Developing a decision-making toolkit for the personalised treatment of inflammatory bowel disease

Crohn's disease (CD) and ulcerative colitis (UC) are the two major forms of inflammatory bowel disease (IBD). CD is characterised by inflammation of the entire digestive tract, while inflammation is restricted to the large intestine in UC. About 300,00 people in the UK are affected by this debilitating disease. Furthermore, the severity and symptoms of IBD vary significantly between patients, and treatments often fail or are not sufficiently effective. Thus, despite the development of immunomodulatory drugs and biologic therapies, up to 80% of IBD patients will require surgery at some point in their lifetime.
A precision medicine-based approach is crucial to improving the treatment of IBD in the future. Precision medicine considers an individual patient's genetic, environmental, and lifestyle factors prior to selecting an appropriate therapy. Using these principles, this project will attempt to identify novel biomarkers for IBD such that patients may be stratified, and clinicians can select appropriate therapies based on molecular profiling of a patient. Currently used biomarkers, such as C-reactive protein and calprotectin, are non-specific and cannot be used to stratify IBD patients. Thus, there is a need to identify novel biomarkers and develop technologies that can detect them, ideally in real-time and without the need for inconvenient stool samples or colonoscopies.
Previous work by the Vendrell group has identified granzyme B as a novel biomarker of IBD. Granzyme B is a serine protease classically associated with its ability to induce cell death; however, in recent years it has been shown that granzyme B plays roles in many inflammatory diseases, from type 2 diabetes to psoriasis. In a large-scale proteomic screen, granzyme B expression levels were found to be increased in IBD patients, particularly those with UC. Following this discovery, the Vendrell group developed a fluorescent smartprobe that can specifically detect granzyme B activity. A key benefit of this smartprobe is that it measures the activity of granzyme B, not simple the amount of granzyme B present.
The aim of this project is to develop a point-of-care technology using this smartprobe. The technology will help stratify patients based on expression of granzyme B, and aid clinicians in selecting an appropriate therapy. Importantly, the technology would detect granzyme B levels in blood, replacing inconvenient stool tests and invasive colonoscopies.
The project is in collaboration with Genentech, who are currently developing the biologic etrolizumab, the efficacy of which appears to be linked to granzyme activity. I will complete an internship with the Early Biomarker Development team at Genentech at some point during the PhD.
During this project, the smartprobe will be characterised and optimised such that granzyme B levels can be rapidly detected in a highly selective manner. Once achieved, the smartprobe will be used to examine granzyme B activity in clinical samples and investigate the role of granzyme B in pathogenesis.
As part of the Precision Medicine DTP, I will be enrolled in a variety of courses that will provide me with skills to successfully execute the aims of the PhD project. In particular, I am developing skills in informatics and data analysis, with an emphasis on their roles in healthcare and medicine.