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: 8281541
• 负责人: ROBIN J SHATTOCK
• 金额: $ 3.48万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8281541
• 关键词: Animal Model; Biological Markers; Biological Models; Cell Culture Techniques; Cell model; Cells; Cervical; Clinical Trials; Collaborations; Dendritic Cells; Development; Drug Formulations; Epithelial; Epithelium; Evaluation; Event; Future; Genomics; Goals; HIV; HIV-1; Histocompatibility; Human; Individual; Infection; Infection prevention; Investigation; Knowledge; Langerhans cell; Learning; Length; Location; Macaca; Macaca mulatta; Measurement; Mediating; Modeling; Monitor; Mononuclear; Mucous Membrane; Mucous body substance; Outcome; Pathway interactions; Pattern; Penetration; Performance; Phase; Phase III Clinical Trials; Physiological; Population; Process; Property; Research; Research Project Grants; Role; Safety; Savings; Science; Scientist; Seminal fluid; Series; Sexual Transmission; Solid; Solvents; System; T-Lymphocyte; Technology; Time; Tissue Model; Tissues; Vagina; Vaginal Ring; Validation; Viral; Virus; Virus Diseases; Work; base; cell type; cellulose sulfate; chemokine; comparative; cost; cytokine; design; efficacy testing; efficacy trial; immune function; in vitro Model; in vivo; inhibitor/antagonist; innate immune function; macrophage; microbial; microbicide; particle; pathogen; pre-clinical; prevent; programs; receptor; rectal; research clinical testing; research study; response; simian human immunodeficiency virus; 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).

杀微生物剂在预防HIV-1粘膜传播中的潜在作用已经很清楚， 鉴定然而，对候选杀微生物剂进行严格的临床前评价对于选择 最好的化合物用于临床试验，因为这将最终节省成本和时间， 正式疗效试验的费用和时间长度。对进行疗效试验的担忧， 优化的杀微生物剂候选物已经通过最近失败或停止的III期试验（COL-2000）而得到强调。 1492，SAVVY和硫酸纤维素）;这些试验表明， 有效的杀微生物剂可能不像最初想象的那么容易。虽然单核细胞培养物和动物 模型可以为评价杀微生物剂、解剖学、生理学和生物学提供重要信息。 免疫学问题表明它们可能不能充分模拟在人粘膜组织中发生的事件。 因此，杀微生物剂候选物的临床前开发的综合计划要求： 可以从几个不同的模型系统中获得信息。因此沙托克博士和罗比亚尼的小组 已经开发了人类粘膜组织的HIV-1感染的最早期事件的体外模型， 树突状细胞驱动的HIV-1传播。这些模型非常适合于测试设计用于 阻断HIV-1的性传播，并已被广泛用于评估潜在的杀微生物剂候选物。 此外，这里描述的实验和与项目III中描述的实验的交叉验证， 可以确定潜在的生物标志物的疗效，安全性和依从性，可以告知未来的临床试验。 在这个项目中，我们将使用这些已建立的模型来评估HIV-i进入的有效性和相容性 抑制剂（单独和组合）及其制剂。这项研究将受到以下因素的影响和指导： 在核心A内进行的工作，将涉及与科学家的广泛互动和合作 领导研究项目II和III。不同群体之间的互动将导致快速跟踪 最有前途的抑制剂组合和制剂，用于在猕猴中进行评价 模型（研究项目III）。