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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.

项目摘要/摘要。合成生物学改变了我们对细胞进行合理编程和使用的能力这种经过工程处理的生物有机体，而不是小分子药物或生物制品，可以作为新的治疗方法。然而，生命疗法的增殖和释放它们的工程遗传信息到自然生物群中。通过水平基因转移。因此，工程生命疗法的广泛使用有必要开发有效的生物遏制技术，不仅防止不必要的细胞的增殖，但也消除了遗传信息(转基因)的释放转基因生物(GMO)。我的提案的首要目标是解决这些挑战并开发第一个微生物宿主对于可编程药物输送，同时提供严密的生物遏制，防止转基因释放 ─水平基因转移─进入野生生物，并为长期药物生产提供更高的稳定性。 PI最近证明了对活细胞的遗传密码进行工程改造提供了一种紧密的、潜在的牢不可破的遗传防火墙，消除了水平的基因转移，并将细胞的生存与如果没有人类的补充，小分子的存在是不可用的。然而，这些早期的实验也揭示了这项技术在临床翻译方面面临的重大障碍。这个项目将克服这些屏障并产生细菌宿主，用于受控的药物生产，阻止转基因释放和病毒捕食，同时提供严格的生物遏制，而不逃脱人类的治疗剂量。这一目标将通过3个具体目标来实现：1)构建具有广泛抗病毒力的微生物宿主通过产生和表征多个人工遗传密码来防止转基因释放。2)创造利用安全的、以食物补充剂为基础的遗传生物遏制的紧密生物包含的微生物宿主系统。最后，在目标3中，PI将把这些发展结合成一个活的治疗宿主，并在概念验证实验中证明该宿主能够稳定、长期地治疗酶在胃肠道内生产。总而言之，这项工作将创造一种能够解决广泛问题技术和微生物宿主治疗开发中未得到满足的需求，并降低使用微生物转基因生物进行临床翻译的风险，可能对从自身免疫和代谢障碍到癌症的各种疾病产生广泛影响。这个拟议的研究和职业发展计划将在乔治·M·丘奇博士的实验室进行哈佛医学院和PI阿科斯·尼尔赫斯博士将接受蛋白质组学方面的广泛培训，使用来自专家咨询团队的K99阶段的动物模型和宿主-病毒相互作用分析。这个哈佛大学的职业发展计划和卓越的科学环境将使PI能够实现这项建议的科学目标，达到科学独立，并成立他的独立研究小组。