Development of a Live Topical Microbicide for Women

女性外用活杀微生物剂的开发

• 批准号: 7336748
• 负责人: Qiang Xu
• 金额: $ 19.83万
• 依托单位: OSEL, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7336748
• 关键词: Address; Adherence; Animals; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Vaginosis; Biological Markers; Biological Products; Biomedical Engineering; Cell Line; Cervical; Chinese People; Chromosomes; Coculture Techniques; Collection; Consultations; Cyanovirin-N; Daily; Development; Dose; Drug Evaluation; Drug Formulations; Epidemiologic Studies; Epithelial Cells; Epithelium; Female; Generations; Genetic; Genetically Modified Organisms; Genital system; Genome Stability; HIV; HIV Entry Inhibitors; HIV-1; Heterosexuals; Human; Human Volunteers; Hydrogen Peroxide; Immune; In Situ; Infection; Investigational Drugs; Investigational New Drug Application; Lactobacillus; Lead; Life; Local Microbicides; Macaca mulatta; Modeling; Opportunistic Infections; Organism; Pharmacologic Substance; Phase; Phase II Clinical Trials; Proteins; Recombinants; Recurrence; Research; Risk; Safety; Seminal Plasma; Sexually Transmitted Diseases; Therapeutic; Transference; United States Dept. of Health and Human Services; United States Food and Drug Administration; Urinary tract infection; Vagina; Viral; Woman; Work; base; design; immunogenicity; immunotoxicity; manufacturing process; microbicide; nonhuman primate; novel; pathogen; pre-clinical; preclinical study; prevent; simian human immunodeficiency virus; transmission process; vaginal lactobacilli; volunteer

DESCRIPTION (provided by applicant): Osel, Inc. is a biopharmaceutical company specializing in the development of bacterial therapeutics. The company's lead product, LACTIN-V, is a naturally occurring human vaginal isolate of Lactobacillus crispatus presently undergoing phase II clinical trials to examine its safety and efficacy in preventing recurrent urinary tract infections and bacterial vaginosis (BV). Both of these infections are characterized by a depletion of hydrogen peroxide (H2O2)-producing lactobacilli that normally protect the vagina from infection by opportunistic pathogens. Epidemiological studies also suggest that loss of vaginal lactobacilli is associated with an increased risk of heterosexual HIV-1 transmission and other sexually transmitted infections. LACTIN-V represents an ecological approach to prevent vaginal infections by re-establishing the protective vaginal flora with a colonizing, H2O2-producing Lactobacillus strain. A second-generation Lactobacillus product, and the topic of this proposal, is a human vaginal isolate of H2O2-producing L. jensenii that has been genetically enhanced to constitutively secrete high levels of the potent HIV entry inhibitor cyanovirin-N (CV-N). This live, self-renewing microbicide may afford an efficacious, yet inexpensive means to deliver a protein-based microbicide and addresses the urgent need for female-controlled approaches to block heterosexual transmission of HIV-1. In this R21 proposal, we will select a microbicide development candidate from a collection of bioengineered strains that contain optimized CV-N expression cassettes stably integrated into the L. jensenii chromosome. We will employ a Chinese rhesus macaque (Macaca mulatta) model that affords persistent vaginal colonization of L. jensenii to conduct preclinical safety and efficacy studies, including in situ CV-N expression, immunotoxicity, and efficacy against mucosal viral transmission. Furthermore, we propose to evaluate potential regulatory issues concerning the pharmaceutical development of a genetically modified organism, and to optimize the formulation and manufacturing processes for this product. Following a pre-IND consultation with the FDA, we will file an exploratory IND application and then initiate two exploratory phase 0 studies in the R33 phase of the proposal to assess the effects of the recombinant L. jensenii strain on safety, tolerability, innate genital tract immune factors, vaginal colonization, and clearance of the organism after antibiotic administration in healthy female volunteers.

描述（由申请人提供）：Osel，Inc。是一家专门从事细菌疗法开发的生物制药公司。该公司的铅产品Lactin-V是一种天然存在的人类阴道分离物，目前正在进行II期临床试验中，目前正在进行II期临床试验，以检查其在防止复发性尿路感染和细菌阴道病（BV）方面的安全性和功效。这两种感染的特征是过氧化氢（H2O2）的耗竭，产生了通常保护阴道免受机会性病原体感染的乳酸杆菌。流行病学研究还表明，阴道乳酸杆菌的丧失与异性恋HIV-1传播和其他性传播感染的风险增加有关。乳蛋白-V代表一种生态学方法，可通过以殖民化的H2O2产生乳酸杆菌菌株来重新建立保护性阴道菌群来预防阴道感染。 第二代乳杆菌产物以及该提案的主题是人类的阴道分离物的H2O2产生H. Jensenii，它在遗传上得到了增强，以构建高水平的高水平的有效的HIV抑制剂抑制剂Cyanovirin-N（CV-N）。这种实时的自我更新杀菌剂可能提供一种有效但廉价的方法，用于提供基于蛋白质的杀菌剂，并解决了对女性控制方法的迫切需求，以阻止HIV-1的异性传播。 在此R21提案中，我们将从一组生物工程菌株中选择一个杀生型候选者，这些菌株包含优化的CV-N表达盒，稳定地集成到Jensenii染色体中。我们将采用中国恒河猴（Macaca Mulatta）模型，该模型可为珍妮丝（L. jensenii）持续进行阴道定植，以进行临床前的安全性和有效性研究，包括原位CV-N表达，免疫毒性，免疫毒性和针对粘膜病毒传播的功效。此外，我们建议评估有关转基因生物的药物开发的潜在调节问题，并优化该产品的配方和制造过程。 Following a pre-IND consultation with the FDA, we will file an exploratory IND application and then initiate two exploratory phase 0 studies in the R33 phase of the proposal to assess the effects of the recombinant L. jensenii strain on safety, tolerability, innate genital tract immune factors, vaginal colonization, and clearance of the organism after antibiotic administration in healthy female volunteers.