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: 7533673
• 负责人: Mary E. Klotman
• 金额: $ 25.42万
• 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/7533673
• 关键词: Acquired Immunodeficiency Syndrome; Address; Animals; Anti-Retroviral Agents; Antiviral Agents; Appendix; Biological; Biopsy; Cell Communication; Cell Line; Cells; Cervical; Chemistry; Class; 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; 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; Numbers; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase III Clinical Trials; Physiological; Placebos; Prevention strategy; Property; Proteins; RNA; Range; 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; concept; cytokine; cytotoxicity; day; experience; human study; 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）：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，这突出表明需要有效的预防战略。不幸的是，迄今为止的第一代候选局部杀微生物剂阻断性传播的临床试验令人失望，因为壬苯醇醚-9（N-9）和最近的硫酸纤维素（CS）都没有阻断传播或实际上增强了传播。这些结果强调了对高效和安全的杀微生物剂候选物的持续需求。该项目将探讨一类新的特异性抗逆转录病毒药物整合酶抑制剂作为局部杀微生物剂候选物的安全性和有效性。整合酶抑制剂GS-9160是一种有效的HIV抑制剂，已在动物中进行了广泛研究，最近在I期人体试验中进行了研究，并且没有显著的毒性。这种药物作为候选杀微生物剂的潜力将分两个阶段进行评估。在R21阶段，将与吉利德科学公司合作生产GS-9160的候选凝胶制剂，并对体外载药量和稳定性进行评价。将在宫颈和阴道上皮细胞单层和宫颈阴道外植体中评价具有良好载量的药物和候选制剂的释放和摄取、细胞毒性以及对原代和实验室分离株的有效性。在人和恒河猴（RM）宫颈阴道外植体中由配制的GS-9160诱导的基因表达的平行评价沿着在R33阶段中对源自体内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外植体模型作为体内宿主应答的筛选。如果候选制剂具有可接受的安全性特征，如通过不存在促炎反应（与N-9相当）确定的，并且在外植体模型中抑制HIV感染，则将启动R33阶段，在（RM）中测试与经阴道递送配制的GS-9160相关的局部和全身药代动力学和毒性，然后在经R5 SHIV阴道激发的RM中进行疗效研究。拟议的研究将直接解决整合酶抑制剂是否应作为一类添加到杀菌剂开发的管道中。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选。2006年，有400多万人新感染了艾滋病毒，性传播是全世界的主要感染方式，这突出表明需要有效的预防战略。可由使用者应用以防止艾滋病毒性传播的局部杀微生物剂迄今在临床试验中令人失望。该提案研究了一种非常有效的抗逆转录病毒药物的局部杀微生物潜力，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，它将被添加到专门针对艾滋病毒的新一代局部杀微生物剂中。