What is the University of Liverpool’s main focus?
Here at the University of Liverpool we contribute to several aspects of TransQST including academic project management, wet laboratory experimentation in the areas of liver and gastrointestinal toxicity (GIT) and data interpretation associated with drug-induced liver injury (DILI).
Our main scientific focus is to provide a better understanding of the translational confidence from non-clinical species such as the mouse and rat to human. This is achieved by assessing the cross-species conservation and in-vivo to in-vitro preservation of gene and protein network responses to drugs that cause DILI and GIT in patients. We can then identify divergences that may account for differential responses to toxicological insult, to better understand which in vivo and in vitro models best reflect the expected human response.
What is TransQST to you and what does the University of Liverpool contribute to the project?
TransQST brings together a unique set of the world’s top scientists and mathematicians from academia and industry with an ambitious, collective and timely aim to improve our ability to predict whether new drugs will cause harm to patients. This is achieved by using new modelling approaches that minimalise the need for animal experimentation and lengthy studies that traditionally delay the drug to market pipeline. Preclinical testing, which has a fundamental role in establishing potential risks associated with new drugs, often fails to adequately predict toxicity in humans as the responses of laboratory animals and humans to chemicals may differ both qualitatively and quantitatively. The liver is one of the tissues most affected by drug toxicity. Indeed, liver toxicity is the most common cause of drug withdrawal from the market and attrition in clinical trials. The liver team at the University of Liverpool has contributed its knowledge and expertise on the events that happen when a drug becomes toxic to the body.
The liver is not the only important organ of the body that suffers from drug-induced toxicity. The University of Liverpool also has expertise in investigating gastrointestinal toxicity and understanding the clinical need in this area. There are fewer datasets available in the public domain and across the consortium partners, that characterise toxicities of the gastrointestinal tract in the required detail, compared to other organ systems, to generate reliable computational models. Therefore, at the University of Liverpool, we are assessing how “mini-gut” cultures from mice respond to drugs that cause gastrointestinal toxicity and providing samples that are analysed by several TransQST partners in academia and industry. This enables cross-species comparisons to be made, similar to those already described for liver. Using these approaches, we aim to understand the reliability of “mini-guts” for predicting adverse gastrointestinal toxicities in humans and contribute to data availability for this organ system.
What are your main achievements in TransQST?
We have led an in vivo study in collaboration with several partners within TransQST, focusing on the extent and causes of species differences in sensitivity to the DILI associated with acetaminophen (paracetamol) and the data generated has helped us better understand the species parameters that should be considered by TransQST partners during the development of computational models designed to better predict the risk of human drug toxicity. Furthermore, findings from this study will help future study design particularly on deciding which is the most appropriate and translatable preclinical model to determine what happens in humans.
Our drug treated “Mini-gut” cultures have produced an abundance of good quality data (morphology and functional assays, transcriptomics, metabolomics, high content confocal imaging) that can now be interrogated computationally by TransQST partners in other work packages to describe GIT mechanisms that are specific to individual drugs and that are common across different drug classes. We have extensively investigated the cytotoxicants 5-FU and doxorubicin as well as the tyrosine kinase inhibitor Gefitinib. Several publications led by the Liverpool team describing results from this work are at various stages of development.
In the development and testing of which tools or models have you been involved in?
Physiologically based pharmacokinetic (PBPK) modelling, and high volume murine gastrointestinal “mini-gut” organoid cultures.
What are they aimed at?
We have used physiologically-based pharmacokinetic (PBPK) modelling in collaboration with Certara (UK), transcriptomic and proteomic data (publicly available as well as newly generated), and Weighted Gene Co-Expression Network Analysis (WGCNA) in the DILI TXG-MAPr app (https://txg-mapr.eu/) developed by the University of Leiden. This integrated approach allowed us to uncover marked differences between preclinical species and humans in the basal and adaptive hepatic capacity of stress response pathways that are known to influence DILI, with significant implications for the selection of preclinical models in some drug safety testing scenarios. The PBPK model predicts the fate of a compound in the human body, in particular its absorption, distribution, metabolism and excretion, and therefore is a useful tool when understanding why a particular compound is toxic or not to the body.
