Highly efficient retrograde gene transfer into motor neurons by a lentiviral vector pseudotyped with fusion glycoprotein.
Highly efficient retrograde gene transfer into motor neurons by a lentiviral vector pseudotyped with fusion glycoprotein.
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DOI：
10.1371/journal.pone.0075896
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kobayashi K
中科院分区：
文献类型：
--
作者：
Hirano M;Kato S;Kobayashi K;Okada T;Yaginuma H;Kobayashi K
基因治疗技术的发展引入了促进神经元存活和保护的转基因，为神经和神经退行性疾病提供了有效的治疗方法。肌内注射腺病毒和腺相关病毒载体，以及狂犬病病毒糖蛋白（RV-G）伪型慢病毒载体，允许基因传递到运动神经元疾病的动物模型中的运动神经元。最近，我们利用融合糖蛋白B型（FuG-B）或FuG-B的变体（FuG-B2）对基于人类免疫缺陷病毒1型（HIV-1）的载体进行假分型，开发了一种高效逆行基因转移载体（HiRet），其中RV-G的细胞质结构域被水疱性口炎病毒糖蛋白（VSV-G）的相应部分所取代。我们还开发了另一种融合糖蛋白C型的神经元特异性逆行基因转移载体（NeuRet），其中RV-G的胞外结构域和跨膜/胞质结构域的短C端片段被VSV-G的相应区域取代。这两种载体提供了高效的逆行基因转移到大脑中不同的神经元群体。在这里，我们研究了HiRet（含FuG-B2）和NeuRet载体在肌肉注射后逆行转移基因到小鼠脊髓和后脑运动神经元的效率，并将其与基于hiv -1的RV-G伪型载体的效率进行了比较。我们的研究结果的主要亮点是，HiRet载体显示出最有效的逆行基因转移到脊髓和后脑运动神经元中，为其作为一种治疗运动神经元疾病的基因治疗方法提供了前景。
The development of gene therapy techniques to introduce transgenes that promote neuronal survival and protection provides effective therapeutic approaches for neurological and neurodegenerative diseases. Intramuscular injection of adenoviral and adeno-associated viral vectors, as well as lentiviral vectors pseudotyped with rabies virus glycoprotein (RV-G), permits gene delivery into motor neurons in animal models for motor neuron diseases. Recently, we developed a vector with highly efficient retrograde gene transfer (HiRet) by pseudotyping a human immunodeficiency virus type 1 (HIV-1)-based vector with fusion glycoprotein B type (FuG-B) or a variant of FuG-B (FuG-B2), in which the cytoplasmic domain of RV-G was replaced by the corresponding part of vesicular stomatitis virus glycoprotein (VSV-G). We have also developed another vector showing neuron-specific retrograde gene transfer (NeuRet) with fusion glycoprotein C type, in which the short C-terminal segment of the extracellular domain and transmembrane/cytoplasmic domains of RV-G was substituted with the corresponding regions of VSV-G. These two vectors afford the high efficiency of retrograde gene transfer into different neuronal populations in the brain. Here we investigated the efficiency of the HiRet (with FuG-B2) and NeuRet vectors for retrograde gene transfer into motor neurons in the spinal cord and hindbrain in mice after intramuscular injection and compared it with the efficiency of the RV-G pseudotype of the HIV-1-based vector. The main highlight of our results is that the HiRet vector shows the most efficient retrograde gene transfer into both spinal cord and hindbrain motor neurons, offering its promising use as a gene therapeutic approach for the treatment of motor neuron diseases.
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