CNS DRUG DELIVERY STRATEGIES TARGETING THE HIV SANCTUARY

针对艾滋病毒庇护所的中枢神经系统药物输送策略

• 批准号: 8172776
• 负责人: RODNEY J.Y. HO
• 金额: $ 46.53万
• 依托单位: UNIVERSITY OF WASHINGTON
• 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 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172776
• 关键词: AIDS Dementia Complex; Address; Adult; Anti-HIV Agents; Binding; Blood - brain barrier anatomy; Blood capillaries; Brain; Capillary Endothelial Cell; Child; Combined Modality Therapy; Computer Retrieval of Information on Scientific Projects Database; Data; Didanosine; Dideoxynucleosides; Drug Combinations; Drug Delivery Systems; Drug Kinetics; Enzymes; Family; Frequencies; Functional disorder; Funding; Glycoproteins; Grant; HIV; HIV-2; Impaired cognition; Indinavir; Infant; Institution; Laboratories; Macaca; Metabolic; Modeling; Motor; Permeability; Pharmaceutical Preparations; Primates; Prodrugs; Protease Inhibitor; Research; Research Personnel; Resources; Reverse Transcriptase Inhibitors; Rodent; Role; Source; Testing; Time; Training; Transport Process; United States National Institutes of Health; Viral; Viral Load result; capillary; improved; in vivo; inhibitor/antagonist; member; uptake

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Due to the inability of currently approved drugs to attain sufficient concentrations in the CNS to completely suppress viral replication over a sustained period of time, concern is growing that the brain may serve as an HIV sanctuary. Adults with advanced HIV may suffer a loss of cognitive and motor function referred to as AIDS dementia complex. HIV induced CNS dysfunction occurs with high frequency in HIV infected children. The problem is addressed along two fronts. First, the rational optimization of delivery of new anti-HIV drugs to CNS will require a quantitative, mechanistic understanding of the role of the blood brain barrier (BBB). The BBB for these agents is not only a passive permeability barrier, but also consists of a host of metabolic-enzymes and efflux transporters localized within the brain capillaries. In aim 1, we quantify the metabolic and transport processes in brain capillary endothelial cells, which constitute the BBB for selected representatives of the dideoxynucleoside reverse-transcriptase inhibitor and protease inhibitor classes for anti-HIV agents. In our laboratories, preliminary data suggested that both protease inhibitor and RT inhibitor brain uptake may be restricted by members of the ATP binding cassette super-family of transporters within the BBB. Secondly, we wish to conduct in vivo studies aimed at improving therapy using existing drug combinations through enhanced CNS delivery. In aim 2, we will test the hypothesis that significantly higher CNS concentrations of anti-HIV agents (didanosine and indinavir) can be attained in combination therapy by modulation of the BBB to inhibit protease inhibitor efflux (with an inhibitor of p-glycoprotein) and by enhancing RT inhibitor uptake using an appropriate prodrug strategy (e.g., 6-Cl-ddp, a CNS-targeted prodrug of didanosine). This study will be done in vivo pharmacokinetic and CNS uptake studies in both rodent and primate models. In aim 3, we will test in infant macaques infected with a neurovirulent train of HIV-2 (HIV-2 287) whether improving the CNS delivery of didanosine and indinavir in combination therapy will reduce HIV viral load in the CNS, reduce CNS damage, and diminish the role of the CNS as an HIV sanctuary.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 中心，不一定是研究者的机构。 由于目前批准的药物无法在中枢神经系统中达到足够的浓度，从而在持续一段时间内完全抑制病毒复制，人们越来越担心大脑可能成为艾滋病毒的避难所。 患有晚期艾滋病毒的成年人可能会丧失认知和运动功能，称为艾滋病痴呆症。 HIV引起的中枢神经系统功能障碍在感染HIV的儿童中发生的频率很高。这个问题是从两个方面解决的。 首先，合理优化新型抗 HIV 药物向 CNS 的输送需要对血脑屏障 (BBB) 的作用有定量、机制的了解。 这些药物的血脑屏障不仅是被动渗透屏障，而且还由位于脑毛细血管内的大量代谢酶和外排转运蛋白组成。 在目标 1 中，我们量化了脑毛细血管内皮细胞的代谢和运输过程，这些细胞构成了抗 HIV 药物的双脱氧核苷逆转录酶抑制剂和蛋白酶抑制剂类别的选定代表的 BBB。 在我们的实验室中，初步数据表明，蛋白酶抑制剂和 RT 抑制剂的大脑摄取可能受到 BBB 内转运蛋白 ATP 结合盒超家族成员的限制。 其次，我们希望进行体内研究，旨在通过增强中枢神经系统输送来改善现有药物组合的治疗。 在目标 2 中，我们将检验以下假设：通过调节 BBB 抑制蛋白酶抑制剂外流（使用 p-糖蛋白抑制剂），联合治疗中可以显着提高抗 HIV 药物（地达诺辛和茚地那韦）的 CNS 浓度，并且通过使用适当的前药策略（例如，6-Cl-ddp，一种中枢神经系统靶向的去羟肌苷前药）来增强 RT 抑制剂的摄取。 这项研究将在啮齿动物和灵长类动物模型中进行体内药代动力学和中枢神经系统摄取研究。 在目标 3 中，我们将在感染神经毒力 HIV-2 (HIV-2 287) 的幼年猕猴中进行测试，在联合治疗中改善去羟肌苷和茚地那韦的 CNS 递送是否会减少 CNS 中的 HIV 病毒载量，减少 CNS 损伤，并削弱中枢神经系统作为艾滋病毒避难所的作用。