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

Autor:	Wang Y; Department of Integrative Physiology, Baylor College of Medicine, Houston, TX 77030., Zhu D; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030.; Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX 77030., Ortiz-Velez LC; Pana Bio, Inc., Houston, TX 77051., Perry JL; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030.; Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX 77030., Pennington MW; Ambiopharm, Inc., North Augusta, SC 29842., Hyser JM; Department of Integrative Physiology, Baylor College of Medicine, Houston, TX 77030.; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030.; Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX 77030., Britton RA; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030.; Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX 77030., Beeton C; Department of Integrative Physiology, Baylor College of Medicine, Houston, TX 77030.; Biology of Inflammation Center, Baylor College of Medicine, Houston, TX 77030.; Center for Drug Discovery, Baylor College of Medicine, Houston, TX 77030.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2023 Jan 10; Vol. 120 (2), pp. e2211977120. Date of Electronic Publication: 2023 Jan 03.
DOI:	10.1073/pnas.2211977120
Abstrakt:	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 (T EM ) 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 T EM 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.
Databáze:	MEDLINE
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