Combination HIV Antiretroviral Rectal Microbicide Program

联合HIV抗逆转录病毒直肠杀菌剂(CHAME)计划满足了开发一种安全有效的直肠杀菌剂的迫切需要，以防止通过无保护的肛交获得艾滋病毒感染。该项目的总体目标是开发一种针对直肠的抗逆转录病毒微杀菌剂组合。候选杀微生物剂将包括替诺福韦、UC781以及替诺福韦和UC781的组合物。该方案有三个科学项目和三个科学核心来支持这一目标。项目1将使用包括结直肠细胞系和人体肠道外植体组织在内的一系列分析方法对杀菌剂的安全性和有效性进行临床前评估，并将由匹兹堡大学的Charlene Dezzutti博士进行。项目2将利用最近开发的艾滋病毒感染的转基因小鼠模型来评估产品在体内动物模型中的疗效，该项目将由德克萨斯大学的Victor Garcia-Martinez博士承担。项目3将进行一系列第一阶段前的人体研究，提供关于候选杀微生物剂的安全性、药代动力学和有效性的初步数据。这些研究的一个特别优势将是能够对接触过体内杀微生物剂产品的参与者的肠道外植体进行体外/体外感染研究。临床研究将在匹兹堡大学、加州大学洛杉矶分校和约翰霍普金斯大学医学院进行。核心A将为这项研究提供行政支助。CORE B将提供监管和信息学支持，并将由亨利·加伯尼克博士指导，他是Conrad的执行董事，Conrad是我们这次提交报告的企业赞助商。总部设在匹兹堡大学的核心C将成为配方开发核心。CORE C将由Lisa Rohan博士领导，并将开发直肠专用配方，将在项目1-3的迭代过程中进行评估。希望到该计划结束时，将产生一种或多种直肠特异性抗逆转录病毒微杀菌剂，可在未来的第一阶段直肠安全性研究中进行临床评估。

The Combination HIV Antiretroviral Rectal Microbicide (CHARM) program addresses the critical need to develop a safe and effective rectal microbicide for the prevention of HIV infection acquired through unprotected anal intercourse. The overall goal of the project is to develop a rectal specific formulation of a combination antiretroviral microbicide. The candidate microbicides will include tenofovir, UC781, and a combination of tenofovir and UC781. The Program has three scientific projects and 3 scientific cores to support this goal. Project 1 will undertake the preclinical evaluation of microbicide safety and efficacy using a range of assays including colorectal cell lines and human intestinal explant tissue and will be conducted by Dr. Charlene Dezzutti at the University of Pittsburgh. Project 2 will exploit a recently developed transgenic murine model of HIV infection to evaluate product efficacy in an in vivo animal model and will be undertaken by Dr. Victor Garcia-Martinez at the University of Texas. Project 3 will undertake a series of pre-Phase 1 human studies that will provide preliminary data on the safety, pharmacokinetics, and efficacy of the microbicide candidates. A particular strength of these studies will be the ability to conduct ex vivo / in vitro infection studies on intestinal explants from participants who have been exposed to the microbicide product in vivo. The clinical studies will be undertaken at the University of Pittsburgh, UCLA, and the Johns Hopkins School of Medicine. Core A will provide administrative support for the study. Core B will provide regulatory and informatics support and will be directed by Dr. Henry Gabelnick who is the Executive Director of CONRAD, our corporate sponsor for this submission. Core C, based at the University of Pittsburgh, will be the Formulation Development Core. Core C will be led by Dr. Lisa Rohan and will develop rectal specific formulations that will be evaluated in an iterative process in Projects 1-3. It is hoped that by the end of the program, one or more rectal specific antiretroviral microbicides will have been generated that can be clinically evaluated in future Phase 1 rectal safety studies.