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.

项目概要/摘要 肽和蛋白质药物（PPD）是治疗多种胃肠外疾病的有效疗法。 由于 PPD 的生物利用度和稳定性较差，其给药受到限制。 我们开发了一种基于益生菌的创新平台技术。 用于口服治疗性 PPD，针对许多具有挑战性的慢性疾病。 我们最近发布的结果表明，该系统稳健、高效、具有成本效益、易于管理且安全。 使用乳酸菌作为活载体输送肽和蛋白质的可行性的概念验证 具有增强的组织生物利用度和功效但是，我们当前的平台在临床上存在一些局限性。 应用，其中包括使用抗生素基因作为选择标记、质粒分离不稳定性和 缺乏内置的生物遏制策略，这可能会引发传播工程微生物的安全问题 该项目的目标是开发下一代基于益生菌的平台。 具体来说，我们将提供具有更稳定和有效的生物防护的肽和蛋白质治疗剂。 (1) 构建、表征和验证无抗生素抗性基因、营养缺陷型互补的 表达系统，以在益生菌菌株中实现治疗肽的稳定和高水平表达 L. paracasei；（2）开发并验证用于生物防护的诱导型杀伤开关的功效和稳定性 基因工程副干酪乳杆菌；（3）验证工程益生菌的功效和稳定性 如果成功，该平台将在动物模型中表达具有内置诱导杀伤开关的治疗肽。 该项目开发的模块化设计将适用于数百种益生菌乳酸菌 已显示出物种特异性的益处，以及提供其他 PPD 的药物输送系统。 适用于多种人类疾病——许多慢性疾病和顽固性疾病——来自代谢、心血管和 它还将为衰老和神经退行性疾病的免疫功能障碍提供强大的研究工具。 调节肠道菌群的结构和功能，进一步研究微生物之间的相互作用 和宿主-微生物相互作用，并阐明促进健康作用的分子机制 这些益生菌。