Efficient gene transfer via retrograde transport in rodent and primate brains using a human immunodeficiency virus type 1-based vector pseudotyped with rabies virus glycoprotein
Efficient gene transfer via retrograde transport in rodent and primate brains using a human immunodeficiency virus type 1-based vector pseudotyped with rabies virus glycoprotein
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DOI：
10.1089/hum.2007.082
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发表时间：
2007-11-01
影响因子：
4.2
通讯作者：
Kobayashi, Kazuto
中科院分区：
文献类型：
--
作者：
Kato, Shigeki;Inoue, Ken-Ichi;Kobayashi, Kazuto
基于人类免疫缺陷病毒1型（HIV-1）的灵长类慢病毒载体系统已广泛用于动物模型的基因治疗试验。在一些病毒载体中观察到的逆行轴突运输为基因转移到位于远离载体注射位点的区域的神经元细胞体赋予了相当大的优势。然而，据报道，用水泡性口炎病毒糖蛋白假型化的基于 HIV-1 的慢病毒载体的逆行轴突运输效率低下。在本研究中，我们利用狂犬病病毒糖蛋白（RVG）假型化的基于 HIV-1 的载体，通过大脑中的逆行运输开发了一种有效的基因转移系统。将RV-G假型HIV-1载体注射到小鼠背侧纹状体中，可以增加大脑皮层、丘脑和腹侧中脑神经元群的基因转移，这些神经元均支配纹状体。此外，将 RV-G 假型载体注射到猴子纹状体（壳核）中，可高效转移到腹侧中脑神经元（黑质纹状体多巴胺神经元）中。我们的结果表明，用 RV-G 假型化 HIV-1 载体可提高小鼠和猴脑中逆行轴突运输的基因转移效率。这种灵长类慢病毒载体系统将通过增强逆行运输为神经系统和神经退行性疾病的基因治疗提供强大的方法。
The primate lentiviral vector system based on human immunodeficiency virus type 1 (HIV-1) has been used for a wide range of gene therapy trials in animal models. Axonal transport in the retrograde direction, which is observed with some viral vectors, confers a considerable advantage to gene transfer into neuronal cell bodies that are localized in regions remote from the injection site of the vectors. However, retrograde axonal transport of the HIV-1-based lentiviral vector pseudotyped with vesicular stomatitis virus glycoprotein is reported to be inefficient. In the present study, we developed an efficient gene transfer system through retrograde transport in the brain with the HIV-1-based vector pseudotyped with rabies virus glycoprotein (RVG). Injection of the RV-G-pseudotyped HIV-1 vector into the dorsal striatum of mice yielded an increase in gene transfer into neuronal populations in the cerebral cortex, thalamus, and ventral midbrain, each of which innervates the striatum. In addition, injection of the RV-G-pseudotyped vector into the monkey striatum (putamen) resulted in highly efficient transfer into neurons in the ventral midbrain (nigrostriatal dopamine neurons). Our results indicate that pseudotyping of the HIV-1 vector with RV-G enhances the efficiency of gene transfer through retrograde axonal transport in both mouse and monkey brains. This primate lentiviral vector system will provide a powerful approach to gene therapy for neurological and neurodegenerative diseases by means of enhanced retrograde transport.