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: 7037421
• 负责人: DAVID S STRAYER
• 金额: $ 38.33万
• 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/7037421
• 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）：这项研究是作为原理证明的：向中枢神经系统递送的基因可以减轻HIV和HIV基因产物对大脑的有害影响。 HIV脑病是艾滋病的潜在毁灭性并发症。目前尚无针对中枢神经系统HIV感染的治疗：常规抗逆转录病毒药物渗透到大脑较差，抗HIV CNS基因疗法尚未报道。当前可用的转基因是高度有效的HIV进入和复制抑制剂。此外，HIV包膜糖蛋白GP120通过HIV脑病中的氧化剂相关机制与神经元细胞死亡有关。我们已经证实，GP120会导致人神经元凋亡，并为这些细胞提供抗氧化剂酶，例如过氧化酶保护它们免受HIV蛋白诱导的凋亡。我们认为工具现在可以首次测试基因输送以解决此问题，并建议使用基因递送技术来检验以下假设 - 抗氧化剂和抗HIV转基因可以保护CNS细胞免受HIV和HIV基因产物引起的神经凋亡。为了检验这一假设，我们将用作源自标签删除的SV40（RSV40）的工具基因输送车。这些载体有效地传递了HIV，即小胶质细胞，神经元和单核细胞衍生的巨噬细胞（MDM）引起的HIV引起的HIV和神经毒性的关键CNS细胞靶标。我们提出4个目标：1。单独识别纵向最佳的转基因，并结合抑制CNS细胞中的HIV 2。评估CNS和外围给药途径以最有效地向大脑传递RSV40s 3。测量3。 产品。尽管CNS HIV感染的频率和严重程度，但患有HIV脑病的人几乎没有治疗选择。我们建议使用向中枢神经系统递送基因递送基因，以保护大脑免受艾滋病毒感染的影响，并减轻HIV诱导的中枢神经系统功能障碍。