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Development of a Gene-Transfer-Resistant and Biocontained Next-Generation Bacterial Host for Controlled Drug Delivery

开发用于受控药物输送的抗基因转移和生物包容的下一代细菌宿主

基本信息

批准号：
10784171
负责人：
Akos Nyerges
金额：
$ 11.67万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-22 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10784171
关键词：
Address Advisory Committees Amino Acids Amino Acyl-tRNA Synthetases Ammonia Animal Model Autoimmune Diseases Bacteria Bacteriophages Biological Assay Biological Products Cell Proliferation Cell Survival Cells Church Clinical Code Codon Nucleotides Development Development Plans Disease Dose Drug Delivery Systems Drug Kinetics Engineering Environment Enzymes Escherichia coli Excretory function Food Supplements Gastrointestinal tract structure Gene Expression Gene Transfer Generations Genes Genetic Genetic Code Genetic Engineering Genetically Modified Organisms Genomics Goals Growth Half-Life Health Horizontal Gene Transfer Human Human body Inherited Laboratories Link Lyase Malignant Neoplasms Mass Spectrum Analysis Mentors Metabolic Diseases Mus Organism Patients Pharmaceutical Preparations Phase Predatory Behavior Prevention Production Proliferating Proteomics Research Resistance Risk Role Safety Sense Codon Supplementation System Technology Terminator Codon Test Result Testing Therapeutic Therapeutic Uses Training Transfer RNA Transgenes Translating Tyrosine Tyrosinemias United States National Institutes of Health Variant Viral Viral Genes Virus Virus Diseases Work addiction bacterial resistance career development cell growth clinical translation colonization resistance drug production experimental study firewall fitness gene function genetic information gut colonization in vivo medical schools microbial microbial host microbiome microorganism mouse model new technology next generation novel therapeutics peptide drug prevent programs research and development small molecule synthetic biology synthetic construct therapeutic development therapeutic enzyme therapeutic gene therapeutic transgene unnatural amino acids viral resistance virus host interaction

项目摘要

Project Summary/Abstract. Synthetic biology transformed our ability to rationally reprogram cells and use such engineered living organisms, instead of small molecule drugs or biologics, as novel therapeutics. However, living therapeutics proliferate and release their engineered genetic information into natural biomes through horizontal gene transfer. Consequently, the widespread use of engineered living therapeutics necessitates the development of efficient biocontainment technologies that not only prevent the unwanted proliferation of cells but also eliminate the release of genetic information (transgenes) from such genetically modified organisms (GMOs). The overarching goal of my proposal is to solve these challenges and develop the first microbial host for programmable drug delivery that simultaneously provides tight biocontainment, prevents transgene release ─ horizontal gene transfer ─ into wild organisms, and offers increased stability for long-term drug production. The PI recently demonstrated that engineering the genetic code of living cells provides a tight, potentially unbreakable genetic firewall that eliminates horizontal gene transfer and links the survival of cells to the presence of small molecules not available without human supplementation. However, these early experiments also revealed significant barriers in front of the clinical translation of this technology. This project will overcome these barriers and generate a bacterial host for controlled drug production that prevents transgene release and viral predation while offering strict biocontainment without escape from human therapeutic doses. This goal will be achieved through 3 specific aims: 1) The construction of a broadly virus-resistant microbial host that prevents transgene release by generating and characterizing multiple artificial genetic codes. 2) The creation of a tightly biocontained microbial host that utilizes a safe, food-supplement-based genetic biocontainment system. Finally, in Aim 3, the PI will combine these developments into a microbial living therapeutic host and demonstrate in a proof-of-concept experiment that this host enables stable, long-term therapeutic enzyme production inside the GI tract. In summary, this work will create a technology and microbial host capable of addressing a wide range of unmet needs in therapeutics development and de-risk the use of microbial GMOs for clinical translation, with potentially broad impact on diseases ranging from autoimmune and metabolic disorders to cancer. The proposed research and career development plan will be conducted in the lab of Dr. George M. Church at Harvard Medical School, and the PI, Dr. Akos Nyerges, will receive extensive training in proteomics, the use of animal models, and host-virus interaction analyses during the K99 phase from an expert advisory team. The career development plan and the outstanding scientific environment of Harvard will enable the PI to achieve the scientific goals of this proposal, reach scientific independence, and launch his independent research group.

项目总结/抽象。合成生物学改变了我们合理地重新编程细胞和使用的能力