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 将测试用于治疗以下疾病的多胺生物合成抑制剂 (PBI) HIV 相关痴呆 (HAD) 基于巨噬细胞激活是艾滋病毒相关性痴呆 (HAD) 的核心这一假设 本病的发病过程。该项目将隶属于夏威夷艾滋病临床研究中心 计划（HACRP，PI：Cecilia Shikuma）夏威夷大学约翰·伯恩斯医学院，并将 与 Pathologica 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 我们的 NINDS 资助的夏威夷艾滋病毒老龄化队列 (HAHC) 并生成体外测试是否感染艾滋病毒的数据 HAD 患者中激活的 M/MO 优先被 PBI 杀死。同时，我们将确定 使用神经心理学的简化组合实时检测患有艾滋病毒认知障碍的患者 测试 (NPZ-4) 与我们患者的 HAD 诊断高度相关。对于这些患者，我们将 定义与相关的独特的血液 M/MO 基因和蛋白质表达模式（“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 HAHC 参与者中招募在 NPZ-4 测试中表现不佳的 HAD 受试者，并在 资助第二年下半年，针对HAD的PBI药物进行1期临床试验。 该提案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 夏威夷艾滋病毒老龄化队列的患者和储存的标本资源，以及 我们团队的转化研究专业知识以及该计划之间密切合​​作的记录 调查人员。所提出的具体目标将扩展我们对 HAD 发病机制的了解， 评估专门针对该疾病的一类化合物的安全性和潜在功效 可能参与 HAD 发展的中心机制。 具体目标 1) 利用库存样本确定所选 PBI 的体外杀伤潜力 对抗来自 HAD 受试者的激活的 M/MO；并评估各种因素（HIV DNA、新的激活 流量标记）可能与其功效相关。待检验的假设：1）PBI 将证明是有效的 从 HAD 对象中杀死激活的 M/MO，2) 激活的 M/MO 中的高 HIV DNA 将与 PBI 增强杀伤作用，3）高水平的新型活化流标记物将与通过 PBI 增强杀伤作用相关 PBI。具体目标 2) 定义“ProMac 配置文件”（血液 M/MO 基因和蛋白质表达模式） 使用在夏威夷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，并评估 PBI 对具有此特征的 M/MO 的杀伤潜力。 待检验的假设 1) 在从 HIV 感染者中分离出的 M/MO 中将发现独特的“ProMac 配置文件” 具有神经认知功能障碍的受试者，2）具有此“ProMac配置文件”的M/MO将优先被杀死 PBI。具体目标 3) 利用 PBI 药物对 HAD 患者进行一期临床试验。 待检验的假设 1) 给予 HAD 患者的 PBI 将被安全耐受，并会导致 表明持续激活的 M/MO 表型的生物标志物减少。