and more efficacious drugs for unmet needs, evolving different synthesis techniques, expanding numbers of leads for potential drug candidates. However, this abundance has also created a new set of challenges in efficient processing of drug libraries for target validation and toxicity assessment.

High-throughput screening (HTS) is thought to be key in handling this flow of new potential therapeutics in a systematic and time-efficient manner. But, there is a strong evidence that in vitro cell-based assays and subsequent preclinical in vivo studies do not yet provide sufficient pharmacological and toxicity data or reliable predictive capacity for understanding drug candidate performance in vivo. The model developed by ZeClinics with specific focus on cell and molecular interactions and physiological parameters improves this situation and helps to determine the corresponding responses to bioactive agents.

The aim of ZeCardio project is to use zebrafish model to develop HTS of large libraries in live organism for cardiotoxicity assessment. Our complete system analyses the impact of drugs and diseases in heart performance (Heart rate, Arrytmia, AV Blockage and Ejection fraction) and the performance of the vascular system (Blood flow and vasodilatation/constriction).
ZeClinics developed ZeCardio®, a unique, fully automated, robotic and software-driven cardiovascular screening platform. It is introduced in the pharmaceutical and biomedical market as an ambitious technological and commercial novel solution, that aims at accelerating early drug discovery by providing in-vivo outputs from zebrafish while maintaining costs and velocity of an in-vitro technology and with a translational relevance to humans of more than 90%.

The obtained results during the project serve as a breakpoint to ZeClinics in the highly competitive market. Thanks to the project, ZeClinics has become a leading CRO zebrafish specialist in cardiovascular and genetics solutions in the drug discovery industry. This was achieved by scaling up and automatization of the ZeCardio® platform that provides High-Throughput Screening (HTS) possibility. The technology has also been protected by a proper IP protection strategy and ZeClinics is leading an implementation of a roadmap towards regulatory acceptance by EU Reference Laboratory for alternatives to animal testing (ECVAM). These achievements position ZeClinics as leader in the field and way ahead of the possible competitors. Moreover, due to the success of the project, a spin out company has been founded – ZeCardio Therapeutics (https://www.zecardiotherapeutics.com/) - a new biopharmaceutical company based on ZeCardio® technology and fully dedicated to the development of novel and disrupting therapies for cardiovascular diseases.

The main achievements during the project have been:
1. Scale up and automation of ZeCardio® platform;
2. Publication ¨Comparison of zebrafish larvae and hiPSC cardiomyocytes for predicting drug induced cardiotoxicity in humans¨ published in Toxicological Sciences journal;
3. Definition of a roadmap towards the ZeCardio® regulatory acceptance; first milestones achieved;
4. New pharma spin out based on ZeCardio® technology – ZeCardio Therapeutics;
5. Global sales closed with large pharmaceutical companies and top-leading academic centres.
ZeCardio platform run far ahead the current state of the art, demonstrating an enormous advantage as compared to classical in vitro cellular screening and low predictive rodent models. Moreover, ZeClinics has initiated the validation process of ZeCardio® technology by regulatory agencies (EMA and ECVAM), a challenging journey that could only be achieved after many years of academic and industry demonstrations. The official acceptance by these agencies will have an important and very significant impact in the 3Rs (Replacement, Reduction and Refinement) concept in the biotechnology and pharma industries. The approval of the model will highly Replace, Reduce and Refine the use of animals in pre-clinical studies. In addition to that, the investigation on alternative applications of the solution in the cosmetics and agro-food industries has been initiated which will further contribute to the 3Rs concept within these industries. Finally, and most importantly, ZeCardio project is aimed at improving the new drug discovery for cardiovascular disorders still accounting for one of the top-3 causes of death worldwide.
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