Targeted Probiotic Yeast for Treating Inflammatory Bowel Diseases

Project Summary Inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, are chronic, relapsing- remitting conditions that affect more than 1.6 million adults and 80,000 children in the US alone. Patients suffer from severe abdominal pain with bloody diarrhea caused by chronic inflammation and ulcer formation in the gastrointestinal tract. Current therapies provide only symptomatic relief, with 25% of IBD patients requiring hospitalization and 45% relapsing. Many of the drugs administered cause severe side-effects. We hypothesize that an orally administered nanobiologic secreted by a bioengineered yeast therapeutic, capable of (a) reducing the inflammatory response and (b) modulating the gut microbiome, will offer a safer and more effective treatment for IBD. To test this hypothesis, we will design, characterize and optimize fibronectin-targeting, nanobody drug- secreting S. boulardii as a function of S. boulardii proliferation and fibronectin density through a stable and dynamic ligand expression system (Aim 1). In Aim 2 we will determine the pharmacokinetics, colon retention, immunogenicity, and biodistribution of the dynamic and stable ulcer-targeting, nanobody drug-secreting S. boulardii. We will use physiologically-based computational modeling to guide dosing regimens. Aim 3 of the study involves evaluating the therapeutic effectiveness of S. boulardii and its potential to modulate the host microbiome in mouse models of ulcerative colitis. Specifically, one of the sub-tasks will involve the use of a human microbiota-associated IBD mouse model. This newly developed approach will be utilized to assess how engineered S. boulardii may alter a human IBD-associated microbiome. Our studies will advance targeted microbial therapeutics and oral nanobiologics towards the clinic to improve outcomes for ulcerative colitis patients. Here we combine pharmacoengineering, computational modeling, pharmacokinetics studies, and microbiome analysis to develop highly integrated, microbe-based therapeutics. We expect that the outcome of these studies will yield new strategies for IBD therapy that will be relevant to other diseases that affect the gastrointestinal tract or other ulcerative conditions.