Characterization of entry inhibitors in human cervical & rectal tissue models & d

人宫颈进入抑制剂的表征

• 批准号: 7418087
• 负责人: ROBIN J SHATTOCK
• 金额: $ 4.48万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-23 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7418087
• 关键词: Animal Model; Biological Markers; Biological Models; Cells; Cervical; Clinical Trials; Collaborations; Condition; Cultured Cells; Dendritic Cells; Development; Drug Formulations; Epithelial; Epithelium; Evaluation; Event; Future; Genomics; Goals; HIV-1; Histocompatibility; Human; Individual; Infection; Infection prevention; Investigation; Knowledge; Langerhans cell; Learning; Length; Localized; Location; Macaca; Macaca mulatta; Measurement; Mediating; Modeling; Monitor; Mononuclear; Mucous Membrane; Mucous body substance; Numbers; Outcome; Pathway interactions; Pattern; Penetration; Performance; Phase; Phase III Clinical Trials; Physiological; Population; Process; Property; Range; Research; Research Project Grants; Role; Safety; Savings; Science; Scientist; Seminal fluid; Series; Sexual Transmission; Solid; Solvents; System; T-Lymphocyte; Technology; Testing; Thinking; Time; Tissue Model; Tissues; Vagina; Validation; Viral; Virus; Virus Diseases; Work; base; cell type; cellulose sulfate; chemokine; comparative; cost; cytokine; design; efficacy trial; immune function; in vitro Model; in vivo; inhibitor/antagonist; macrophage; microbial; microbicide; particle; pathogen; pre-clinical; prevent; programs; receptor; rectal; research clinical testing; research study; response; transmission process; uptake

The potential role of microbicides in preventing the mucosal transmission of HIV-i has been clearly identified. However, rigorous pre-clinical evaluation of candidate microbicides is essential to the selection of the best compounds for clinical trials, since this will, in the end, provide savings in costs and time, given the expense and length of formal efficacy trials. Concerns with performing efficacy trials with incompletely optimized microbicide candidates have been highlighted by recent failed or halted Phase III trials (COL- 1492, SAVVY and Cellulose Sulphate); these trials have suggested that development and formulation of effective microbicides may not be as easy as first thought. While mononuclear cell cultures and animal models may provide important information for the evaluation of microbicides, anatomical, physiological and immunological issues suggest they may not adequately model events that occur in human mucosal tissue. Therefore a comprehensive program for pre-clinical development of microbicide candidates requires that information be accrued from several different model systems. Hence Dr. Shattock's and Robbiani's groups have developed in vitro models of the earliest events in HIV-i infection of human mucosal tissue and dendritic cell driven HIV-i spread. These models are ideally suited to test the efficacy of agents designed to block HIV-i sexual transmission and have been widely used to evaluate potential microbicide candidates. Furthermore, experiments described here and cross validation with experiments described in project III, may identify potential biomarkers of efficacy, safety and compliance that could inform future clinical trials. In this project, we will use these established models to evaluate the efficacy and compatibility of HIV-i entry inhibitors (alone and in combination) and their formulations. This research will be influenced and guided by work carried out within Core A, and will involve extensive interactions and collaborations with the scientists leading Research Projects II and III. The interactions between the different groups will result in the fasttracking of the most promising inhibitor combinations and formulations for evaluation in the macaque model (Research Project III).

杀菌剂在预防 HIV-i 粘膜传播方面的潜在作用已被明确证实 确定。然而，对候选杀菌剂进行严格的临床前评估对于选择 临床试验的最佳化合物，因为这最终将节省成本和时间，因为 正式疗效试验的费用和持续时间。对不完全进行疗效试验的担忧 最近失败或停止的 III 期试验强调了优化的候选杀菌剂（COL- 1492，SAVVY 和硫酸纤维素）；这些试验表明，开发和制定 有效的杀菌剂可能并不像最初想象的那么容易。虽然单核细胞培养物和动物 模型可以为评估杀菌剂、解剖学、生理学和 免疫学问题表明它们可能无法充分模拟人类粘膜组织中发生的事件。 因此，候选杀菌剂临床前开发的综合计划要求： 信息可以从几个不同的模型系统中获得。因此，Shattock 博士和 Robbiani 的团队 开发了人类粘膜组织 HIV-i 感染最早事件的体外模型 树突状细胞驱动 HIV-i 传播。这些模型非常适合测试药物的功效，这些药物旨在 阻止 HIV-i 性传播，并已广泛用于评估潜在的杀菌剂候选物。 此外，此处描述的实验以及与项目 III 中描述的实验的交叉验证， 可以识别潜在的功效、安全性和依从性生物标志物，为未来的临床试验提供信息。 在这个项目中，我们将使用这些已建立的模型来评估HIV-i进入的功效和兼容性 抑制剂（单独和组合）及其制剂。本研究将受到以下因素的影响和指导： 核心 A 内开展的工作，将涉及与科学家的广泛互动和合作 主导研究项目II和III。不同群体之间的互动将导致快速跟踪 用于在猕猴中进行评估的最有希望的抑制剂组合和制剂 模型（研究项目 III）。