Targeted Delivery of Therapeutics by Engineered Commensal Microbes

通过工程共生微生物进行靶向治疗

• 批准号: 10676079
• 负责人: Shannon Julianne Sirk
• 金额: $ 18.19万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676079
• 关键词: Address; Antibiotic Resistance; Antibiotics; Antibodies; Antibody Formation; Area; Bacteria; Bacterial Proteins; Biochemical; Biological Response Modifier Therapy; Bypass; Clostridium difficile; Coculture Techniques; Collection; Communicable Diseases; Communities; Complex; Disease; Ecosystem; Engineering; Engraftment; Ensure; Extracellular Space; Fermentation; Food; Future; Gastrointestinal Diseases; Gastrointestinal tract structure; Gene Expression; Genetic; Genomics; Germ-Free; Goals; Growth; Health; Human; Human body; Immunoglobulin Fragments; In Situ; In Vitro; Infection; Intravenous; Knowledge; Lactobacillus casei; Measures; Metabolism; Microbe; Modeling; Mus; Oral; Oral Administration; Passive Immunity; Pathogenicity; Performance; Physiological; Plasmids; Probiotics; Production; Protein Secretion; Proteins; Recombinant Proteins; Resistance; Resources; Site; Source; Specificity; Support System; System; Technology; Testing; Therapeutic; Therapeutic antibodies; Time; Tissues; Toxic effect; biological development; combinatorial; commensal bacteria; commensal microbes; cost; delivery vehicle; fitness; flexibility; gastrointestinal; gastrointestinal infection; genetic manipulation; gut bacteria; gut microbes; gut microbiota; human microbiota; in vitro activity; in vivo; insight; metabolic engineering; microbial; microbial community; neutralizing antibody; pathogen; pathogenic microbe; protein expression; response; synthetic biology; targeted delivery; targeted treatment; tool; tumor

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.

项目摘要 人体是一个复杂的生态系统，与成千上万的微生物物种保持共生关系。 对宿主的健康和新陈代谢至关重要。对这些相互作用的探索导致了无数 深入了解微生物代谢和群落动态等领域。随着知识的不断增长， 现在有机会利用我们对人类微生物群日益复杂的理解 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 已经完全适合于各种生理生态位的安全和有效的定植;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的生化工厂的能力。这 该提案旨在开发人类共生微生物作为递送治疗化合物的载体， 目标身体部位，这需要一个多方面和协同工程方法的奋进。具体地说， 我们的目标是设计肠道细菌，以产生和分泌靶向生物治疗剂， 在现场的碎片，以解决人类健康的多个关键问题的目标。抗体提供了一种毒性较小的 替代标准的非特异性治疗，如广谱抗生素和化疗药物。由于 由于抗体具有高度的特异性，因此它们能够选择性地发挥作用，例如抑制病原体的生长。 微生物，而不干扰天然微生物群落，并消除肿瘤，而不损害健康 组织.然而，使用抗体治疗剂来有效治疗广泛的感染和疾病是不可能的。 受到两个主要障碍的阻碍：（1）生产和管理它们的成本可能非常昂贵， 特别是在细菌感染性疾病的情况下，以及（2）标准静脉内递送对于 胃肠道治疗，而口服治疗性抗体产生差的结果。因此我们将 设计一个系统，其中治疗性抗体片段由人类肠道微生物产生 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、毒性和耐药性的关键问题，同时建立了 为进一步开发更低成本和更方便的生物疗法奠定了基础。