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

Ferenczi, Szilamér and Solymosi, Norbert and Horváth, István and Szeőcs, Natália and Grózer, Zsuzsanna and Kuti, Dániel and Juhász, Balázs and Winkler, Zsuzsanna and Pankotai, Tibor and Sükösd, Farkas and Stágel, Anikó and Paholcsek, Melinda and Dóra, Dávid and Nagy, Nándor and Kovács, Krisztina J. and Szállási, Zoltán (2021) Efficient treatment of a preclinical inflammatory bowel disease model with engineered bacteria. MOLECULAR THERAPY-METHODS AND CLINICAL DEVELOPMENT, 20. pp. 218-226. ISSN 2329-0501

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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 small hairpin RNA (shRNA) targeting tumor necrosis factor (TNF) into the cytoplasm of the target cells. The expression levels of TNF and other cytokines significantly decreased upon this treatment in dextran sulfate sodium (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.

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