Targeted Delivery of Therapeutics by Engineered Commensal Microbes

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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.