Project 3: PREVENT: A first-in-human clinical trial of Griffithsin, an HIV entry

预防计划的首要目标是开发一种Griffithsin（GRFT）直肠 在接受性肛交（RAI）前使用凝胶，以降低感染艾滋病毒的风险 男男性行为者（MSM）感染。项目3将进行一项随机， 安慰剂对照1期前人体研究，以测量GRFT安全性， 药代动力学（PK）和药效学（PD）。我们将招募18名健康男性 参与一项前瞻性试验，以评价GRFT卡波姆凝胶与匹配的 2：1随机化设计中的安慰剂。该研究将解决传统产品安全问题 和PK参数，但我们也将评估产品对适应性 通过进行三个阶段的研究来对GRFT免疫。第一阶段将涉及一个单一的 药物暴露在第2和第3阶段，男性将接受5剂凝胶产品， 间隔两周洗脱期的连续天数。直肠活检和其他 在基线和第1-3阶段采集的样本将用于表征粘膜 对GRFT的应答，包括HIV靶细胞的计数和 直肠中代表性的HIV受体和上皮连接蛋白 免疫组织化学和流式细胞术。活检也将用于PD 通过用HIV-1离体激发组织进行评估。此外，我们还将聘请 系统生物学方法，包括转录组学、蛋白质组学和微生物组学 分析，分析GRFT治疗对粘膜环境的总体影响 在直肠里

The overarching goal of the PREVENT Program is to develop a Griffithsin (GRFT) rectal gel that could be used prior to receptive anal intercourse (RAI) to reduce the risk of HIV infection by men who have sex with men (MSM). Project 3 will conduct a randomized, placebo-controlled pre-Phase 1 human study to measure GRFT safety, pharmacokinetics (PK) and pharmacodynamics (PD). We will recruit 18 healthy men to participate in a prospective trial to evaluate GRFT carbopol gel versus a matched placebo in a 2:1 randomization design. The study will address traditional product safety and PK parameters, but we will also evaluate the effect of the product on adaptive immunity to GRFT by conducting a three stage study. The first stage will involve a single drug exposure. In Stages 2 and 3, men will receive 5 doses of gel product on consecutive days separated by a two week washout period. Rectal biopsies and other samples taken at baseline and during Stages 1-3 will be used to characterize mucosal responses to GRFT including enumeration of HIV target cells and detection of representative HIV receptors and epithelial junction proteins in the rectumby immunohistochemistry and flow cytometry. The biopsies will also be used for a PD assessment by ex vivo challenge of the tissue with HIV-1. Additionally, we will employ a systems biology approach, including transcriptomics, proteomics and microbiome analysis, to analyze the global impact of GRFT treatment on the mucosal environment in the rectum.