A Lentiviral Strategy for Highly Efficient Retrograde Gene Transfer by Pseudotyping with Fusion Envelope Glycoprotein
A Lentiviral Strategy for Highly Efficient Retrograde Gene Transfer by Pseudotyping with Fusion Envelope Glycoprotein
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DOI：
10.1089/hum.2009.179
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发表时间：
2011-02-01
影响因子：
4.2
通讯作者：
Kobayashi, Kazuto
中科院分区：
文献类型：
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作者：
Kato, Shigeki;Kobayashi, Kenta;Kobayashi, Kazuto
基于人类免疫缺陷病毒1型（HIV-1）的慢病毒载体系统广泛用于神经系统和神经退行性疾病的基因治疗试验。病毒载体的逆行轴突运输为将基因递送到位于远离注射部位的区域的神经元细胞体提供了很大的优势。带有狂犬病病毒糖蛋白（RV-G）选择性变体的基于 HIV-1 的载体的假型化通过逆行转运增加了基因转移到中枢神经系统。由于基因治疗试验的大规模应用需要高滴度的载体库存，因此需要对慢病毒载体进行假型化，以产生更有效的逆行运输。在本研究中，我们通过假型化具有融合包膜糖蛋白（称为FuG-B）的HIV-1载体，开发了一种用于高效逆行基因转移的新型载体系统，其中RV-G的胞质结构域被水泡性口炎病毒糖蛋白的相应部分取代。 FuG-B假型改变了慢病毒载体的转导特性，并增强了逆行转运介导的基因转移到神经纹状体的不同大脑区域，其效率比RV-G假型在小鼠中更高。此外，将FuG-B假型载体注射到猴纹状体（尾核和壳核）中，可以将基因高效地传递到黑质纹状体多巴胺系统中，这是帕金森病基因治疗的主要靶点。我们的策略通过慢病毒载体促进逆行基因传递，为治疗某些神经系统和神经退行性疾病提供了强大的工具。
The lentiviral vector system based on human immunodeficiency virus type 1 (HIV-1) is used extensively in gene therapy trials of neurological and neurodegenerative diseases. Retrograde axonal transport of viral vectors offers a great advantage to the delivery of genes into neuronal cell bodies that are situated in regions distant from the injection site. Pseudotyping of HIV-1-based vectors with selective variants of rabies virus glycoprotein (RV-G) increases gene transfer via retrograde transport into the central nervous system. Because large-scale application for gene therapy trials requires high titer stocks of the vector, pseudotyping of a lentiviral vector that produces more efficient retrograde transport is needed. In the present study, we developed a novel vector system for highly efficient retrograde gene transfer by pseudotyping an HIV-1 vector with a fusion envelope glycoprotein (termed FuG-B) in which the cytoplasmic domain of RV-G was substituted by the corresponding part of vesicular stomatitis virus glycoprotein. The FuG-B pseudotype shifted the transducing property of the lentiviral vector and enhanced the retrograde transport-mediated gene transfer into different brain regions innervating the striatum with greater efficiency than that of the RV-G pseudotype in mice. In addition, injection of the FuG-B-pseudotyped vector into monkey striatum (caudate and putamen) allowed for highly efficient gene delivery into the nigrostriatal dopamine system, which is a major target for gene therapy of Parkinson's disease. Our strategy provides a powerful tool for the treatment of certain neurological and neurodegenerative diseases by promoting retrograde gene delivery via a lentiviral vector.