RHESUS SV40 ANTIOXIDANT GENE DELIVERY TO THE CNS

RHESUS SV40 抗氧化剂基因输送至中枢神经系统

• 批准号: 8173000
• 负责人: Bruce A. Bunnell
• 金额: $ 3.94万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 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/8173000
• 关键词: AIDS neuropathy; Animals; Antioxidants; Apoptosis; Applications Grants; Brain; Cells; Computer Retrieval of Information on Scientific Projects Database; Conduct Clinical Trials; Consequences of HIV; Cuprozinc Superoxide Dismutase; Data; Degenerative Disorder; Encephalopathies; Enzymes; Funding; Gene Delivery; Goals; Grant; HIV Envelope Protein gp120; HIV Infections; HIV-1; Human; In Vitro; Infection; Institution; Lead; Macaca mulatta; Neurodegenerative Disorders; Neurons; Oxidants; Pilot Projects; Primates; Process; Proteins; Recombinants; Research; Research Personnel; Resources; Rodent; Safety; Simian virus 40; Source; Toxic effect; Transgenes; Translating; United States National Institutes of Health; base; data modeling; gene therapy; glutathione peroxidase; in vivo; neurotoxicity; oxidant stress; tissue culture; transduction efficiency; transgene expression; vector

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. The first step, proposed here, is to document that these vectors deliver transgene expression to the primate CNS, durably and safely. All of the animals have been injected with the SV40 vectors. To date, analysis has revealed efficient transduction of the NHP CNS by the SV40 based vectors. No toxicity has been observed. 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.

这个子项目是众多研究子项目之一