Development of non-mammalian, pre-clinical screening tools for the predictive analysis of cardiotoxicity

Potential new drugs developed to treat cancer, diabetes or any other disease can cause additional unwanted side effects including cardiotoxicity. The failure to predict such drug-induced toxicity during drug development is a major problem contributing to a high attrition rate and tremendous costs.

Drug induced cardiotoxicity can affect all components and functions of the cardiovascular system either directly or indirectly and can be functional and or structural in nature. In vitro single isolated organ and cell-based assays are limited in what they can test. Even organoid model systems cannot completely recapitulate a fully functioning cardiovascular system.

Xenopus laevis (African claw toed frog) tadpoles have a fully functioning cardiovascular system with a three chambered heart and flowing blood. We therefore hypothesise Xenopus embryos can assist in vitro drug-induced toxicity safety assessment in the early phases of drug development before moving on to expensive preclinical trials in mammals. This would lead to a reduction in mammalian animal experiments consistent with the philosophy of the 3Rs. We have previously shown Xenopus to be a good system to look at general toxicity and liver toxicity (Webster et al. 2016; Saide et al. 2019). In this project the student will develop Xenopus as a model for the prediction of heart specific toxicity.

The PhD candidate will test for cardiotoxicity by measuring heart rate and the release of cardiotoxicity biomarkers into the blood. Embryo heart rates will be recorded using movies of live tadpole hearts. To measure blood markers the student will utilise a novel method we have developed where we dissect the specific organ (ie. heart) and tail of the Xenopus tadpole. The tail has an extensive vasculature and so will contain blood born biomarkers that can be readily assessed using qRT-PCR, immunoassays and ELISAs.