HIV Integrase as a Target for Topical MIcrobicide Development

HIV整合酶作为外用杀菌剂开发的目标

• 批准号: 7846609
• 负责人: Mary E. Klotman
• 金额: $ 3.01万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-05 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7846609
• 关键词: Acquired Immunodeficiency Syndrome; Address; Animals; Anti-Retroviral Agents; Antiviral Agents; Biological; Biopsy; Cell Communication; Cell Line; Cells; Cervical; Chemistry; Clinical Trials; Collaborations; Data; Development; Diamond; Dose; Drug Formulations; Drug Kinetics; Epithelial Cells; Evaluation; Exposure to; Female; Gel; Gene Expression; Generations; Genital system; Goals; Grant; HIV; HIV Infections; HIV Integrase; HIV-1; HIV-1 integrase; Histologic; Human; Immune response; In Vitro; Individual; Infection; Integrase; Integrase Inhibitors; Intervention; Intravaginal Administration; Laboratories; Lead; Letters; Light; Liquid substance; Local Microbicides; Macaca; Macaca mulatta; Measures; Modeling; Mucous Membrane; Nonoxynol 9; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase III Clinical Trials; Physiological; Placebos; Prevention strategy; Property; Proteins; RNA; Reading; Relative (related person); Reporting; Research; Research Personnel; SIV; Safety; Science; Serum; Sexual Transmission; Sexually Transmitted Diseases; Specificity; System; Systemic Therapy; Testing; Time; Tissues; Topical application; Toxic effect; Upper arm; Vaccines; Vagina; Vaginal Douching; Vaginal delivery procedure; Validation; Viral; Viral Proteins; Virus; Virus Integration; Work; antimicrobial; antimicrobial peptide; cellulose sulfate; chemokine; cytokine; cytotoxicity; drug candidate; experience; hydroxyethylcellulose; improved; in vitro Model; in vivo; inhibitor/antagonist; lymph nodes; medical schools; microbicide; monolayer; nonhuman primate; pre-clinical; prevent; response; simian human immunodeficiency virus; small molecule; transmission process; uptake

DESCRIPTION (provided by applicant): Over 4 million individuals were newly infected with HIV in 2006 with sexual transmission the predominant mode of infection worldwide, highlighting the need for effective prevention strategies. Unfortunately clinical trials to date, with the first generation of candidate topical microbicides to block sexual transmission, have been disappointing as both nonoxynol-9 (N-9) and more recently cellulose sulfate (CS) either did not block transmission or actually enhanced transmission. These results highlight the continued need for highly efficacious and safe microbicide candidates. This project will address the safety and efficacy of a new class of specific anti-retrovirals as topical microbicide candidates, integrase inhibitors. The integrase inhibitor, GS-9160, is a potent inhibitor of HIV which has been extensively studied in animals and most recently in a Phase I human trial and has had no significant toxicity. The potential of this drug as a candidate microbicide will be evaluated in two phases. In the R21 phase, a candidate gel formulation of GS-9160 will be generated in collaboration with Gilead Sciences and evaluated for in vitro drug loading and stability. The drug and candidate formulation with favorable loading will be evaluated in cervical and vaginal epithelial cell monolayers and cervicovaginal explants for release and uptake, cytotoxicity and efficacy against primary and laboratory isolates. The parallel evaluation of gene expression induced by formulated GS-9160 in human and rhesus macaque (RM) cervicovaginal explants along with a similar analysis of tissue and cervical vaginal lavage (CVL) fluid derived from in vivo RM studies in the R33 phase will validate the cervicovaginal explant model as a screen for host responses in vivo. If the candidate formulation has an acceptable safety profile as determined by the absence of a proinflammatory response (comparable to N-9) and inhibits HIV infection in the explant model, the R33 phase will be initiated with testing of local and systemic pharmacokinetics and toxicity associated with vaginal delivery of formulated GS-9160 in (RM) followed by an efficacy study in RM vaginally challenged with R5 SHIV. The proposed studies will directly address whether integrase inhibitors as a class should be added to the pipeline for microbicide development. In addition, studies proposed will validate the genital explant model as a screen for host responses in vivo Over 4 million individuals were newly infected with HIV in 2006 with sexual transmission the predominant mode of infection worldwide, highlighting the need for effective prevention strategies. Topical microbicides that could be applied by the user to protect against sexual transmission of HIV have to date been disappointing in clinical trials. This proposal exams the topical microbicide potential of a very potent antiretroviral drug that inhibits integration of the virus into host cells. If successful in these studies it would be added to a new generation of topical microbicides in the pipeline that specifically target HIV.

描述（由申请人提供）：超过400万个人在2006年新感染了HIV，性传播是全球感染的主要感染模式，强调了有效预防策略的需求。不幸的是，迄今为止的临床试验是候选局部杀菌剂以阻止性传播，因为非氧基诺酚-9（N-9）和最近的硫酸纤维素硫酸盐（CS）都不会阻止传播或实际增强传播。这些结果突显了对高效和安全的杀微生物候选物的持续需求。该项目将解决一类新的特定抗逆转录病毒作为局部杀菌剂候选物，集成酶抑制剂的安全性和有效性。集成酶抑制剂GS-9160是一种有效的HIV抑制剂，在动物中已广泛研究，最近在I期人类试验中，没有明显的毒性。该药物作为候选杀菌剂的潜力将分为两个阶段。在R21阶段，将与Gilead Sciences合作生成GS-9160的候选凝胶配方，并评估用于体外药物负荷和稳定性。将在宫颈和阴道上皮细胞单层和宫颈阴道外植体中评估具有有利负荷的药物和候选配方，以释放和摄取，对原代和实验室分离株的摄取，细胞毒性和功效。人类和恒河猴（RM）子宫颈阴道外植体中的GS-9160诱导的基因表达的平行评估，以及对R33相中的体内RM研究中的组织和宫颈阴道灌注（CVL）流体的类似分析，R33相可以验证颈椎探险仪的模型。如果候选公式具有可接受的安全性，取决于缺乏促炎反应（与N-9相当）并抑制Explant模型中的HIV感染，则R33阶段将通过与形式的GS-9160相关的（RM）进行挑战的局部和系统的药代动力学和毒性的测试来启动R33阶段。拟议的研究将直接解决是否应将整合酶抑制剂作为类别添加到菌心发育的管道中。此外，提出的研究将验证生殖器外植体模型，作为在2006年，超过400万人在体内宿主反应的筛选，并在2006年被性传播新近感染了HIV，而性传播是全球范围内的主要感染模式，强调了对有效预防策略的需求。用户可以应用以防止艾滋病毒性传播的局部菌心必须在临床试验中令人失望。该提案检查一种非常有效的抗逆转录病毒药物的局部菌心电位，该药物抑制病毒整合到宿主细胞中。如果在这些研究中取得成功，它将被添加到新一代的局部杀菌剂中，这些局部菌皮特定针对HIV。