Efficient treatment of a preclinical inflammatory bowel disease model with engineered bacteria

Abstract We developed an orally administered, engineered bacterium-based, RNA interference mediated therapeutic method to significantly reduce the symptoms in the most frequently used animal model of inflammatory bowel disease. This bacterium mediated RNA interference strategy was based on the genomically stable, non-pathogenic E. coli MDS42 strain, which was engineered to constitutively produce invasin and the listeriolysin O cytolysin. These proteins enabled the bacteria first to invade the colon epithelium and then degrade in the phagosome. This allowed the delivery of a plasmid encoding shRNA targeting TNF into the cytoplasm of the target cells. The expression levels of TNF and other cytokines significantly decreased upon this treatment in DSS induced colitis and the degree of inflammation was significantly reduced. With further safety modifications this method could serve as a safe and side-effect free alternative to biologicals targeting TNF or other inflammatory mediators.