Engineering next generation probiotics for delivery of therapeutics

设计下一代益生菌以提供治疗

• 批准号: 10697438
• 负责人: Richard Wagner
• 金额: $ 32.5万
• 依托单位: MEDOSOME BIOTEC, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10697438
• 关键词: ACE2; Acceleration; Adsorption; Affect; Aging; Alzheimer' s disease model; Animal Model; Antibiotic Resistance; Antibiotics; Applications Grants; Biodistribution; Biological Availability; Biological Products; Biomedical Engineering; Cardiovascular system; Chronic; Chronic Disease; Classification; Complement; Complex; Development; Diabetic Retinopathy; Disease; Drosophila genus; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Engineered Probiotics; Engineering; Environment; Environmental Risk Factor; Face; Food; Formulation; Gastrointestinal tract structure; Genes; Genetic Engineering; Goals; Health; Health Benefit; Health Promotion; Homeostasis; Human; Human body; Immune System Diseases; Investigation; Lactobacillus; Medical; Medicine; Metabolic; Methods; Microbe; Molecular; Neurodegenerative Disorders; Oral; Oral Administration; Organ; Patients; Peptides; Pharmaceutical Preparations; Pharmacology; Phase; Plasmids; Play; Positioning Attribute; Predisposition; Probiotics; Production; Proteins; Publishing; Rattus; Renin-Angiotensin System; Reporting; Research; Rodent; Role; Safety; Small Business Innovation Research Grant; Structure; System; Technology; Testing; Therapeutic; Tissues; Toxicology; Translations; aged; clinical application; cognitive function; cost effective; delivery vehicle; design; efficacy validation; expression vector; frontier; gastrointestinal; gut dysbiosis; gut microbiome; gut microbiota; gut-brain axis; host-microbe interactions; human disease; improved; innovation; microbial community; microbiome; microorganism; next generation; parenteral administration; peptide drug; pressure; prevent; resistance gene; risk minimization; scale up; segregation; targeted treatment; technology platform; therapeutic protein; tool

PROJECT SUMMARY / ABSTRACT Peptide and protein drugs (PPDs) are potent therapeutics to treat a broad spectrum of diseases. Parenteral administration is limited due to their poor bioavailability and stability. Oral delivery of PPDs faces additional obstacles in the gastrointestinal tract. We have developed an innovative, probiotics-based platform technology for the oral delivery of therapeutic PPDs that targets a number of challenging chronic diseases. This delivery system is robust, highly efficient, cost effective, easy to administer and safe. Our recent published results provide proof-of concept for the feasibility of using Lactobacillus as a live vector for the delivery of peptide and protein with enhanced tissue bioavailability and efficacy. However, our current platform has several limitations for clinical application, which include the use of an antibiotic gene as selection marker, plasmid segregation instability and lack of built-in biocontainment strategy, which may raise safety concern with engineered microbes disseminated into the environment. The goal of this project is to develop a next generation probiotics-based platform for the delivery of peptide and protein therapeutics with more stable and effective biocontainment. Specifically, we will (1) construct, characterize and validate an antibiotic-resistance-gene free, auxotrophic complementation-based expression system to achieve stable and high-level expression of the therapeutic peptide in a probiotic strain of L. paracasei; (2) develop and validate the efficacy and stability of inducible kill-switches for the biocontainment of genetically engineered L. paracasei; and (3) validate the efficacy and stability of engineered probiotics expressing the therapeutic peptide with a built-in inducible kill-switch in animal models. If successful, the platform developed in this project with its modular design will be applicable to hundreds of probiotic Lactobacillus species that have shown species-specific benefits, as well as to deliver other PPDs. This drug delivery system will be applicable to numerous human diseases – many chronic and recalcitrant - from metabolic, cardiovascular and immune dysfunction to aging and neurodegenerative diseases. It will also provide a powerful research tool to modulate the structure and function of the gut microbiota, to further investigate the interplay of microbe-microbe and host-microbe interactions, and elucidate the molecular mechanisms involved in the health-promoting effects of these probiotics.

项目摘要 /摘要 肽和蛋白质药物（PPD）是治疗广泛疾病的潜在疗法。肠胃外 由于其生物利用度和稳定性差，管理受到限制。 PPD的口服交付额外 胃肠道的障碍物。我们已经开发了一种创新的，基于益生菌的平台技术 对于针对许多慢性疾病挑战的治疗性PPD的口服递送。这个交付 系统坚固，高效，具有成本效益，易于管理和安全。我们最近发表的结果提供了 使用乳酸杆菌作为辣椒和蛋白质的实时载体的可行性概念证明 具有增强的组织生物利用度和效率。但是，我们当前的平台有一些临床的局限性 应用，包括使用抗生素基因作为选择标记，质粒隔离不稳定性和 缺乏内置的生物内在策略，这可能会因散布工程的微生物而引起安全关注 进入环境。该项目的目的是开发一个基于下一代益生菌的平台 递送胡椒和蛋白质疗法，并具有更稳定和有效的生物内在。具体来说，我们会的 （1）构造，表征和验证抗生素抗性基因的，基于相思的基于抗生素的结构 表达系统以在益生菌菌株中实现治疗肽的稳定和高级表达 L. paracasei; （2）开发和验证诱导型杀伤开关的效率和稳定性 一般设计的L. paracasei; （3）验证工程益生菌的效率和稳定性 在动物模型中用内置诱导杀伤开关表达治疗性肽。如果成功，平台 在该项目中开发的模块化设计将适用于数百种益生菌乳酸菌物种 显示出特定于规格的好处，以及提供其他PPD。这个药物输送系统将是 适用于许多人类疾病 - 许多慢性和顽固疾病 - 来自代谢，心血管和 免疫功能障碍对衰老和神经退行性疾病。它还将为 调节肠道微生物群的结构和功能，以进一步研究微生物微生物的相互作用 和宿主 - 微生物相互作用，并阐明了参与健康促进作用的分子机制 这些益生菌。