Clinical Studies

项目3的计划申请将测试多胺生物合成抑制剂（PBIs）的治疗， HIV相关性痴呆（HAD）基于巨噬细胞活化是HIV相关性痴呆的核心的假设。 这个疾病的发病过程。该项目将设在夏威夷艾滋病临床研究中心内 项目（HACCP，PI：Cecilia Shikuma）夏威夷大学John A.伯恩斯医学院，并将 与Pathologica中心核心实验室密切合作进行（项目1，核心B和C） 以及在哈佛进行的猿PBI试验（项目2）。项目3将利用来自 我们的NINDS资助的夏威夷艾滋病毒老化队列（HAHC），并产生体外测试数据， 来自HAD患者的活化的M/MO优先被PBI杀死。同时，我们将确定 艾滋病认知障碍患者的实时使用的简化组合神经心理 试验（NPZ-4）显示与我们患者的HAD诊断高度相关。在这些患者中，我们将 定义与以下疾病相关的独特血液M/MO基因和蛋白质表达模式（“ProMac谱”） 神经认知功能障碍最后，与我们的合作者NIMH和FDA密切合作，我们建议 从在NPZ-4测试中表现不佳的HAHC参与者中招募HAD受试者， 第二年的下半年，一项针对HAD的PBI药物的1期临床试验。 这项建议的优势在于我们现有的艾滋病毒临床试验基础设施，我们的神经认知特征良好， 患者和库存标本资源的夏威夷老龄与艾滋病毒队列，和 我们团队的翻译研究专业知识，与项目之间密切合作的记录 investigators.提出的具体目标将扩大我们对HAD发病机制的认识， 评估一类化合物的安全性和潜在功效，特别是针对 可能是HAD发展的核心机制。 具体目的1）利用库存样本，在体外确定所选PBI的杀伤潜力 针对HAD受试者的活化M/MO;并评估各种因素（HIV DNA、新活化 流动标志物）可能与其功效相关。待检验的假设：1）PBIs将证明有效 HAD受试者的活化M/MO的杀伤，2）活化M/MO中的高HIV DNA将与 3）高水平的新型活化流动标志物将与通过PBIs增强的杀伤相关， PBI。具体目标2）定义“ProMac谱”（血液M/MO基因和蛋白质表达模式） 使用在夏威夷内实时捕获的新鲜标本， 艾滋病毒老化队列，并评估PBI对具有此特征的M/MO的杀伤潜力。 1）在从艾滋病毒感染者中分离出的M/MO中将发现独特的“ProMac特征”， 具有神经认知功能障碍的受试者，2）具有这种“ProMac特征”的M/MO将优先被以下方法杀死： PBI。具体目标3）在患有HAD的个体中利用PBI药物进行I期临床试验。 待检验的假设1）HAD患者接受的PBI将安全耐受，并将导致 指示持续活化的M/MO表型的生物标志物减少。

Project 3 of the program application will test polyamine biosynthesis inhibitors (PBIs) for the treatment of HlV-associated dementia (HAD) based on the hypothesis that macrophage activation is central to the pathogenesis of this disease process. This project will be housed within the Hawaii AIDS Clinical Research Program (HACRP, PI: Cecilia Shikuma) University of Hawaii John A. Burns School of Medicine, and will be performed in close collaboration with the central core laboratory at Pathologica (Project 1, Cores B and C) and with the simian PBI trials conducted at Harvard (Project 2). Project 3 will utilize banked specimens from our NINDS-funded Hawaii Aging with HIV Cohort (HAHC) and generate data in vitro testing whether HIV-infected activated M/MOs from HAD patients are preferentially killed by PBIs. In tandem, we will identify patients with HIV cognitive impairment in real-time using an abridged combination of neuropsychological tests (NPZ-4) shown to correlate highly with the diagnosis of HAD in our patients. In these patients, we will define the unique blood M/MO gene and protein expression pattern ("ProMac Profile") associated with neurocognitive dysfunction. Finally, working closely with our collaborators, NIMH and the FDA, we propose to recruit subjects with HAD from HAHC participants who performed poorly on NPZ-4 testing, and launch, in the later half of the second year of funding, a phase 1 clinical trial of a PBI drug targeting HAD. The strengths of this proposal lie in our existing HIV clinical trials infrastructure, our neurocognitively well-characterized patient and banked specimen resources of the Hawaii Aging with HIV Cohort, and the translational research expertise of our team with a track record of close collaboration among the Program investigators. The specific aims as proposed will extend our knowledge of the pathogenesis of HAD and assess the safety and potential efficacy of a class of chemical compounds specifically directed against the likely central mechanism involved in the development of HAD. Specific Aim 1) Utilizing banked specimens, to determine in vitro the killing potential of the selected PBI(s) against activated M/MOs from subjects with HAD; and to assess various factors (HIV DNA, novel activation flow markers) potentially related to its efficacy. Hypothesis to be tested: 1) PBIs will demonstrate effective killing of activated M/MOs from HAD subjects, 2) High HIV DNA within activated M/MOs will correlate to enhanced killing by PBIs, 3)High levels of novel activation flow markers will correlate to enhanced killing by PBIs. Specific Aim 2) To define the "ProMac profile" (blood M/MO gene and protein expression patterns) associated with neurocognitive impairment using fresh specimens captured in real-time within the Hawaii Aging with HIV Cohort, and to evaluate the killing potential of PBIs against M/MOs with this profile. Hypotheses to be tested 1) A unique "ProMac profile" will be found in M/MOs isolated from HIV-infected subjects with neurocognitive dysfunction, 2) M/MOs with this "ProMac profile" will be preferentially killed by PBIs. Specific Aim 3)To conduct Phase 1 clinical trials utilizing a PBI drug in individuals with HAD. Hypothesis to be tested 1) PBIs given to patients with HAD will be safely tolerated and will result in a decrease in biomarker(s) indicative of a persistently activated M/MO phenotype.