Differential and persistent expression patterns of CNS gene transfer by an adeno-associated virus (AAV) vector
Differential and persistent expression patterns of CNS gene transfer by an adeno-associated virus (AAV) vector
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DOI：
10.1016/0006-8993(95)01488-8
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发表时间：
1996-03-25
期刊：
影响因子：
2.9
通讯作者：
Samulski, RJ
中科院分区：
文献类型：
--
作者：
McCown, TJ;Xiao, X;Samulski, RJ
安全、长期的基因表达是脑中有效基因治疗的主要标准，因此开始研究以评估腺相关病毒（AAV）载体将报告基因转移到大鼠脑的特定位点。在4天大的大鼠中，3周后，AAV-CMV-lacZ（1 μ l; 5 × 10（4）颗粒）的位点输注在海马和下丘中产生神经元β-半乳糖苷酶基因表达，但在大脑皮层中没有。在成年大鼠中输注AAV-CMV-lacZ病毒载体（1 μ l）7天后，在嗅结节、尾状核、海马、梨状皮质和下丘中发现β-半乳糖苷酶基因表达，主要是在靠近输注部位的多极神经元中。载体微输注后三个月，嗅结节和下丘中的基因表达水平相似，尾状核中的基因表达有所减少，但海马和梨状皮质中的β-半乳糖苷酶基因表达大幅减少。在所有病例中均未观察到明显的毒性体征。因此，AAV载体可以将外源基因转移到成人和新生儿CNS中，但基因表达的模式和寿命取决于所研究的脑区域。
Safe, long-term gene expression is a primary criteria for effective gene therapy in the brain, so studies were initiated to evaluate adeno-associated virus (AAV) vector transfer of a reporter gene into specific sites of the rat brain. In the 4 day old rat, site infusions of AAV-CMV-lacZ (1 mu l; 5 X 10(4) particles) produced neuronal beta-galactosidase gene expression 3 weeks later in the hippocampus and inferior colliculus, but not in the cerebral cortex. Seven days after infusion of AAV-CMV-lacZ viral vectors (1 mu l) in the adult rat, beta-galactosidase gene expression was found in the olfactory tubercle, caudate, hippocampus, piriform cortex and inferior colliculus, primarily in multipolar neurons close to the infusion site. Three months after vector microinfusion, similar levels of gene expression remained in the olfactory tubercle and the inferior colliculus, with some reduction found in the caudate, but substantial reductions in beta-galactosidase gene expression occurred in the hippocampus and piriform cortex. In no case were obvious signs of toxicity noted. Therefore, AAV vectors can transfer foreign genes into the adult and neonatal CNS, but the pattern and longevity of gene expression depends upon the area of brain being studied.