Clinical Studies

临床研究

• 批准号: 8061611
• 负责人: Cecilia M. Shikuma
• 金额: $ 45.01万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8061611
• 关键词: Acquired Immunodeficiency Syndrome; Age; Aging; Anabolism; Biological Markers; Blood; Burn injury; Chemicals; Clinical Research; Clinical Trials; Collaborations; DNA; Data; Dementia; Development; Diagnosis; Disease; Drug Delivery Systems; Functional disorder; Funding; Gene Proteins; HIV; Hawaii; Housing; Impaired cognition; Impairment; In Vitro; Individual; Knowledge; Laboratories; Macrophage Activation; National Institute of Mental Health; Neurocognitive; Neuropsychological Tests; Participant; Pathogenesis; Patients; Pattern; Pharmaceutical Preparations; Phase I Clinical Trials; Phenotype; Polyamines; Process; Recruitment Activity; Research Infrastructure; Research Personnel; Resources; Safety; Specimen; Testing; Time; Translational Research; Universities; Work; base; cohort; in vitro testing; inhibitor/antagonist; killings; medical schools; novel; programs; protein expression; time use

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.

该计划申请的项目3将测试多胺生物合成抑制剂（PBI）的治疗 HLV相关痴呆（HAD）基于以下假设：巨噬细胞激活对 这种疾病过程的发病机理。该项目将安置在夏威夷艾滋病临床研究中 计划（HACRP，PI：Cecilia Shikuma）夏威夷大学约翰·A·伯恩斯医学院，将是 与病理学中心核心实验室密切合作（项目1，核B和C） 以及在哈佛大学进行的猿猴PBI试验（项目2）。项目3将利用来自银行的标本 我们的Ninds资助的HIV队列（HAHC）老化的夏威夷老化，并在体外测试中生成数据是否感染了HIV 来自HAT患者的激活的M/MOS被PBI杀死。同时，我们将确定 使用神经心理学的删节组合实时实时艾滋病毒认知障碍患者 证明与患者的诊断相关的测试（NPZ-4）。在这些患者中，我们将 定义与与 神经认知功能障碍。最后，与我们的合作者NIMH和FDA紧密合作，我们建议 来自HAHC参与者的招募受试者，他们在NPZ-4测试中表现不佳，并启动， 资金第二年后的后半段是PBI药物靶向的1期临床试验。 该提案的优势在于我们现有的HIV临床试验基础设施，即我们的神经认知良好的表征 夏威夷老化的患者和银行标本资源与艾滋病毒队列以及 我们团队的翻译研究专业知识，并具有该计划密切合作的记录 调查人员。拟议的具体目的将扩展我们对HAT和HAT的发病机理的了解 评估专门针对该化合物的一类化合物的安全性和潜在功效 可能参与HAD的发展中心机制。 特定目的1）利用库存的标本，以确定所选PBI的杀戮潜力 反对来自HAD受试者的激活的M/MOS；并评估各种因素（HIV DNA，新型激活 流量标记）可能与其功效有关。要测试的假设：1）PBI将证明有效 杀死受试者激活的M/MOS，2）激活的M/MOS中的高HIV DNA将与 PBIS增强杀戮，3）高水平的新型激活流量标记将与增强的杀戮相关 PBIS。特定目的2）定义“ Promac概况”（血液M/mo基因和蛋白质表达模式） 使用夏威夷实时捕获的新鲜标本与神经认知障碍相关 使用HIV队列衰老，并通过此概况评估PBI对M/MOS的杀戮潜力。 要测试的假设1）在从HIV感染的M/MOS中找到独特的“ Promac概况” 神经认知功能障碍的受试者2）M/MOS具有此“ Promac概况”的M/MOS将优先杀死 PBIS。具体目的3）在患有HAT的个体中使用PBI药物进行1期临床试验。 要测试的假设1）给予患者的PBI将被安全耐受，并将导致 降低生物标志物（s）表示持续激活的m/mo表型。