Department of Integrative Physiology, Baylor College of Medicine, Houston, TX 77030.
Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030.
Proc Natl Acad Sci U S A. 2023 Jan 10;120(2):e2211977120. doi: 10.1073/pnas.2211977120. Epub 2023 Jan 3.
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 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) 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 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 as a novel oral delivery platform for the peptide ShK-235 and provides an efficacious strategy to deliver other biologics with great translational potential.
用于生物制剂递送的工程微生物是治疗各种疾病（如慢性炎症性疾病和代谢性疾病）的有前途的途径。在这项研究中，我们开发了一种基因工程益生菌递送系统，该系统可高效将肽递送至肠道。我们在益生菌中构建了一个诱导型系统，以分泌 Kv1.3 钾通道阻滞剂 ShK-235（LrS235）。我们发现 LrS235 培养上清液可阻断 Kv1.3 电流，并优先抑制体外人 T 效应记忆（T）淋巴细胞的增殖。单次口服给予 LrS235 可使健康大鼠体内循环中有足够的功能性 ShK-235，从而减轻 T 细胞介导的特应性皮炎迟发型超敏反应模型中的炎症。此外，每日口服给予 LrS235 可显著减轻类风湿关节炎模型大鼠的疾病和关节炎症的临床症状，而不会引起针对 ShK-235 的免疫原性。这项工作证明了使用益生菌作为新型口服递送平台来递送肽 ShK-235 的有效性，并为递送其他具有巨大转化潜力的生物制剂提供了一种有效的策略。
