Development of a Live Combinational Microbicide for Women

女性用活性复合杀微生物剂的开发

基本信息

批准号：
7786986
负责人：
Laurel A. Lagenaur
金额：
$ 19.51万
依托单位：
OSEL, INC.
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-15 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7786986
关键词：
Address Adherence Animals Anti-Inflammatory Agents Anti-inflammatory Antiviral Agents Bacteria Bacterial Chromosomes Bacterial Vaginosis Biological Containment Biological Products Biomedical Engineering CCR5 gene Cell Line Cells Cervical Chemokine (C-C Motif) Receptor 5 Chinese People Chromosomes Clinical Trials Collection Consultations Cyanovirin-N Development Dose Drug Formulations Engineering Epidemiologic Studies Epithelial Cells Epithelium Evaluation Female Generations Genetic Genetically Modified Organisms Genital system HIV HIV Entry Inhibitors HIV Infections HIV-1 Heterosexuals Human Hydrogen Peroxide Immune In Situ In Vitro Individual Infection Intravaginal Administration Lactobacillus Lead Life Macaca mulatta Modeling Mus Opportunistic Infections Organism Oryctolagus cuniculus Pathway interactions Peripheral Blood Mononuclear Cell Pharmacologic Substance Phase Phase II Clinical Trials Phenotype Production Proteins RANTES Recurrence Resistance Risk Safety Seminal Plasma Sexually Transmitted Diseases Therapeutic Toxic effect Urinary tract infection Vagina Variant Viral Woman base biomaterial compatibility candidate selection design fitness immunogenicity immunotoxicity inhibitor/antagonist irritation manufacturing process microbial microbicide mucosal site nonhuman primate novel pathogen pre-clinical preclinical safety prevent protein expression self-renewal simian human immunodeficiency virus success transmission process vaginal lactobacilli

项目摘要

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 (UTIs) and bacterial vaginosis (BV). Both UTIs and BV are associated with 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, currently under development, is a human vaginal isolate of H2O2-producing L. jensenii that has been genetically modified to constitutively secrete high levels of a single protein-based potent HIV envelope-targeted entry inhibitor, an N-terminally modified cyanovirin-N (CV-N) (P51G). This live, self-renewing microbicide may afford an efficacious, yet inexpensive means to deliver a protein-based microbicide and address the urgent need for female-controlled approaches to block heterosexual transmission of HIV-1. Among the microbicide candidates currently in clinical trials, almost all of them are "coital dependent" products, or are being formulated for development based on a single active ingredient. The need to develop "non-coital dependent" microbicides or combinational microbicides that act at multiple sites of the mucosal HIV infection pathway represents a significant gap in microbicide development. In this R21 proposal, we plan to develop a novel live combinational microbicide by employing an H2O2-producing vaginal L. jensenii 1153 genetically modified to constitutively secrete the N-terminally modified CV-N (P51G) and an effective CCR5- targeted entry inhibitor, C1C5-RANTES. The latter is an N-terminally modified RANTES that targets the major HIV co-receptor CCR5 with an increased antiviral and anti-inflammatory activity. In this proposal, we will explore the possibility of delivering CV-N and C1C5-RANTES from a single strain of Lactobacillus, or from a mixture of two strains, each delivering a single inhibitor. We will select a microbicide development candidate from a collection of bioengineered strains that contain optimized expression cassettes stably integrated into the L. jensenii chromosome. The R33 phase will follow after a successful completion of the proposed milestones in the R21 phase proposal. For the R33 phase, we propose to conduct preclinical animal safety and efficacy studies in mouse, rabbit, and non-human primates. We will employ a Chinese rhesus macaque (Macaca mulatta) model that allows persistent vaginal colonization of L. jensenii to conduct preclinical safety and efficacy studies, including in situ CV-N and C1C5-RANTES 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 which delivers combinational microbicides and to have a pre-IND consultation with FDA.

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（UTI）和细菌性阴道（BV）方面的安全性和功效。 UTI和BV都与产生乳杆菌的产生乳酸（H2O2）的耗竭相关，该乳酸杆菌通常可以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。目前正在开发的第二代乳酸杆菌是产生H2O2的人类阴道分离株，它已在遗传上进行了遗传修饰，以组成分泌高水平的基于蛋白质的高水平的基于蛋白质的HIV型HIV靶向靶向靶向的靶向抑制剂，N-ensilienciped Cyanovirin-n（CV-N）（CV-N）（CV-N）（CV-N）（C51）（p51）。这种实时的自我更新杀菌剂可能提供一种有效但廉价的手段，可提供基于蛋白质的杀菌剂，并迫切需要对女性控制的方法阻止HIV-1的异性传播。在目前正在临床试验中的菌心候选物中，几乎所有的都是“依赖”产品，或者是根据单个活性成分制定的。在粘膜HIV感染途径的多个部位起作用的“非毛有依赖性”菌皮或组合菌皮的需求代表了微生物剂发育的显着差距。在此R21提案中，我们计划通过采用H2O2产生的阴道L. jensenii 1153进行基因修饰，以组建N端修饰的CV-N（P51G）和有效的CCR5靶向靶向的入口抑制剂C1C5-RANTES，从而开发一种新型的实时组合微生物剂。后者是一种N末端修饰的狂欢，靶向主要的HIV共受体CCR5，其抗病毒和抗炎活性增加。在此提案中，我们将探索从单个乳杆菌菌株或两种菌株的混合物中输送CV-N和C1C5龙也的可能性，每种菌株都提供一个抑制剂。我们将从一系列生物工程菌株中选择一个杀菌剂的发育候选者，该菌株包含稳定整合到Jensenii染色体中的优化表达盒。 R33阶段将在R21相建议中成功完成拟议的里程碑之后。对于R33阶段，我们建议对小鼠，兔子和非人类灵长类动物进行临床前动物的安全性和有效性研究。我们将采用中国恒河猕猴（Macaca Mulatta）模型，该模型允许L. jensenii的阴道持续进行临床前的安全性和有效性研究，包括原位CV-N和C1C5-RANTES表达，免疫毒性，免疫毒性和抗粘膜病毒传播的功效。此外，我们建议评估有关转基因生物体的药物开发的潜在调节问题，该生物可以提供合并菌物的组合菌心，并与FDA进行预先咨询。