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: 6539840
• 负责人: Beverly L. Davidson
• 金额: $ 26.95万
• 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/6539840
• 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）溶酶体存储疾病 影响多个组织。全身性疾病可以通过多种 方法。但是，由于血脑的相对不渗透性 障碍，CNS缺陷的校正将需要递送酶 直接到CNS。根据我们先前使用腺病毒和非病毒的工作 向量系统，以及我们最近与MMLV和基于HIV的媒介的工作，新颖 在MPS VII模型中提出了使用慢病毒载体的实验 溶酶体储存疾病。在此提案中概述的实验我们 将测试1）将β-葡萄糖醛酸酶分泌到CSF中会导致酶 渗透到实质中并纠正疾病，2） 可以诱导β-葡萄糖醛酸苷酶或重组慢病毒载体 要从CSF进入大脑，3）在核内囊内感染哪些细胞类型 在正常和患病的小鼠脑中注射慢病毒载体，以及 感染细胞类型会影响表达的持续性，在MPS VII中 小鼠，校正，4）如何从CSF或实质中递送β-葡萄糖醛酸苷酶 细胞对MPS VII模型中的行为度量产生影响，5）如果慢病毒 可以修改向量以转导血管内皮。结果 我们的研究将对CNS疾病产生重要影响 其他存储缺陷和其他向量系统。