Development of a Live Topical Microbicide for Women

女性外用活杀微生物剂的开发

• 批准号: 7931197
• 负责人: Qiang Xu
• 金额: $ 33.94万
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7931197
• 关键词: Address; Adherence; Animals; Antibiotic Resistance; Antibiotics; Bacteria; Biological Markers; Cell Line; Cervical; Chinese People; Coculture Techniques; Cyanovirin-N; Development; Dose; Drug Evaluation; Drug Formulations; Epithelial Cells; Epithelium; Evaluation Research; Female; Genetic; Genetically Modified Organisms; Genital system; Genome Stability; HIV; HIV Entry Inhibitors; HIV-1; Heterosexuals; Human; Human Volunteers; Hydrogen; Immune; In Situ; Investigational Drugs; Investigational New Drug Application; Lactobacillus; Lead; Life; Local Microbicides; Macaca mulatta; Modeling; Pharmacologic Substance; Phase; Proteins; Recombinants; Safety; Seminal Plasma; Transference; United States Dept. of Health and Human Services; Vagina; Viral; Woman; Work; base; design; immunogenicity; manufacturing process; microbicide; nonhuman primate; novel; pre-clinical; preclinical study; prevent; self-renewal; simian human immunodeficiency virus; transmission process; 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.

简介（由申请人提供）：Osel, Inc.是一家专门从事细菌治疗药物开发的生物制药公司。该公司的主要产品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，以检查其预防复发性尿路感染和细菌性阴道病（BV）的安全性和有效性。这两种感染的特征都是产生过氧化氢（H2O2）的乳酸菌的消耗，这种乳酸菌通常保护阴道免受机会性病原体的感染。流行病学研究还表明，阴道乳酸菌的缺失与异性传播HIV-1和其他性传播感染的风险增加有关。LACTIN-V代表了一种生态方法，通过重新建立保护性阴道菌群，产生h2o2的乳酸杆菌菌株来预防阴道感染。