£2.5m fellowship to advance emerging approach to targeting oxidative stress

The University of Liverpool’s Dr Ian Copple has been awarded a prestigious five year, £2.5m Senior Fellowship from the Medical Research Council (MRC) to develop a platform to support the pharmacological targeting of the Nrf2 pathway in humans.

Harnessing Nrf2 is an emerging therapeutic approach to targeting oxidative stress, which is caused when there is an imbalance between harmful free radicals and protective antioxidants in the body – and is linked to many forms of human disease.

Several pharmaceutical companies are developing drugs that dampen oxidative stress by stimulating Nrf2. This protein controls the expression of hundreds of protective genes, some of which help the body to make more antioxidants and remove harmful free radicals.

However, as high levels of Nrf2 activity have been detected in many forms of cancer, it’s essential to determine whether stimulating Nrf2 in patients with diseases linked to a higher chance of developing cancer could result in enhanced formation of tumours. The fellowship will address this knowledge gap in the context of fatty liver disease, which affects up to 1 in 3 of the UK population, and is linked to the development of liver cancer.

The findings will also be relevant for other diseases in which Nrf2 appears to be a promising new therapeutic target. These include lung and kidney conditions that involve oxidative stress, but which are also linked to an increased risk of developing cancer.

The fellowship, which will enable the appointment of two post-doctoral researchers and one PhD student within Dr Copple’s team, will also determine the best way to monitor the response of Nrf2 to drug stimulation in patients, using samples such as blood. This will provide a means of confirming that a drug has stimulated Nrf2 in order to link this to any positive effects on a disease. To do this, Dr Copple’s team will identify the genes/proteins that are altered the most in blood from individuals taking Nrf2 activating drugs.

In the long term, this may lead to the development of specific tests of the Nrf2 response based on the measurement of these genes/proteins. Such tests could be used to better interpret the effects of Nrf2 activating drugs in patients, and to confirm stimulating Nrf2 with drugs is a promising therapeutic strategy.

Dr Ian Copple, Department of Pharmacology & Therapeutics, said: “This is a really exciting time to work in the field of Nrf2 pharmacology, as several drugs targeting Nrf2 have recently entered the clinical stages of development. This funding will allow us to work with leading UK and international researchers to tackle two major knowledge gaps in this area and therefore support the development of Nrf2 activators as novel treatments for a range of diseases.

“Whilst this is a personal fellowship, it reflects the efforts and support from my team and many other colleagues both here in Liverpool and elsewhere. These relationships really enhance the research that I do.”

Prof Reecha Sofat, Head of the Department of Pharmacology & Therapeutics, said: “This is a great achievement for Ian. These fellowships are very competitive and take a great deal of work to prepare for. The award is a testament to his perseverance as well as acknowledging and allowing his cutting-edge translational research to continue and thrive. As a Department we are excited to track his success!”

Prof Sonia Rocha, Executive Dean of the Institute of Systems, Molecular and Integrative Biology, said: We are incredibly proud of Ian’s hard work in this area. Ian is already a leader in his field of research, so we are excited and looking forward to the amazing findings that will arise from this project. This is a testament to Ian’s ingenuity, dedication, team approach and leadership.”