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

  • 2023-01-03
  • Proceedings of the National Academy of Sciences of the United States of America 120(2)
    • Yuqing Wang
    • Duolong Zhu
    • Laura C Ortiz-Velez
    • Jacob L Perry
    • Michael W Pennington
    • Joseph M Hyser
    • Robert A Britton
    • Christine Beeton

Study Design

Population
healthy rats
Methods
A genetically engineered probiotic delivery system in Lactobacillus reuteri to secrete the Kv1.3 potassium blocker ShK-235 (LrS235); single oral gavage and daily oral gavage in rat disease models
Engineered microbes for the delivery of biologics are 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 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.

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