Project 2: PREVENT Preclinical safety and efficacy studies

项目2：预防临床前安全性和有效性研究

基本信息

批准号：
8769379
负责人：
KENNETH E PALMER
金额：
$ 58.76万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8769379
关键词：
Address Adult Affect Affinity Anal Sex Animals Anti-Retroviral Agents Antiviral Agents Anus Attention Awareness Binding Biological Assay Biopsy CCR5 gene CD209 gene Carbopol Cell surface Cells Clinical Clinical Research Clinical Trials Clinical Trials Design Colorectal Communities Community Health Control Animal Data Data Set Detection Development Dose Drug Formulations Drug Kinetics Effectiveness Environment Enzyme-Linked Immunosorbent Assay Epithelial Epithelial Cells Exposure to Female Flow Cytometry Gel Gene Expression Goals HIV HIV-1 Health Hepatitis C virus Heterosexuals Human Human Herpesvirus 2 Human Volunteers Immune Immune response Immunity Immunoassay Immunohistochemistry Incidence Infection Laboratories Lectin Link Liquid substance Local Microbicides Lymphocyte Macaca Macaca mulatta Mass Spectrum Analysis Measures Metagenomics Methods Metric Modeling Mucous Membrane Mus Outcome Pharmaceutical Preparations Pharmacodynamics Phenotype Placebo Control Placebos Polysaccharides Population Prevention Proteins Proteomics Rectum Reporting Research Design Safety Sexual Transmission Staging Structure Surface Systems Biology Techniques Testing Tissues Trauma Vagina Viral Virus Diseases Virus Receptors Virus Shedding Woman base cohort crosslink design experience immunotoxicity in vivo inflammatory marker langerin male men who have sex with men microbial community microbicide microbiome novel placebo controlled study preclinical efficacy preclinical safety prevent product development protective efficacy rRNA Genes rectal rectal microbicide research clinical testing response safety testing simian human immunodeficiency virus transcriptomics transmission process

项目摘要

The antiviral lectin Griffithsin (GRFT) has broad spectrum activity against human immunodeficiency viruses (HIV) types 1 and 2, herpes simplex virus type 2 (HSV-2) and hepatitis C virus (HCV) (1-4). Griffithsin-based topical microbicide formulations offer the potential for use as a multipurpose, non- antiretroviral based method to prevent HIV-1 and epidemiologically linked infections. The Project 2 objective is to show that GRFT containing rectal microbicide products are safe and effective in the Rhesus macaque model of rectal HIV transmission. These studies are designed to be complementary to the human clinical studies proposed in Project 3. We have three specific aims: Aim 1 is to evaluate the safety, pharmacokinetics and pharmacodynamics (PK/PD) of GRFT carbopol gel. We will conduct a three stage placebo controlled PK/PD study in adult male Rhesus macaques with the GRFT rectal gel formulation and matched placebo gel supplied by Core B. The proposed macaque study is designed to address specific translational questions concerning immunotoxicity and health of the mucosal environment after GRFT exposure. Favorable stage 1 outcomes include detection of active HIV-1 inhibitory concentrations of GRFT in rectal fluids and acceptable clinical safety metrics, which allows progression to the efficacy Stage 2. Using a cohort of GRFT treatment experienced animals will allow us to determine whether pre-existing immunity to GRFT affects product efficacy. Stage 3 will test the GRFT and placebo products in SHIV infected animals, where we will compare amounts of virus shed in experimental versus control animals, providing an additional safety metric. Aim 2 is to assess the impact of GRFT treatment on the mucosal immune environment. We will use multiplexed immunoassays and gene expression arrays to measure markers of inflammatory immune responses. The highly sensitive immunohistochemistry (IHC) techniques refined in Prof. Kristina Broliden's laboratory will be applied to compare the number, distribution and activation state of HIV target cells and expression of HIV receptor targets CD4, CCR5, DC-SIGN and Langerin plus markers of epithelial integrity in rectal biopsies from animals treated with GRFT active drug or matched placebo. Flow cytometry analyses will also enumerate and phenotype lymphocytes in biopsy tissues. Aim 3 is to assess the impact of GRFT treatment on the mucosal environment in the rectum using a systems biology approach that utilizes modern mass spectrometry proteomics assays to compare tissues and rectal secretions from animals that receive active drug versus placebo, and to evaluate the effect of GRFT treatment on the rectal microbiota of treated animals.

抗病毒凝集素 Griffithsin (GRFT) 具有广谱的抗人类免疫缺陷活性病毒 (HIV) 1 型和 2 型、单纯疱疹病毒 2 型 (HSV-2) 和丙型肝炎病毒 (HCV) (1-4)。基于 Griffithsin 的外用杀菌剂制剂具有用作多用途、非杀菌剂的潜力。基于抗逆转录病毒的方法，预防 HIV-1 和流行病学相关感染。项目2 目的是证明含有直肠杀菌剂产品的 GRFT 在以下方面是安全有效的：直肠艾滋病毒传播的恒河猴模型。这些研究旨在补充项目 3 中提出的人体临床研究。我们有三个具体目标：目标 1 评估 GRFT 的安全性、药代动力学和药效学 (PK/PD) 卡波姆凝胶。我们将对成年雄性恒河猴进行三阶段安慰剂对照 PK/PD 研究使用 Core B 提供的 GRFT 直肠凝胶配方和匹配的安慰剂凝胶对猕猴进行实验。拟议的猕猴研究旨在解决有关的具体转化问题 GRFT 暴露后的免疫毒性和粘膜环境的健康。有利阶段1 结果包括检测直肠液中 GRFT 的活性 HIV-1 抑制浓度，以及可接受的临床安全指标，允许进展到疗效阶段 2。使用队列 GRFT 治疗经验丰富的动物将使我们能够确定是否预先存在免疫力 GRFT 影响产品功效。第三阶段将在 SHIV 感染者中测试 GRFT 和安慰剂产品动物，我们将比较实验动物和对照动物中排出的病毒量，提供额外的安全指标。目标 2 是评估 GRFT 治疗对粘膜免疫环境。我们将使用多重免疫测定和基因表达阵列测量炎症免疫反应的标志物。高度敏感的将应用 Kristina Broliden 教授实验室精制的免疫组织化学 (IHC) 技术比较HIV靶细胞的数量、分布和激活状态以及HIV的表达受体靶向 CD4、CCR5、DC-SIGN 和 Langerin 以及直肠上皮完整性标记物来自接受 GRFT 活性药物或匹配安慰剂治疗的动物的活检。流式细胞术分析还将对活检组织中的淋巴细胞进行计数和表型分析。目标 3 是评估影响使用系统生物学方法对直肠粘膜环境进行 GRFT 治疗，利用现代质谱蛋白质组学分析来比较组织和直肠分泌物来自接受活性药物与安慰剂的动物，并评估 GRFT 治疗的效果对治疗动物的直肠微生物群的影响。