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）：本研究拟作为原理证明：向中枢神经系统递送基因可减轻HIV和HIV基因产物对大脑的有害影响。艾滋病脑病是艾滋病的一种潜在的毁灭性并发症。目前尚无治疗中枢神经系统HIV感染的方法：常规抗逆转录病毒药物对大脑的渗透性较差，抗HIV中枢神经系统基因治疗尚未报道。目前可获得的转基因是HIV进入和复制的高效抑制剂。此外，HIV包膜糖蛋白gp 120通过HIV脑病中的氧化剂相关机制参与神经元细胞死亡。我们已经证实，gp 120导致人类神经元凋亡，并提供这些细胞与抗氧化酶，如过氧化氢酶保护他们免受艾滋病毒蛋白诱导的凋亡。我们提出，现在可以使用的工具来测试基因传递第一次来解决这个问题，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CNS细胞免受HIV和HIV基因产物引起的神经细胞凋亡。为了检验这一假设，我们将使用来自标签缺失的SV 40（rSV 40）的基因递送载体作为工具。这些载体有效地抑制HIV和HIV诱导的神经毒性的关键CNS细胞靶，即，小胶质细胞、神经元和单核细胞衍生的巨噬细胞（MDM）。我们提出4个目标：1。确定纵向最佳的转基因单独和组合，以抑制中枢神经系统细胞中的HIV 2。评估CNS和外周给药途径以最有效地将rSV 40递送至大脑3.测量体内递送的抗CCR 5基因在体外和体内减少MDM和小胶质细胞CCR 5基因递送至凋亡诱导产物的能力。尽管CNS HIV感染的频率和严重程度，但HIV脑病患者的治疗选择很少。我们建议使用基因递送到CNS来解决这一治疗挑战，既保护大脑免受HIV感染，又减轻HIV诱导的CNS功能障碍。