A Novel Immunological Probiotic for Treating Inflammatory Bowel Disease

Project Summary The goal of this project is to develop a novel probiotic based therapeutic for the treatment of inflammatory bowel diseaseIBDthat is ideal for long term maintenance treatmentOvermillion adults and children in the United States suffer from IBDan umbrella term encompassing two chronic inflammatory diseases of the gastrointestinal tractCrohnandapos s diseaseCDand ulcerative colitisUCIBD is typically diagnosed in the second or third decades of lifeit is life longand there is no cureIBD is treated most commonly with systemic immune suppressants or cytokinee gTNFILblockers that can have serious side effect profilesespecially when used long termThusnewsafer alternativesparticularly for long term maintenance therapyare needed and would be life changing for patients suffering from these difficult gastrointestinal diseasesIntestinal immune regulatory signals tightly govern healthy gut homeostasisBreakdown of such regulatory mechanisms may result in IBDe gCDUCThe human microbiomeharboring trillions of bacteriais a critical regulator of these immune mechanismsCommensal bacteria function to maintain integrity of the intestinal epithelial barrieras well as regulate innate and adaptive immune cell function and immune homeostasisOne common commensal bacteriumLactobacillus acidophiluscontains unique surface layer proteinsSlpsincluding SlpASlpBSlpXand lipoteichoic acidLTAThese Slps interact with pattern recognition receptorsPRRe gC type lectin receptorsexpressed on innate immune intestinal cells to mobilize fine tuned immunity in steady state and disease conditionsRecentlyour research team demonstrated that SlpA binding to the C type lectin Specific Intracellular adhesion moleculeGrabbing Non integrin homolog RelatedSIGNRreceptor expressed on dendritic cells lining the gut prevents experimentally induced colitis in multiple modelsOral delivery of SlpA reduced inflammatory cytokinesstrengthened the mucosal membrane barrierand supported a healthier microbiota make up in animal models of gut inflammationIn contrastthese effects and protection was not observed in Signrmicesuggesting that SlpA interaction with SIGNRplays a key protective role in regulating the disease conditionOur goal is to develop Ra novel LactococcusLlactis probiotic recombinantly expressing SlpA that will carry this SlpA biological targeting agent to the intestinal space and function via natural gut immunemicrobiome pathways to induce protective regulatory signals in innate cellse gdendritic cellsetcRwill reduce gut inflammation maintaining gastrointestinal mucosal barrier function and promoting more normal microbiota homeostasisThe specific aims are togenerate Llactis clones recombinantly expressing SlpA from a genome integrated operonselect a Rclinical candidate based on functional screeninggrowth rateSlpA expressionand stabilityanddemonstrate activity in the murine T cell induced colitis modelSuccessful commercialization of Rwill provide a profound medical advancement in the treatment of IBD Project Narrative Overmillion adults and children in the United States suffer from inflammatory bowel diseaseIBDThis project aims to develop a novel recombinant probiotic therapeuticRfor the treatment of IBDIn our prior preclinical validation studiesoral delivery of SlpAdecreased gut inflammationstrengthened the gut mucosal barrier functionsupported maintenance of a healthy gut microbiotaand showed no ill effects on treated animalsBased upon these propertiescommercialization of Rcould provide an important new maintenance treatment for IBD that is oral basedsafer than current drug optionsand potentially lower cost