Fishing for answers: screening drug cardiotoxicity using zebrafish

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Rodents have a well-established place in history as our most common animal models. Even the word lab-rat has become so commonplace it is a common lay-man term. However, could it be that another animal may prove even more helpful in our pursuit of new drugs? The scientists at ZeClinics, a Spanish biotech-pharma company, certainly think so. At ZeClinics they are using zebrafish for pre-clinical drug trials, and business is booming. We spoke to Dr Javier Terriente, Chief Scientific Officer at ZeClinics, about some of their most recent projects, including the cardio-analysis technology ZeCardio®.

By Amy LeBlanc

Why fish?

The most natural question is: why fish? When considering animals used to model human beings, mice seem like a much more natural choice than zebrafish. Nonetheless, there are a whole slew of benefits to using these small fresh-water creatures. In the pharmaceutical industry, pre-clinical trials are a time-consuming and expensive part of the drug development process, accounting for as much as 30% of the already substantial cost of creating a new product. By using zebrafish to assess the toxicity and efficacy of new drugs, companies can obtain the data they need in a faster and more inexpensive manner. Zebrafish have a surprisingly high degree of homology with human genes and physiological processes (70-80%), and are very cheap to maintain compared to rodents (zebrafish maintenance costs are less than 1/1000th of mice maintenance costs). Administering drugs is also easier in fish than in rodents, as the drugs can be put directly into their water, and organ function can be observed directly through their translucent skin. Zebrafish truly are a peerless tool for pre-clinical drug trials.

We wish to make the most of using zebrafish as part of the drug discovery pipeline in the pharmaceutical industry.

It is no wonder that in 2013, ZeClinics decided to use zebrafish as the basis for their biotech company. Dr Javier Terriente gave some explanations about about the young and vibrant company:

Terriente: “Our business aim at ZeClinics is to become the foremost zebrafish company in the market. As to our scientific aim: we wish to make the most of using zebrafish as part of the drug discovery pipeline in the pharmaceutical industry. It comes altogether: you cannot become the leader in the market if you don’t have a good scientific background.

So far it’s going very well. We are growing in revenues, public funding, personnel, service portfolio and indications in which we are doing research. Everything is moving very fast, but is coming along very well.”

ZeClinics have developed three main services for their pharma, academic and biotech clients. ZeTox, which are ready-to-use safety screenings for acute and chronic toxicity of new drugs; ZeEfficacy, which is used to test drug efficacy accurately, quickly and cheaply using zebrafish disease models; and ZeGenesis, which are mutant, transgenic lines of zebrafish generated through CRISPR/Cas9. In addition to these services, ZeClinics have also developed several other cutting-edge projects.

Cheaply evaluating cardiovascular parameters

Terriente: “We have 2-3 projects that are ZeClinics signatures. One is ZeCardio: a high throughput screening platform that allows to test cardiovascular parameters in living animals. It can be used for addressing if a drug can promote cardiotoxicity and may also be employed to discover new cardiovascular drugs.

The imaging and analysis software we have created for ZeCardio is unique. It allows us to measure a lot of different physiological parameters that other software in the market simply cannot assess. The standing product before ZeCardio was only able to analyze differences in heart beats per minute (BPM). The ZeCardio software, on the other hand, not only allows us to check if a molecule is bradycardic or pericardial, but also allows for an understanding of arrhythmias. For example, QTc intervals (a measure of ventricular depolarization and repolarization) are a very important concern in the pharmaceutical industry. About 30% of the marketed drugs which have been withdrawn in the last year, have been withdrawn because of QTc problems. ZeCardio imaging also allows you to have an understanding of the contractility of the heart and blood flow throughout the animal. If you compare this to an in vitro system, such as cardiomyocytes or organoids, the in vitro systems are always going to provide inferior data on this front as they are totally isolated from the systemic cardiovascular system.

Furthermore, the readouts in ZeCardio are extremely non-invasive. We are looking at a transparent embryo, obtaining in vivo information about their cardiovascular system. There is no non-invasive way of monitoring this in other animal models. I would say this is the main advantage of ZeCardio over alternate cardio analysis methods: being able to non-invasively measure the effect of a drug on the cardiovascular system of a living animal.”

ZeClinics also has several other exciting new initiatives on the go. These include ZeOncoTest (a project for understanding cancer progression) and the company’s functional genomics work (ZeClinics were the first zebrafish company in the world to obtain the license to work with CRISPR/Cas9 commercially). Furthermore, ZeClinics is working towards establishing their own R&D department: ZePharma.

Terriente: “Business and research in ZeClinics always go together. We really believe that we cannot do business if there isn’t the science to back it up. So, ZeClinics is increasingly investing research into developing our own drug discovery pipeline, along with continuing our commitment to providing other biotech and pharmaceutical companies with first-rate zebrafish drug screening technology.”