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: 7680141
• 负责人: Mary E. Klotman
• 金额: $ 21.19万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7680141
• 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.

说明(申请人提供)：2006年有400多万人新感染艾滋病毒，性传播是全世界的主要感染方式，突出了有效预防战略的必要性。不幸的是，到目前为止的临床试验，第一代候选局部杀微生物剂阻止性传播，一直令人失望，因为壬醇-9(N-9)和最近的硫酸纤维素(CS)要么没有阻止传播，要么实际上增强了传播。这些结果突显了对高效和安全的杀微生物剂候选者的持续需求。该项目将解决一类新的特定抗逆转录病毒药物作为局部杀微生物剂候选药物-整合酶抑制剂的安全性和有效性。整合酶抑制剂GS-9160是一种有效的艾滋病毒抑制剂，已在动物身上进行了广泛的研究，最近在一期人体试验中，没有明显的毒性。这种药物作为一种候选杀菌剂的潜力将分两个阶段进行评估。在R21阶段，将与Gilead Sciences合作产生GS-9160的候选凝胶配方，并对其体外药物载量和稳定性进行评估。具有良好载药量的药物和候选制剂将在宫颈和阴道上皮细胞单层和宫颈阴道外植体中进行释放和摄取、细胞毒性和对原发和实验室分离株的疗效评估。对配方GS-9160在人和恒河猴(RM)宫颈阴道移植体内诱导的基因表达的平行评估，以及对来自R33期在体RM研究的组织和宫颈阴道灌洗液(CVL)的类似分析，将验证宫颈阴道移植模型作为体内宿主反应的筛选。如果候选制剂在外植体模型中没有促炎反应(与N-9相似)并抑制HIV感染，确定的候选制剂具有可接受的安全性，则R33阶段将开始，测试局部和全身药代动力学和与经阴道递送配方GS-9160相关的毒性，然后对经阴道注射R5 SHV的RM进行疗效研究。拟议的研究将直接涉及是否应将整合酶抑制剂作为一类添加到杀菌剂开发的流水线中。此外，拟议的研究将验证生殖器外植体模型作为体内宿主反应的筛查，2006年有400多万人新感染艾滋病毒，性传播是全球主要的感染方式，突出了有效预防战略的必要性。到目前为止，使用者可以用来防止性传播艾滋病毒的局部杀微生物剂在临床试验中一直令人失望。这项建议检查了一种非常有效的抗逆转录病毒药物的局部杀微生物剂潜力，这种药物可以抑制病毒整合到宿主细胞中。如果这些研究成功，它将被添加到正在研制的专门针对艾滋病毒的新一代局部杀微生物剂中。