Targeting HIV infection of the cns using gene delivery

利用基因传递靶向中枢神经系统的 HIV 感染

• 批准号: 6851717
• 负责人: DAVID S STRAYER
• 金额: $ 39.25万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6851717
• 关键词: AIDS dementia complex; AIDS therapy; antioxidants; apoptosis; biotechnology; clinical research; drug administration rate /duration; gene delivery system; gene therapy; human fetus tissue; human subject; laboratory rat; macrophage; microglia; monocyte; neural degeneration; neuroprotectants; technology /technique development; tissue /cell culture; transfection; transfection /expression vector; virus cytopathogenic effect

DESCRIPTION (provided by applicant): This study is proposed as a proof of principle: that gene delivery to the central nervous system can mitigate the harmful effects of HIV and HIV gene products on the brain. HIV encephalopathy is a potentially devastating complication of AIDS. There is no current therapy for CNS HIV infection: conventional antiretroviral drugs penetrate the brain poorly and anti-HIV CNS gene therapy has not been reported. Transgenes are currently available that are highly potent inhibitors of HIV entry and replication. Further, HIV envelope glycoprotein, gp120, has been implicated in neuron cell death via oxidant-related mechanisms in HIV encephalopathy. We have confirmed that gp120 causes apoptosis in human neurons, and that providing these cells with antioxidant enzymes, such as catalase protects them from apoptosis induced by HIV proteins. We submit that tools are now available to test gene delivery for the first time to address this problem, and propose to use gene delivery techniques to test the following hypothesis - Anti-oxidant and anti-HIV transgenes can protect cns cells from HIV and neural apoptosis caused by HIV gene products. To test this hypothesis, we will use as tools gene delivery vehicles derived from Tag-deleted SV40 (rSV40s). These vectors efficiently transduce key CNS cell targets for HIV and neurotoxicity induced by HIV, i.e., microglia, neurons, and monocyte-derived macrophages (MDM). We propose 4 aims: 1. Identify longitudinally optimal transgenes individually and in combination to inhibit HIV in CNS cells 2. Assess CNS and peripheral routes of administration to deliver rSV40s to the brain most effectively 3. Measure the ability of anti-CCR5 genes delivered in vivo to reduce MDM and microglial CCR5 gene delivery in vitro and in vivo to apoptosis-induced products. Despite the frequency and severity of CNS HIV infection, people with HIV encephalopathy have few treatment options. We propose to address this therapeutic challenge using gene delivery to the CNS, both to protect the brain from HIV infection and to mitigate HIV-induced CNS dysfunction.

描述（由申请人提供）：本研究旨在证明原理：将基因传递到中枢神经系统可以减轻 HIV 和 HIV 基因产物对大脑的有害影响。 HIV 脑病是艾滋病的一种潜在的破坏性并发症。目前还没有针对中枢神经系统HIV感染的治疗方法：传统的抗逆转录病毒药物很难渗透到大脑中，并且抗HIV中枢神经系统基因治疗尚未见报道。目前转基因是艾滋病毒进入和复制的高效抑制剂。此外，HIV 包膜糖蛋白 gp120 在 HIV 脑病中通过氧化相关机制与神经元细胞死亡有关。我们已经证实，gp120 会导致人类神经元细胞凋亡，并且为这些细胞提供抗氧化酶（例如过氧化氢酶）可以保护它们免受 HIV 蛋白诱导的细胞凋亡。我们提出，现在首次有工具可以测试基因传递来解决这个问题，并建议使用基因传递技术来测试以下假设：抗氧化剂和抗HIV转基因可以保护中枢神经系统细胞免受HIV感染以及HIV基因产物引起的神经细胞凋亡。为了检验这一假设，我们将使用衍生自标签删除的 SV40 (rSV40s) 的基因传递载体作为工具。这些载体有效转导 HIV 和 HIV 诱导的神经毒性的关键 CNS 细胞靶标，即小胶质细胞、神经元和单核细胞源性巨噬细胞 (MDM)。我们提出了 4 个目标： 1. 单独和组合识别纵向最佳转基因，以抑制 CNS 细胞中的 HIV 2. 评估 CNS 和外周给药途径，以最有效地将 rSV40 递送至大脑 3. 测量体内递送的抗 CCR5 基因在体外和体内减少 MDM 和小胶质细胞 CCR5 基因递送诱导细胞凋亡的能力 产品。尽管中枢神经系统艾滋病毒感染的频率和严重程度很高，但患有艾滋病毒脑病的人几乎没有治疗选择。我们建议通过向中枢神经系统传递基因来解决这一治疗挑战，既可以保护大脑免受艾滋病毒感染，又可以减轻艾滋病毒引起的中枢神经系统功能障碍。