Dr Nick Powell (Chrohn’s Disease)
Institution: King’s College London
Title: TNFα responsive transcriptional networks in the human intestinal epithelium- the key to predicting therapeutic responses to anti-TNFα in Crohn’s disease?
Project start date: 1st August 2018
Completion date: 31st July 2019
Crohn’s Disease is a long-term, incurable disease affecting the gut. It can have a significantly impact on people’s lives. The discovery of medicines that target specific chemicals associated with the excessive gut inflammation that occurs in Crohn’s Disease have provided hope and relief to millions of affected people around the world. Unfortunately, at the moment, we don’t have a good way of telling which of these medicines will work best for each patient. This results in a ‘trial and error’ approach which can be costly and unrewarding. Patients, nurses, doctors and researchers agree that it is a priority to find predictive tests (called ‘biomarkers’) that can be performed prior to starting a new medicine, so that the ‘right medicine can be given to the right person at the earliest opportunity’.
With this study, Dr Powell will aim to identify biomarkers to predict response to medicines targeting the key chemical called TNFα (the molecule that is targeted by one of the key medications used in Crohn’s Disease). To improve his chance of success the team will focus their research on the cells that line the bowel wall (called epithelial cells), as these are targeted by TNFα, leading to the gut damage associated with Crohn’s Disease. Epithelial cells are the ‘building blocks’ of the gut barrier that stops damaging substances or microbes from invading the human body. Exploring which genes these key cells express in response to TNFα may hold the key to achieving our aim.
To carry out the study gut samples will be taken from patients with Crohn’s Disease and people without the disease. These samples will be transferred to the laboratory. Following simple steps, gut epithelial cells will be isolated, grown in plastic plates and treated with TNFα. Genetic material will then be isolated and analysed. Dr Powell will test the predictive value of these changes by seeing how these genes are expressed in gut biopsies from patients who we know have responded to anti-TNFα treatments, versus those who failed to respond. To perform this aspect of the study Dr Powell has formed a partnership with a major pharmaceutical company. This company has stockpiled gut biopsies from many hundreds of patients immediately prior to treating them with anti-TNFα drugs in clinical trials. Comprehensive information is also available about which of these patients responded to these drugs. Accordingly, Dr Powell can build a picture of gene expression changes in biopsies from responders and non-responders to the drug. This will tell him whether the discovered gene changes can reliably tell the difference between responders and non-responders. With this data, he plans to build a new biomarker, which will predict the Crohn’s Disease patients who are likely to respond to anti-TNFα therapy. Those predicted to have a poor response will be treated with alternative therapies.
By developing a biomarker able to predict response to medicines targeting TNFα Dr Powell will be providing a useful tool to patients and healthcare professionals. It will empower them to make better choices in selecting the therapy with the highest likelihood of success.
We are delighted to receive this support from forCrohn’s and CORE. There is a pressing need to get the best out of the medicines we have available to treat Crohn’s Disease. In this project we will scrutinise the dialogue that occurs between a key inflammatory chemical called TNFα, and the cells that line the bowel wall (called epithelial cells). By decoding this dialogue we hope to identify molecular signatures that we can then harness to predict whether Crohn’s Disease patients are likely to respond to anti-TNFα drugs, which are commonly used to treat Crohn’s Disease. Patients shown to have a molecular footprint indicative of excessive TNFα activity could then be fast-tracked to a medicine that is likely to be highly effective for them at the earliest opportunity.Dr Nick Powell