Towards a better understanding of the human heart: development of a predictive in vitro model of cardiac safety

The project aims to develop and validate methods for the in vitro prediction of cardiac side-effects using human cardiac cells and tissues. Drug-induced cardiac safety issues are a major concern of the drug development industry not only because of the severity of complications involving the heart but also because of the possibility that potentially valuable drugs are lost upon the discovery of cardiac safety issues. Several drugs have been withdrawn from the market following instances of drug-induced arrhythmia and many more commonly used drugs are associated with short-term pro-arrhythmic effects (e.g. amiodarone, terfenadine, cisapride) or longer term deleterious effects on heart function (anthracyclines such as doxorubicin). In a recent survey by the Drug Safety Council, safety pharmacologist and toxicologists within pharmaceutical companies rated their highest priority innovative technologies to be 'in vitro cardiovascular risk'. This survey also highlighted the perceived shortcomings of existing cell-based and in vivo animal tests and requests from regulatory bodies for greater emphasis to be placed on newer more predictive models of cardiovascular risk. Biopta aims to address this opportunity by expanding its current tests of human cardiovascular isolated tissues to include cardiac safety tests that specifically address the main drug-related risk of pro-arrhythmic activity. A secondary objective will be to identify markers of tissue health and function that may indicate long-term risks related to cell stress. The student will aim to develop methods using human ventricular and atrial tissues in order to better predict the risk of drugs inducing arrhythmia. Current methods are laborious, technically challenging and dependent on tissue obtained immediately from patients. Furthermore, throughput is a problem because tissues do not survive long enough and neither do the tissue samples generate enough test conditions. These factors have limited the use of human tissue, despite human tissue being accepted as a gold standard test system. The project will aim to extend the lifespan of fresh tissues through the development of more effective transport and storage conditions and will seek to minimise the amount of tissue required for each assay. In addition the project will investigate variability between human tissues and responses of different populations/patient groups to drugs known to induce pro-arrythmic effects in order to improve prediction and provide better care. In addition to reducing time and costs involved in drug development, the creation of such predictive in vitro models does fit with the priority of UK research councils to reduce the use of animals and in vivo experiments in research. Biopta previously received small grant from the NC3Rs fund to develop alternative methods for the study of gastrointestinal function and the use of human tissues in models of tumour function. The main goal of the project, however, is to develop a novel validated method for predicting cardiovascular risk.