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 are a promising avenue for the treat-ment of various conditions such as chronic inflammatory disorders and metabolic dis-ease. In this study, we developed a genetically engineered probiotic delivery system that delivers a peptide to the intestinal tract with high efficacy. We constructed an inducible system in the probiotic Lactobacillus reuteri to secrete the Kv1.3 potassium blocker ShK-235 (LrS235). We show that LrS235 culture supernatants block Kv1.3 currents and preferentially inhibit human T effector memory (TEM) lymphocyte proliferation in vitro. A single oral gavage of healthy rats with LrS235 resulted in sufficient 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 the probiotic L. reuteri as a novel oral delivery platform for the peptide ShK-235 and provides an efficacious strategy to deliver other biologics with great translational potential.

Automated summary

Engineered probiotic Lactobacillus reuteri was developed to deliver the Kv1.3 potassium blocker ShK-235 (LrS235) to the intestinal tract with high efficacy. The LrS235 culture supernatants showed the ability to block Kv1.3 currents and inhibit human T effector memory (TEM) lymphocyte proliferation in vitro. Oral administration of LrS235 effectively reduced inflammation in a delayed-type hypersensitivity model of atopic dermatitis and clinical signs of disease and joint inflammation in a model of rheumatoid arthritis.