Within the gastrointestinal toxicity workpackage, we have utilised “mini-gut” cultures derived from the murine small intestine (enteroids) and colon (colonoids). These cultures contain all differentiated cell populations found in mice and humans in vivo. The culture system replicates the dynamics and 3D structures of cell populations within the gut which is very important for replicating in vivo function and response to drugs within a dish. We have developed approaches to maximise the yield and health of cultures to undertake the assays that are required for several high throughput analyses by TransQST colleagues.
How does this work align and interact with other project activities, tools and models?
The PBPK model aligns well with other computational tools that focus on other types of data such as transcriptomics and proteomics, both of which provide information on the biological response of the body to a particular stimulus. Combining all the different tools will provide a holistic, and therefore more informative, approach in understanding how a body responds to a stimulus, which can be applied to better understand differences in response across commonly used preclinical models. Ultimately, these tools will enable us to better predict the toxic potential of new drug candidates in humans.
Our murine-derived “mini-guts” data are being compared with data generated from human “mini-gut” cultures (from the University of Maastricht and Bohringer Ingelheim) and murine in vivo data (from Janssen) following the same drug treatments. Computational modellers at AstraZeneca and GlaxoSmithKline are developing approaches to determine which mechanisms of toxicity “mini-guts” can reliably model and whether murine “mini-guts” can reliably predict in vivo drug responses in mice and humans. Modelling approaches are co-ordinated by these partners within work packages that address toxicities of different organ systems.
How do you see this work will impact the current practice?
There is a whole consortium aim to reduce, replace and refine all in vivo experimentation within the drug to market pipeline, whilst also making the process of drug development more accurate, cost effective and shorter to enable a larger proportion of novel drug candidates to make it to the clinic.
Tools developed and adapted by Liverpool in collaboration with TransQST partners will not only help us to better predict clinical outcomes in response to new drugs, but within the drug development workflow, will play an important role in improving experimental design and contribute to the 3Rs (replace, reduce and refine) framework. In addition to the generation of more accurate mathematical and computational models that may reduce the current need for in vivo experimentation, we have also characterised the reliability and utility of “mini-gut” cultures for predicting in vivo and patient responses. The implications of this extend beyond influencing the current drug safety framework by impacting further on basic science research associated with the gastrointestinal tract.
How has working with TransQST contributed towards your PhD experience?
“Working within the GI work package has been great for forming connections and meeting collaborators and peers who are working on similar projects or have similar research interests and goals. The wide variety of industries and institutions involved in the project allows for a wide spectrum of ideas and expertise. The work package meetings and conferences are a great way to network, share ideas and inspire new directions in research for the project and in your personal research. Being able to share my work and data and have these contribute towards the project has been a huge honour and privilege.” – Colette Kelly
A tribute to Prof Kevin Park
We are a highly motivated and friendly team working towards common goals; an ethos embedded in our culture and exemplified by Prof Kevin Park who sadly passed away in January 2022. Kevin was always there for his colleagues, always interested, always one step ahead of most of us. We don’t think we will ever really know his like again. Indeed, the field of drug safety science has lost a giant. He would certainly be excited to see how far we have come in TransQST.
Kevin was the original TransQST academic coordinator, he steered the application through the successful award stage, and co-led the project with the Abbvie industry lead for the first three years until his retirement. Kevin was at the University of Liverpool for 52 years, 45 years as an academic. He trained more than 135 PhD students in drug safety science, notably leading the fields of drug-induced liver injury and immune hypersensitivity. He was widely admired for his genuine scientific interest. Whilst he had many senior faculty roles, it was always that love of science that drove him, not faculty politics. Kevin also work ed for many years on government advisory committees helping to protect patients. We will miss him greatly.