Targeting aberrantly activated leukocytes in inflammatory bowel disease

Inflammatory Bowel Disease (IBD) represents a group of chronic inflammatory conditions of the gastro-intestinal tract. IBD is characterized by an immunological imbalance in the gut resulting in uncontrolled intestinal inflammation. A healthy human gut hosts around 10-100 trillion symbiotic and mutualistic microbes, this bacterial population is referred to as the microbiome and has been a focal point in scientific research over the last decade. While healthy individuals acquired immunological tolerance towards the microbiome, IBD patients lost this tolerance resulting in unwanted infiltration of leukocytes that leads to intestinal inflammation. Current therapies rely on both traditional immunosuppressive drugs as well as novel biologics like antibodies that block TNF-α. These therapies however, render the patients vulnerable to infections because they lack specificity. Therefore, we aim to design novel therapeutics that target only a specific population of leukocytes in order to minimize side effects. We devised lipid nanoparticles (LNPs) capable of delivering siRNA specifically to leukocytes that actively cause intestinal inflammation. This is achieved by utilizing a recombinant protein that has the ability to specifically bind a certain receptor that is mainly present on gut-homing leukocytes. This targeting protein is designed to contain a functional domain that can be conjugated to the surface of the LNPs. This enables the LNPs to specifically bind the correct leukocyte population in vivo. This delivery strategy has been tested and optimized in two different models of experimental colitis: DSS colitis (acute) and colitis in IL-10KO mice (chronic). The targeted LNPs enabled in vivo gene silencing in both colitis models while no significant gene knockdown was observed in healthy mice, emphasizing the specificity. Having obtained these important results, we now plan to deliver siRNA that silences a pro-inflammatory gene such as IFN-γ and assess the therapeutic efficacy. Furthermore, we are working on an approach to employ the targeting protein in microPET/CT imaging to establish a novel diagnostic tool for IBD.