Macrophage Targeted Therapy for HAD and HIV Disease

描述（由申请人提供）：该计划项目资助的总体目标是通过研究猿猴模型和随后的HIV相关性痴呆（HAD）人类，确定HIV感染的巨噬细胞在晚期HIV疾病发病机制中的作用，以及长寿的HIV感染的巨噬细胞储库。用一类新的药物（多胺生物合成抑制剂，PBI）在体外进行的初步研究表明，选择性杀死HAD和晚期HIV疾病患者的含HIV DNA的血液巨噬细胞。在恒河猴猴免疫缺陷病毒（SIV）脑炎诱导模型中使用PBI的初步研究显示，在三次注射药物后，体内含有SIV的血液和脑组织巨噬细胞选择性丧失。拟议的研究将由Michael麦格拉思医学博士协调，PhD.他在评估MO在HIV疾病发病机制和巨噬细胞靶向药物开发中的作用方面有着悠久的历史。该计划项目将包括研究SIV疾病的卓越中心（哈佛的Ken威廉姆斯），体内抗HIV和痴呆药物的临床评价（Valcour，Shikuma，Shiramizu，夏威夷大学），以及开发HIV DNA库和巨噬细胞相关疾病的新诊断和治疗方法（Ken Hadlock，Pathologica LLC，Burlingame CA）。该计划符合RFA-AI-06-009公告的要求，因为它结合了旨在开发新型HIV疗法的学术和企业研究计划，整合了动物和人类系统的临床前和临床计划。三个项目，一个在每个中心和3个核心提出了计划项目赠款。该项目的具体组成部分包括：项目1）PL：Ken Hadlock，Pathologica LLC。多胺生物合成抑制剂（PBI）在杀死/调节HIV感染的巨噬细胞中的机制，项目2）PL：Ken威廉姆斯，哈佛。HAD猴模型中的PBI活性研究，项目3）晚期HIV疾病和HAD患者中HIV DNA库的临床前和临床研究，管理核心A）UCSF主任Michael麦格拉思。该核心对三个项目中定义的所有研究和另外两个核心进行监督和协调，试验核心B）负责人：Ken Hadlock，Pathologica，LLC。该核心计划为所有三个项目提供定量分子检测支持。PBI药物生产核心C）总监：Ken Hadlock，Pathologica，LLC。该核心为所有三个项目提供药物，从项目1和3的临床前研究到动物（项目2）和人类（项目3）的临床研究。

DESCRIPTION (provided by applicant): The overall goal of this program project grant is to define the role that HIV infected macrophages play in the pathogenesis of advanced HIV disease, and the long lived HIV infected macrophage reservoir by studying simian models and subsequently humans with HIV associated dementia (HAD). Preliminary studies with a novel class of drugs (polyamine biosynthesis inhibitors, PBI) in vitro showed selective killing of HIV DNA containing blood macrophages from patients with HAD and advanced HIV disease. Initial studies with a PBI in a rhesus monkey simian immunodeficiency virus (SIV) encephalitis induction model showed selective loss of SIV containing blood and brain tissue macrophages in vivo after three injections of drug. The proposed studies will be coordinated by Michael McGrath M.D., PhD. at UCSF who has a long history of evaluating the role of MOs in the pathogenesis of HIV disease and in macrophage targeted drug development. This program project will incorporate centers of excellence for studying SIV disease in vivo (Ken Williams, Harvard), clinical evaluation of anti-HIV and dementia drugs in vivo (Valcour, Shikuma, Shiramizu, U of Hawaii), and the development of novel diagnostic and therapeutic approaches to the HIV DNA reservoir and macrophage associated diseases (Ken Hadlock, Pathologica LLC, Burlingame CA.) This program fulfills requirements of the RFA-AI-06-009 announcement in that it incorporates both academic and corporate research programs aimed at developing novel HIV therapies, integrating both preclinical and clinical programs in animal and human systems. Three projects, one at each center and 3 cores are proposed for the program project grant. Specific components of this program include: Project 1) PL: Ken Hadlock, Pathologica LLC. Mechanism of polyamine biosynthesis inhibitors (PBI) in killing/regulation of HIV infected macrophages, Project 2) PL: Ken Williams, Harvard. Studies of PBI activities in simian models of HAD, Project 3) Preclinical and clinical studies of HIV DNA reservoir in patients with advanced HIV disease and HAD, Administrative Core A) Director Michael McGrath, UCSF. This core provides the oversight and coordination of all of the studies defined in the three projects and two other cores, Assay Core B) Director: Ken Hadlock, Pathologica, LLC. This core program provides quantitative molecular assay support for all three projects. PBI drug manufacture Core C) Director: Ken Hadlock, Pathologica, LLC. This core provides drug for use in all three projects, from the preclinical studies in Projects 1 and 3 to the clinical studies in animals (project 2) and humans (project 3).