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