Targeted Delivery of Therapeutics by Engineered Commensal Microbes

项目总结 人体是一个复杂的生态系统，支持数千种微生物的共生关系。 它们对宿主的健康和新陈代谢是不可或缺的。对这些相互作用的探索导致了无数次 对微生物新陈代谢和群落动态等领域的洞察。随着知识的不断增长， 现在有机会利用我们对人类微生物区系日益复杂的理解 通过将我们的努力从发现和表征扩展到工程。共生微生物是 已经非常适合安全和有效地殖民各种生理利基；剩下的是 利用它们令人难以置信的基因组可塑性和作为强大生化工厂的能力。这 该提案旨在开发人类共生微生物作为载体，将治疗性化合物输送到 以身体部位为目标，这一努力需要多方面和协同的工程方法。具体来说， 我们的目标是改造肠道细菌来生产和分泌有针对性的生物疗法，如抗体 现场碎片，目的是解决人类健康中的多个关键问题。抗体提供了毒性较小的 替代标准的非特异性治疗，如广谱抗生素和化疗药物。到期 由于其精妙的特异性，抗体能够选择性地作用，例如抑制致病菌的生长。 不干扰当地微生物群落，在不损害健康的情况下消灭肿瘤 组织。然而，使用抗体疗法有效地治疗广泛的感染和疾病是 受到两个主要障碍的阻碍：(1)生产和管理它们的成本可能高得令人望而却步， 尤其是在细菌感染性疾病和(2)标准静脉给药对 口服治疗性抗体的同时进行胃肠治疗效果不佳。因此，我们将 设计一种由人类共生微生物产生治疗性抗体片段的系统 驻留在肠道中，为胃肠道感染提供持续的现场靶向治疗 疾病。这种方法解决了抗生素特异性、毒性和耐药性方面的关键问题，同时建立了 为以更低的成本和更大的便利进一步开发生物疗法奠定了基础。

PROJECT SUMMARY The human body is a complex ecosystem supporting symbiotic relationships with thousands of microbial species that are integral to the health and metabolism of their hosts. Exploration of these interactions has led to countless insights into areas such as microbial metabolism and community dynamics. With this growing body of knowledge, the opportunity now exists to capitalize on our increasingly sophisticated understanding of the human microbiota by expanding our efforts beyond discovery and characterization, toward engineering. Commensal microbes are already perfectly suited for safe and effective colonization of various physiological niches; what remains is to take advantage of their incredible genomic plasticity and ability to function as robust biochemical factories. This proposal aims to develop human commensal microbes as vehicles for delivery of therapeutic compounds to targeted body sites, an endeavor that requires a multifaceted and synergistic engineering approach. Specifically, we aim to engineer gut bacteria to produce and secrete targeted biological therapeutics such as antibody fragments in situ, with the goal of addressing multiple critical issues in human health. Antibodies offer a less toxic alternative to standard, non-specific treatments such as broad-spectrum antibiotics and chemotherapeutics. Due to their exquisite specificity, antibodies are capable of selective action, such as inhibiting the growth of pathogenic microbes without disturbing the native microbial community, and abolishing tumors without damaging healthy tissue. The use of antibody therapeutics to efficiently treat a broad range of infection and disease, however, is hindered by two major obstacles: (1) the cost to produce and administer them can be prohibitively expensive, especially in the case of bacterial infectious disease and (2) standard intravenous delivery is inefficient for gastrointestinal therapy while oral administration of therapeutic antibodies yields poor results. We will therefore engineer a system in which therapeutic antibody fragments are produced by human commensal microbes residing in the gut, providing continuous on-site delivery of targeted treatments for gastrointestinal infections and disease. This approach addresses key issues in antibiotic specificity, toxicity, and resistance, while establishing the groundwork for further development of biological therapeutics at lower cost and greater convenience.