Efficient Gene Delivery and Selective Transduction of Glial Cells in the Mammalian Brain by AAV Serotypes Isolated From Nonhuman Primates
Efficient Gene Delivery and Selective Transduction of Glial Cells in the Mammalian Brain by AAV Serotypes Isolated From Nonhuman Primates
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DOI：
10.1038/mt.2009.170
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发表时间：
2009-10-01
影响因子：
12.4
通讯作者：
During, Matthew J.
中科院分区：
文献类型：
--
作者：
Lawlor, Patricia A.;Bland, Ross J.;During, Matthew J.
腺相关病毒（腺相关病毒）载体已成为体细胞基因转移至中枢神经系统（CNS）的主要载体。迄今为止，AAV介导的基因递送至CNS是基于血清型1-9，尚未观察到仅选择性和广泛转导神经胶质细胞的有效基因转移至神经元。最近，已经从非人灵长类动物组织中分离出另外的内源性AAV。在这项研究中，将用腺相关病毒血清型bb 2、cy 5、rh 20、rh 39和rh 43获得的转导与用腺相关病毒8获得的转导进行了比较，腺相关病毒8是另一种先前显示在哺乳动物大脑中表现良好的非人灵长类动物分离株。滴度匹配的载体编码增强型绿色荧光蛋白（EGFP）报告，驱动的组成型CAG启动子，被注射到海马，纹状体，或黑质（SN）的成年大鼠。在输注cy 5、rh 20和rh 39后观察到比用AAV 8观察到的更广泛的神经元转导。感兴趣的是，用rh 43观察到星形胶质细胞的优先转导。为了优化神经胶质转导，产生了由细胞特异性启动子驱动的载体储备物-广泛的，并且使用rh 43和AAV 8观察到星形胶质细胞和少突胶质细胞的靶向转导，其由神经胶质细胞酸性蛋白（GFAP）和髓鞘碱性蛋白（MBP）启动子驱动，扩展了AAV用于建模和治疗涉及神经胶质细胞病理学的疾病的效用。
Adeno-associated viral (AAV) vectors have become the primary delivery agent for somatic gene transfer into the central nervous system (CNS). To date, AAV-mediated gene delivery to the CNS is based on serotypes 1-9, with efficient gene transfer to neurons only-selective and widespread transduction of glial cells have not been observed. Recently, additional endogenous AAVs have been isolated from nonhuman primate tissues. In this study, transduction obtained with AAV serotypes bb2, cy5, rh20, rh39, and rh43 was compared to that obtained with AAV8, another nonhuman primate isolate previously shown to perform well in mammalian brain. Titer-matched vectors encoding the enhanced green fluorescent protein (EGFP) reporter, driven by the-constitutive CAG promoter, were injected into the hippocampus, striatum, or substantia nigra (SN) of adult rats. More widespread neuronal transduction was observed following infusion of cy5, rh20, and rh39 than observed with AAV8. Of interest, preferential transduction of astrocytes was observed with rh43. To optimize glial transduction, vector stocks driven by cell-specific promoters were generated-widespread and targeted transduction of astrocytes and oligodendrocytes was observed using rh43 and AAV8, driven by the glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP) promoters, expanding the utility of AAV for modeling and treating diseases involving glial cell pathology.