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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.是一家生物制药公司，专门从事细菌疗法的开发。该公司的主导产品LACTIN-V是一种天然存在的卷曲乳杆菌人类阴道分离物，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（UTIs）和细菌性阴道病（BV）的安全性和有效性。UTI和BV都与产生过氧化氢（H2 O2）的乳酸杆菌的消耗有关，这些乳酸杆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，阴道乳酸杆菌的损失与异性间HIV-1传播和其他性传播感染的风险增加有关。LACTIN-V代表了一种生态学方法，通过用定殖的、产生H2 O2的乳酸杆菌菌株重建保护性阴道植物群来预防阴道感染。目前正在开发的第二代乳杆菌产品是产H2 O2乳杆菌的人阴道分离物。jensenii，其已被遗传修饰以组成性地分泌高水平的基于单一蛋白质的有效的HIV病毒靶向进入抑制剂，N-末端修饰的氰病毒蛋白-N（CV-N）（P51 G）。这种活的、自我更新的杀微生物剂可以提供一种有效但廉价的手段来提供基于蛋白质的杀微生物剂，并解决对女性控制的方法的迫切需要，以阻断HIV-1的异性传播。在目前临床试验中的候选杀微生物剂中，几乎所有都是“性交依赖”产品，或正在基于单一活性成分进行开发。需要开发作用于粘膜HIV感染途径的多个位点的“非性交依赖性”杀微生物剂或组合杀微生物剂，这代表了杀微生物剂开发中的显著空白。在这个R21的建议，我们计划开发一种新的活的组合杀微生物剂，采用H2 O2生产阴道L。jensenii 1153，经遗传修饰以组成性分泌N-末端修饰的CV-N（P51 G）和有效的CCR 5靶向进入抑制剂C1 C5-RANTES。后者是N-末端修饰的RANTES，其靶向主要的HIV共受体CCR 5，具有增加的抗病毒和抗炎活性。在该提案中，我们将探索从单一乳杆菌菌株或从两种菌株的混合物中递送CV-N和C1 C5-RANTES的可能性，每种菌株递送单一抑制剂。我们将从一系列生物工程菌株中选择一种杀微生物剂开发候选物，这些菌株含有稳定整合到L。詹氏染色体R33阶段将在成功完成R21阶段提案中的拟议里程碑之后进行。对于R33阶段，我们建议在小鼠、兔和非人灵长类动物中进行临床前动物安全性和有效性研究。我们将采用中国恒河猴（Macaca mulatta）模型，使持续阴道定植的L。Jensenii进行临床前安全性和有效性研究，包括原位CV-N和C1 C5-RANTES表达，免疫毒性和对粘膜病毒传播的有效性。此外，我们建议评估有关转基因生物（可提供组合杀微生物剂）药物开发的潜在监管问题，并与FDA进行IND前咨询。