用基因工程微生物疗法控制人类肠道的定植

IF 45.8 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2025-07-17 DOI:10.1126/science.adu8000

Weston R. Whitaker, Zachary N. Russ, Elizabeth Stanley Shepherd, Lauren M. Popov, Alexander Louie, Kathy Lam, David M. Zong, Clare C. C. Gill, Jeanette L. Gehrig, Harneet S. Rishi, Jessica A. Tan, Areta Buness, Janeth Godoy, Domenique Banta, Sonia Jaidka, Katheryne Wilson, Jake Flood, Polina Bukshpun, Richard Yocum, David N. Cook, Tariq Warsi, Lachy McLean, Justin L. Sonnenburg, William C. DeLoache

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引用次数: 0

摘要

精确的微生物组编程治疗应用是有限的挑战，实现可复制的结肠定植。之前，我们创造了一个独特的生态位，我们使用卟啉益生元将工程细菌植入小鼠体内的各种微生物群中。在这种方法的基础上，我们现在通过用卟啉诱导启动子取代天然必需基因调控，将条件衰减改造成一种利用卟啉的Phocaeicola vulgatus菌株，以允许可逆植入。在临床前模型中，将五基因草酸降解途径导入可逆移植菌株中，可以减少高草酸尿（肾结石的一种原因）的治疗候选物。我们的1/2a期临床试验证明了卟啉的剂量依赖性丰度和人体可逆植入，尿液中草酸盐的减少，以及实现长期治疗的遗传稳定性挑战。

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Controlled colonization of the human gut with a genetically engineered microbial therapeutic

Precision microbiome programming for therapeutic applications is limited by challenges in achieving reproducible colonic colonization. Previously, we created an exclusive niche that we used to engraft engineered bacteria into diverse microbiota in mice by using a porphyran prebiotic. Building on this approach, we have now engineered conditional attenuation into a porphyran-utilizing strain of Phocaeicola vulgatus by replacing native essential gene regulation with a porphyran-inducible promoter to allow reversible engraftment. Engineering a five-gene oxalate degradation pathway into the reversibly engrafting strain resulted in a therapeutic candidate that reduced hyperoxaluria, a cause of kidney stones, in preclinical models. Our phase 1/2a clinical trial demonstrated porphyran dose–dependent abundance and reversible engraftment in humans, reduction of oxalate in the urine, and characterized genetic stability challenges to achievinglong-term treatment.

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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