A bioengineered probiotic for the oral delivery of a peptide Kv1.3 channel blocker to treat rheumatoid arthritis

Engineered microbes for the delivery of biologics is a promising avenue for the treatment of various conditions such as chronic inflammatory disorders and metabolic disease. In this study, we developed a genetically engineered probiotic delivery system that delivers the small molecular biologic to the intestinal tract with high efficacy and minimized side effects. We constructed an inducible system in the probiotic Lactobacillus reuteri to secret functional Kv1.3 potassium blocker ShK-235 (LrS235). We show that LrS235 is capable of blocking Kv1.3 currents and preferentially inhibiting human T effector memory (TEM) cells proliferation in vitro. A single oral gavage of healthy rats with LrS235 resulted in adequate functional ShK-235 in the circulation to reduce inflammation in a delayed-type hypersensitivity model of atopic dermatitis mediated by TEM cells. Furthermore, the daily oral gavage of LrS235 dramatically reduced clinical signs of disease and joint inflammation in rats with a model of rheumatoid arthritis without eliciting immunogenicity against ShK-235. This work demonstrates the efficacy of using probiotic L. reuteri as a novel oral delivery platform for the small molecule ShK-235, and provides a efficacious strategy to deliver other biologics with great translational potential.