Replacement of animal use in measuring cardiomyocyte response to drug safety profiling using a novel NMR metabolomics technology

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The development of drugs for therapeutic treatment depends on animal testing to ensure that they are safe for people to use. In the past some drugs that were thought to be safe went on to cause serious heart problems, and even fatalities. Harmful drugs were found to stop the heart from functioning properly by altering the behaviour of molecules that control the electrical activity and energy required to work, and ultimately the ability of the heart to beat properly. In response to this, all drugs that are developed must be tested for harmful effects on animal hearts. Our project is focused on a relatively new technology 'NMR metabolomics', which can accurately identify changes in how the heart uses energy at the cell level, allowing us to study the harmful effects of drugs by monitoring human heart cells without the need to perform experiments on mice (and other animals).It is estimated that 350,000 animals are used globally in drug testing. We have calculated that at least 1,400 mice are used in published studies each year, specifically for testing harmful effects on the heart. However, differences in the biology of humans and animals means that these tests are not always appropriate. Potentially harmful effects specific to humans might be missed, or else effects not harmful in humans are detected and the drug discarded. Therefore, more animals are used in drug tests than are needed.To address this, academic research groups and Pharma have begun to use human cells to detect and understand harmful drug effects. Human stem cells, which can be turned into heart cells in the laboratory, have proved a popular choice for studying changes in electrical activity and energy use in response to drug treatment. However, there is a lack of technologies that are sensitive enough to detect the subtle and complex changes that cause the heart to fail. Confidence in the replacement of animal tests with human equivalents has therefore been slow and limited. Our novel implementation of NMR metabolomics technology offers a more advanced analysis than the current techniques being used to study energy use in human cells, being capable of detecting much more information with significant sensitivity. In this project we will test NMR metabolomics technology on heart cells that we make from human stem cells. We treat the heart cells with harmful drugs that we know cause changes in electrical activity and energy use. We also manipulate the heart cells so that they are more sensitive to the effects of the drugs. This mimics the real-life situation where some people have a greater risk of heart failure in response to harmful drugs. The results are validated using data that we have already produced from human patient stem cells that are damaged due to heart disease.We estimate that employing NMR metabolomics technology with stem cells could replace up to 50% of the animals that would be used to test drugs for harmful effects on the heart. In addition, increased understanding of how drugs cause harmful effects helps to improve design for other tests in which animals are used, leading to further reduction. To achieve our 3Rs impact, we are during the course of the project engaging with academic research groups and Pharma who are identified as being end users of the technology in order to understand fully the animal tests that they perform and how they would use this NMR metabolomics technology. We also create digital training materials and workshop activities that support uptake and use of NMR metabolomics in stem cells as an animal replacement technology. Beyond this project we anticipate that demonstration of the potential for NMR metabolomics with stem cells will drive future application as a replacement for animal tests used in other disease and testing settings.