Optimization, Manufacturing and Testing of a Lead Therapeutic Bacteriophage Cocktail for the Treatment of Antibiotic-Resistant Klebsiella pneumoniae Infections

用于治疗耐抗生素肺炎克雷伯菌感染的先导治疗噬菌体混合物的优化、制造和测试

• 批准号: 10674294
• 负责人: Derrick E Fouts
• 金额: $ 92.13万
• 依托单位: J. CRAIG VENTER INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-21 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10674294
• 关键词: Acute; Address; Antibiotic Resistance; Antibiotic Therapy; Antibodies; B-Lymphocytes; Bacteria; Bacteriophages; Bar Codes; Benchmarking; Blood Circulation; Clinical; Clinical Research; Clinical Trials; Cyclic GMP; Development; Dose; Engineering; Enterobacteriaceae; Formulation; Funding; Future; Genome; Genomics; Goals; Health; Human; Immune response; Immunity; In Vitro; Infection; Inflammation; Investigational Drugs; Investigational New Drug Application; Klebsiella pneumoniae; Label; Lead; Lung infections; Methods; Modeling; Modification; Mus; Pharmaceutical Preparations; Phase I Clinical Trials; Preparation; Production; Public Health; Recording of previous events; Research Institute; Research Personnel; Resistance; Sepsis; Septicemia; Specificity; Staphylococcus aureus; System; T-Lymphocyte; Technology; Testing; Therapeutic; Toxicity Tests; Urinary tract; Virus; Work; Wound Infection; Yeasts; alternative treatment; cGMP production; carbapenem resistance; cellular development; cytokine release syndrome; design; drug testing; efficacy testing; experience; experimental study; genome sequencing; immunoregulation; improved; in vivo; ineffective therapies; innovation; interest; lead candidate; lead optimization; manufacture; microbiome; mortality; mouse development; mouse model; pathogen; pathogenic bacteria; pharmacokinetics and pharmacodynamics; preclinical study; prevent; process optimization; public health relevance; receptor binding; resistant Klebsiella pneumoniae; respiratory; safety testing; scale up; stability testing; synthetic biology; synthetic genomics; therapeutic candidate; treatment strategy; whole genome; wound treatment

PROJECT SUMMARY/ABSTRACT Infections caused by Klebsiella pneumoniae are increasingly prevalent and difficult to treat due to ineffective treatment options due to increased antibiotic resistance. Bacteriophages, viruses that infect and kill bacteria, are being used to effectively treat and cure infections caused by a number of bacterial pathogens. To address the need for new treatments for wound and pulmonary infections caused by K. pneumoniae, our group has developed a 5-phage lead candidate therapeutic cocktail that is capable of infecting 53 of our 100-strain test panel. The goal of this proposal is to optimize our lead therapeutic and its production as well as to conduct the required pre-Investigational New Drug (IND) testing and benchmarking necessary for the successful submission and review of an IND application for a phase 1 clinical trial. The proposed work will be conducted through a partnership between the J. Craig Venter Institute (JCVI), the Walter Reed Army Institute of Research (WRAIR) and Adaptive Phage Therapeutics (APT). It will leverage JCVI’s history of synthetic and phage genomics, WRAIR’s experience developing phage therapeutics, development of mouse models, and APTs cGMP production capabilities and experience with phage clinical trials. The goal to prepare our lead candidate therapeutic for IND submission to FDA will materialize through three main objectives: 1) To optimize the lead therapeutic, 2) To conduct IND-required testing, and 3) To optimize and scale-up for cGMP manufacturing and testing. The workflow to achieve these objectives is innovative, utilizing cutting-edge technologies, and encompasses the entire process from optimization and testing to GMP production of the therapeutic. More significantly, it will be a platform for developing future phage-based therapeutics for other important bacterial pathogens.

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