Clinical Studies

计划申请的项目3将测试多胺生物合成抑制剂(PBI)，用于治疗 HLV相关性痴呆(HAD)基于巨噬细胞激活是HLV相关性痴呆 这种疾病的发病过程。该项目将设在夏威夷艾滋病临床研究中心内 项目(HACRP，PI：Cecilia Shikuma)夏威夷大学约翰·A·伯恩斯医学院，将 与病理中心核心实验室密切合作(项目1，核心B和C) 以及在哈佛大学进行的猿猴PBI试验(项目2)。项目3将利用来自 我们由NINDS资助的夏威夷老龄化与艾滋病毒队列(HAHC)和生成数据的体外测试是否艾滋病毒感染 来自HAD患者的激活的M/MO优先被PBI杀死。同时，我们将确定 使用一种简化的神经心理学组合实时检测HIV认知障碍患者 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 定义与以下相关的独特血液M/MO基因和蛋白表达模式(ProMac Profile) 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参与者中招募患有HAD的受试者，并在 在资助的第二年下半年，一种PBI靶向药物的第一阶段临床试验发生了。 这项提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 夏威夷老年艾滋病毒队列患者和银行标本资源，以及 我们团队的翻译研究专业知识，在项目之间有密切合作的记录 调查人员。建议的具体目标将扩大我们对HAD和HAD发病机制的认识 评估一类化合物的安全性和潜在疗效 可能是参与HAD发展的中央机制。 具体目的1)利用文库标本，体外测定选定的PBI的杀伤能力(S) 抗HAD受试者激活的M/MOS；并评估各种因素(HIV DNA，新的激活 流动标记物)可能与其疗效有关。有待检验的假设：1)PBI将证明有效 从HAD受试者中杀死激活的M/MO，2)激活的M/MO中高HIV DNA将与 增强PBI的杀伤力，3)高水平的新激活流标记将与增强杀伤力相关 PBIS。具体目的2)确定“ProMac图谱”(血液M/MO基因和蛋白表达模式) 使用在夏威夷地区实时捕获的新鲜标本与神经认知障碍相关 与HIV队列一起老化，并使用此简档评估PBI对M/MOS的杀伤潜力。 有待检验的假设1)从HIV感染者分离的M/MOS中将发现独特的“ProMac图谱” 有神经认知功能障碍的受试者，2)具有此“ProMac特征”的M/MOS将优先被 PBIS。具体目标3)利用一种PBI药物在HAD患者身上进行第一阶段临床试验。 有待检验的假设1)给予HAD患者的PBI将被安全耐受，并将导致 生物标志物(S)的减少表明M/MO表型持续激活。

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.