Targeted epigenetic therapy in inflammatory bowel disease

Current inflammatory bowel disease (IBD) treatments have high rates of non‐responsiveness, necessitating more specific and safer options to be introduced. This dissertation addresses the potential of epigenetic medicines in IBD. The first wave of epigenetic drugs lack specificity and have wide range of toxicities that limit clinical translation of their potent anti-inflammatory properties. Therefore more selective epigenetic therapies are required. Chapter 1 reviews advancements in developing inhibitors for specific histone deacetylases (HDAC) and bromodomain-containing proteins (BCPs) to enhance their anti-inflammatory properties while minimizing toxicity. Chapters 2 and 3 investigate esterase-sensitive motif (ESM) tagged HDAC and bromodomain and extra-terminal motif (BET) inhibitors, that target CES1 enzyme-expressing mononuclear myeloid cells (MMCs) in inflamed intestinal tissues and peripheral blood of IBD patients. These compounds accumulate selectively in monocytes and macrophages, displaying augmented anti-inflammatory effects and demonstrating efficacy in preclinical IBD models. Chapter 4 uncovers CES1 role in modulating dendritic cell (DC) phenotype and inflammatory response, highlighting its potential as a therapeutic target. Chapter 5 introduces a domain-specific BET inhibitor with modest efficacy in T cell transfer colitis model. Chapter 6 employs single-cell omics to study vedolizumab responsiveness, revealing altered myeloid cell responses. In summary, the dissertation highlights the potential of the newly developed targeted epigenetic medicines in IBD. These novel therapeutic strategies of targeting the immune epigenome tackle the tolerability issues observed with earlier generations of epigenetic medicines. These provide a novel therapeutic avenues to the IBD treatment landscape, contributing to the advancement of personalized medicine in this field.