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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 由于目前批准的药物无法在中枢神经系统中获得足够的浓度，无法在持续的一段时间内完全抑制病毒复制，因此人们担心大脑可以作为HIV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，称为艾滋病痴呆症综合体。 HIV诱导的中枢神经系统功能障碍发生在HIV感染儿童中高频。这个问题沿两个方面解决了。 首先，将新的抗HIV药物递送到中枢神经系统的合理优化将需要对血脑屏障（BBB）作用的定量，机械理解。 这些药物的BBB不仅是被动的渗透性障碍，而且还包括许多代谢性酶和脑毛细血管内的外排转运蛋白。 在AIM 1中，我们量化了脑毛细血管内皮细胞中的代谢和运输过程，这构成了二乙氧基核苷反向转录酶抑制剂和抗HIV剂的蛋白酶抑制剂的某些代表的BBB。 在我们的实验室中，初步数据表明，蛋白酶抑制剂和RT抑制剂脑摄取可能受到BBB中转运蛋白的ATP结合纸盒的成员的限制。 其次，我们希望进行旨在通过加强CNS递送使用现有药物组合来改善治疗的体内研究。 在AIM 2中，我们将测试以下假设：在联合治疗中，可以通过调节BBB来实现CNS浓度较高的抗HIV剂（Didanosine和Indinavir），以抑制蛋白酶抑制剂外排（使用P-糖蛋白的抑制剂），并通过使用适当的RT抑制RT抑制RT抑制RT抑制RT抑制RT抑制RT抑制RT抑制RT抑制RT抑制RT抑制剂（E. E. CNS靶向的Didanosine的前药）。 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AIM 3中，我们将在感染的HIV-2（HIV-2 287）中感染的婴儿猕猴中进行测试，无论是否改善CNS在组合疗法中的CNS递送和Indinavir是否会减少CNS中的HIV病毒载荷，减少CNS损害，并减少CNS作为HIV SANCTARE的作用。