This award aims to validate the use of NMR metabolomics in human stem cell-derived cardiac cells to replace the use of rodents in some cardiotoxicity studies.
Drug-induced cardiotoxicity is one of the leading causes for attrition during pharmaceutical development and can also result in drugs being withdrawn after market approval. In the early stages of drug development, in vitro assays using heart tissue and cells are used to assess cardiotoxicity alongside in vivo studies in rodent models. Worldwide there are a number of efforts to provide more predictive tools using human-induced pluripotent stem cell-derived cardiomyocytes and in silico models in order to further the use of animal models in early testing. Dr Rachel Oldershaw has previously developed a method using NMR metabolomics to detect changes in cardiomyocytes, including changes in energy use within the cells. This method is more sensitive than biomarkers used in other in vitro assays and is also amenable to use with genetically modified cells enabling cells recapitulating genetic heart disease to be tested.
The student will validate the use of NMR metabolomics to screen for drug-induced cardiotoxicity using differentiated stem cells. The cells will be treated with cardiotoxic drugs and results validated by comparing to clinical data from patient stem cells damaged due to heart disease. The student will also use genome editing to replicate the clinical situation where some patients are more susceptible to cardiotoxic drugs demonstrating the utility of the model. The student will develop skills in cell culture, omics and create digital training materials to enable others to take up the method.
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 new technology called 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 NMR metabolomics technology is more advanced 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 our NMR metabolomics technology on heart cells that we make from human stem cells. We will treat the heart cells with harmful drugs that we know cause changes in electrical activity and energy use. We will 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 will be confirmed using data that we have already produced from human patient stem cells that are damaged due to heart disease.
We believe that our 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 will help to improve design for other tests in which animals are used, leading to further reduction. To achieve our 3Rs impact, we will during the course of the project engage 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 our NMR metabolomics technology. We will 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 believe 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.