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An animal-free 3D liver model to test drug safety in patients with fatty liver disease

Professor Chris Goldring

Professor Chris Goldring

University of Liverpool

Animals to be replaced: Mice, rats, guinea pigs and rabbits

Professor Christopher Goldring at the University of Liverpool is developing human liver models to improve drug safety predictions for both widely used drugs and those in development. He works closely with and shares data with other academics, clinicians and the pharmaceutical industry to make sure his work is human-relevant and has a patient focus.

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The Problem – Drug Induced Liver Injury

Healthy liver vs unhealthy liver

Non-alcoholic fatty liver disease is the most common liver disease worldwide,

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, caused by a gradual accumulation of fat within the liver. This condition affects 1 in 4 people (over 5 million people in the UK alone) and it can also affect children.

The liver is an important organ involved in many bodily functions including food digestion and the breakdown of drugs into inactive forms. Once the liver has processed a drug, it is usually removed from the body through the digestive tract. However, sometimes drugs can remain active or be changed into a more harmful form, which can make it harder for the liver to remove. If the drug is taken repeatedly, harmful toxins can build up in the liver and cause drug induced liver injury (DILI).

People with a fatty liver may be more sensitive to the toxic effects of some drugs, including commonplace medicines such as paracetamol and antibiotics, and so may be at a higher risk of developing DILI. The link between NAFLD and DILI development is not well understood, but as a quarter of the global population has fat accumulation in the liver, there is an urgent clinical need to understand this issue.

Animal experiments are often used for NAFLD drug testing, usually mice or rats which have induced symptoms from dietary, chemical or genetic intervention. Guinea pigs and hamsters are also becoming more commonly used in this field. Over 150 research papers were published in just the first half of 2023, with each study using at least 20-40 animals. However, due to differences between animal and human liver function and anatomy, no animal can fully reproduce all the characteristic features of human NAFLD, meaning it is difficult to predict when DILI will develop.

Although all drugs taken by patients will have successfully passed animal testing, around 9.4% of DILI patients will die or need a liver transplant within 2 years. Human-relevant models that include all essential cell types found in the liver are therefore urgently needed to replace animal experiments.

Finding the link

Development of patient-derived liver spheroids over a 7 day growth period.

Development of patient-derived liver spheroids over a 7 day growth period.

In this Animal Free Research UK funded pilot study, Professor Christopher Goldring at the University of Liverpool is developing a complex 3D human cell model of the liver. Importantly, fat can accumulate in this liver model as it would in the body, accurately mimicking the conditions found in NAFLD. Drugs can then be tested on the cells to understand how fatty livers process drugs compared to those with less fat. It is hoped that this technology will help to understand the link between a fatty liver and the body’s ability to process drugs.

This type of research often uses animal-derived products to help the cells grow in a lab-based environment, however in this pilot study Professor Goldring will develop a new completely animal-free model of fatty liver disease. The simple nature of this model will also mean that the experiments can be easily reproduced by any laboratory. This could lead to the wider replacement of animals used for drug testing, saving the lives of millions of animals and forwarding research into safe and effective drugs to benefit patients worldwide.

Reducing the risk of Drug Induced Liver Injury

This study may highlight a need for testing of fatty liver status before patient treatment choices are made. Helping NAFLD patients to avoid drugs known to cause toxicity problems could reduce the risk of DILI, directly benefiting millions of patients worldwide. The results will be used to apply for larger follow up grants to continue testing drugs on the fatty liver models, establishing a reliable, human-relevant way to predict DILI in patients with NAFLD. The data will also be used as part of a Medical Research Council Career Development Award fellowship application by Primary Scientist Dr Giusy Russomanno, a Research Associate working in Professor Goldring’s department, supporting her transition to becoming an independent researcher in this field.