Bioengineering bacterially derived immunomodulants: a novel therapeutic approach to IBDProject SummaryThe long term goal is to develop novel, effective therapeutics that harness the immunomodulatory properties ofbacterial molecules for the treatment of inflammatory bowel disease (IBD). The proposal aims to exploit theevolved ability of intestinal pathogens to control inflammatory related signaling pathways in their host, byadapting bacterial effector molecules as therapeutics. A major challenge in realizing the therapeutic potential ofthese molecules is the ability to engineer a delivery system capable of delivering protein inside intestinalepithelial cells. The objective of this proposal is to create bacterial protein nanoparticles with the ability todeliver bacterial effector proteins, suppress epithelial inflammation, and attenuate the symptoms of IBD. Keyoutcomes are: (1) a new, long-needed IBD therapeutic that arrests inflammation at the source; (2) a newtherapeutic paradigm that utilizes bacterial immunoregulatory mechanisms and engineers a nanoparticledelivery strategy essential for clinical viability.
Three specific aims have been set:
Aim 1. Engineer the cellular uptake and trafficking properties of nanoparticles to maximize proteindelivery. Bacterial protein nanoparticles will be fabricated with different physiochemical features including size,crosslinking density, targeting ligands, and endosomal escape motifs. Epithelial cells exposed to nanoparticlesin vitro will be assessed for particle internalization, endosomal escape, and disassociation into soluble protein.
Aim 2. Assess in vitro and exvivo biological response to bacterial protein nanoparticles. Variousnanoparticle formulations, including those from Aim 1 as well as particles optimized in this aim for transportthrough mucus, will be applied to unpolarized and polarized epithelial cells, and ex vivo mucosal preparationsat a range of dosages. Functional activity will be measured by mucosal uptake, suppression of immunesignaling pathways, and reduced levels of inflammatory cytokines.
Aim 3. Determine the therapeutic effect of protein nanoparticles optimized for in vivo delivery ondiseased animals. Nanoparticles will be modified via surface coatings to increase their ability to traverse thegastrointestinal tract and target inflamed mucosa. These particles will be administered to mice with inducedchemical, immunological and genetic models of colitis and to healthy controls. Clinical parameters, mucosaland systemic inflammatory markers, and histopathology will be tracked over relevant time points.
Bioengineering bacterially derived immunomodulants: a novel therapeutic approach to IBD Project Narrative Inflammatory bowel disease (IBD) is a chronic disorder of the intestinal tract with debilitating symptoms, such as abdominal pain and bloody diarrhea, and current treatments have serious side effects. We have discovered that some intestinal bacterial pathogens have evolved proteins that are capable of blocking inflammation in intestinal cells. The goal of our work is use these proteins as new therapeutics for IBD by packaging them into very small particles that can travel through the gastrointestinal tract and deliver the proteins inside intestinal cells to stop inflammation.