STRATEGIES TO ENHANCE GENE TRANSFER TO THE CNS

增强中枢神经系统基因转移的策略

• 批准号: 6319180
• 负责人: Beverly L. Davidson
• 金额: $ 3.5万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-02-14 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6319180
• 关键词: Lentivirus; Vesiculovirus; behavior test; beta glucuronidase; cell type; central nervous system; cerebrospinal fluid; defective virus; dengue virus; gene expression; gene therapy; genetic transduction; human immunodeficiency virus; inborn lysosomal enzyme disorder; laboratory mouse; learning; neurotropic virus; space perception; transfection /expression vector; virus cytopathogenic effect

DESCRIPTION: (adapted from applicant's abstract) Lysosomal storage diseases affect multiple tissues. The systemic disease can be corrected by a variety of methods. However, because of the relative impermeability of the blood-brain barrier, correction of the CNS deficits will require delivery of the enzyme directly to the CNS. Based on our prior work with adenoviruses and non-viral vector systems, and our recent work with MMLV- and HIV-based vectors, novel experiments with lentivirus vectors are proposed in the MPS VII model of lyososomal storage disease. Trough the experiments outlined in this proposal we will test if 1) secretion of beta-glucuronidase into CSF results in enzyme penetration into the parenchyma and correction of the disease, 2) if beta-glucuronidase enzyme or the recombinant lentivirus vector can be induced to enter brain from CSF, 3) what cell types are infected after intraparenchymal injections of lentivirus vectors in normal and diseased mouse brain, and if the cell type infected affects the persistence of expression, and, in the MPS VII mouse, correction, 4) how delivery of beta-glucuronidase from CSF or parenchyma cells impacts on behavioral measures in the MPS VII model, and 5) if lentivirus vectors can be modified for transduction of vascular endothelium. The results of our studies will have important implications for CNS disease resulting from other storage deficiencies and for other vector systems.

描述：（改编自申请人的摘要）溶酶体贮积病 影响多个组织。全身性疾病可以通过多种方法得到纠正 方法。然而，由于血脑的相对不渗透性 屏障，纠正中枢神经系统缺陷将需要传递酶 直接到达中枢神经系统。基于我们之前对腺病毒和非病毒的研究 载体系统，以及我们最近对基于 MMLV 和 HIV 的载体的研究，新颖 在 MPS VII 模型中提出了慢病毒载体实验 溶酶体贮积病。通过本提案中概述的实验，我们 将测试 1) β-葡萄糖醛酸酶分泌到 CSF 中是否会产生酶 渗透到实质并纠正疾病，2）如果 可诱导β-葡萄糖醛酸酶或重组慢病毒载体 从脑脊液进入大脑，3）实质内感染后哪些细胞类型被感染 在正常和患病小鼠大脑中注射慢病毒载体，如果 感染的细胞类型会影响表达的持久性，并且在 MPS VII 中 小鼠，校正，4) 如何从脑脊液或实质中递送 β-葡萄糖醛酸酶 细胞对 MPS VII 模型中行为测量的影响，以及 5) 如果慢病毒 可以修饰载体以转导血管内皮。结果 我们的研究将对中枢神经系统疾病产生重要影响 其他存储缺陷和其他载体系统。