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）具有针对人类免疫缺陷的广泛频谱活性病毒（HIV）类型1和2，单纯疱疹病毒2型（HSV-2）和丙型肝炎病毒（HCV）（1-4）。基于格里菲斯的局部杀菌剂配方提供了用作多功能，非 - 基于抗逆转录病毒的方法，可预防HIV-1和流行病学上连接的感染。项目2 目的是表明含有直肠菌皮剂的GRFT在直肠HIV传播的恒河猕猴模型。这些研究被设计为与项目3中提出的人类临床研究的补充。我们有三个具体的目标： AIM 1是评估GRFT的安全性，药代动力学和药效学（PK/PD）卡博波尔凝胶。我们将在成年男性恒河猴中进行三阶段安慰剂控制的PK/PD研究带有GRFT直肠凝胶配方的猕猴和由Core B提供的匹配的安慰剂凝胶。拟议的猕猴研究旨在解决有关的特定翻译问题 GRFT暴露后粘膜环境的免疫毒性和健康。有利的阶段1 结果包括在直肠液中检测活性HIV-1抑制浓度的GRFT和可接受的临床安全指标，该指标允许进展到功效阶段2。经验丰富的动物的GRFT治疗将使我们能够确定是否存在免疫力 GRFT会影响产品功效。第3阶段将在SHIV感染中测试GRFT和安慰剂产品动物，我们将比较在实验动物和对照动物中分散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。我们将使用多路复用的免疫测定和基因表达阵列测量炎症免疫反应的标记。高度敏感 Kristina Broliden教授的实验室将应用免疫组织化学（IHC）技术比较HIV靶细胞的数量，分布和激活状态和HIV的表达受体靶标CD4，CCR5，DC-SIGN和LANGERIN以及直肠上上皮完整性的标记用GRFT活跃药物或匹配的安慰剂治疗的动物的活检。流式细胞仪分析还将在活检组织中列举和表型淋巴细胞。目标3是评估使用系统生物学方法的直肠粘膜环境的GRFT治疗利用现代质谱蛋白质组学测定法比较组织和直肠分泌物从接受活性药物与安慰剂的动物，并评估GRFT治疗的效果在治疗动物的直肠菌群上。