RHESUS SV40 ANTIOXIDANT GENE DELIVERY TO THE CNS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 神经艾滋病是艾滋病毒感染的一种常见且令人虚弱的后果。目前还没有公认的治疗神经艾滋病的方法。中枢神经系统HIV-1感染对神经元的主要毒性被认为是HIV-1蛋白引起的氧化损伤，主要是包膜蛋白(Gp120)和TAT。将抗氧化剂基因输送到中枢神经系统可能是一种有效的方法，不仅可以治疗神经艾滋病，还可以治疗其他被认为涉及氧化剂相关神经毒性的退行性疾病。在体外，暴露于HIV-1gp120或Tat的人或啮齿动物神经元发生凋亡，而SV(SOD1)和/或SV(GPX1)的转导几乎完全保护了细胞的凋亡。在体内，实质内或脑室内接种这些载体会导致这些抗氧化酶的长期表达，并类似地保护局部免受重组HIV-1gp120和Tat的攻击。这个试点项目的最终目标是研究重组标签缺失的SV40衍生载体(RSV40)在中枢神经系统导向的基因传递中的应用，以治疗神经艾滋病和其他与氧化应激有关的神经退行性疾病。这一过程的第一步，也是这些研究的直接目标，是确认rSV40将神经保护性抗氧化酶和抗慢病毒转基因基因的表达安全地输送到灵长类动物大脑的能力。通过这样做，希望将组织培养中的人和啮齿动物CNS细胞产生的数据转化为灵长类动物模型，并在啮齿动物研究中记录rSV40基因向CNS传递的转导效率和安全性。这项研究中产生的数据将被用于随后的NIH拨款建议，以研究和优化铜/锌超氧化物歧化酶(SOD1)和谷胱甘肽过氧化物酶(GPX1)的rSV40基因传递，以治疗SIV引起的脑病。NIH提议进行神经艾滋病基因治疗的临床试验将紧随其后。这里提出的第一步是证明这些载体将转基因表达持久和安全地传递到灵长类中枢神经系统。

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. NeuroAIDS is a common and debilitating consequence of HIV infection. No accepted therapies exist for neuroAIDS. The major toxicity of CNS HIV-1 infection for neurons is thought to be oxidant damage caused by HIV-1 proteins, mainly envelope (gp120) and Tat. Antioxidant gene delivery to the CNS may be an effective approach to treating not only neuroAIDS but other degenerative diseases that are thought to involve oxidant-related neurotoxicity. In vitro, human or rodent neurons exposed to HIV-1 gp120 or Tat undergo apoptosis, from which transduction with SV(SOD1) and/or SV(GPx1) is almost completely protective. In vivo, intraparenchymal or intracerebroventricular, inoculation of these vectors leads to long-term expression of these antioxidant enzymes and similarly protects from local challenge with recombinant HIV-1 gp120 and Tat. The ultimate goal to which this pilot project will lead is to study the use of recombinant Tag-deleted SV40-derived vectors (rSV40s) in CNS-directed gene delivery, to treat neuroAIDS other neurodegenerative diseases involving oxidant stress. The first step in this process, and the immediate goal of these studies is to confirm the ability of rSV40s to deliver expression of neuroprotective antioxidant enzymes and antilentiviral transgenes safely to the primate brain. In so doing, it is hoped to translate to a primate model the data generated with human and rodent CNS cells in tissue culture, and in vivo in rodent studies, documenting the transduction efficiency and safety of rSV40 gene delivery to the CNS. Data generated in this study will be used in ensuing NIH grant proposals to study and optimize rSV40 gene delivery of Cu/Zn superoxide dismutase (SOD1) and glutathione peroxidase (GPx1) to treat SIV-induced encephalopathy. NIH proposals to conduct clinical trials of gene therapy for neuroAIDS would follow. The first step, proposed here, is to document that these vectors deliver transgene expression to the primate CNS, durably and safely.