Lentiviral vectors as a gene delivery system in the mouse midbrain:: Cellular and behavioral improvements in a 6-OHDA model of Parkinson's disease using GDNF
Lentiviral vectors as a gene delivery system in the mouse midbrain:: Cellular and behavioral improvements in a 6-OHDA model of Parkinson's disease using GDNF
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DOI：
10.1006/exnr.2000.7409
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发表时间：
2000-07-01
影响因子：
5.3
通讯作者：
Aebischer, P
中科院分区：
文献类型：
--
作者：
Bensadoun, JC;Déglon, N;Aebischer, P
治疗性分子的局部递送代表了治疗神经变性病症的限制因素之一。使用病毒载体的体内基因转移构成了克服这种限制的有力策略。本研究的目的是验证慢病毒载体作为一种基因传递系统在小鼠中脑的角度筛选帕金森氏病小鼠模型中的生物活性分子。将LacZ编码载体注射到C57 BL/6 j小鼠黑质上方的初步研究表明，慢病毒载体可以感染大约40，000个细胞并长距离扩散。基于这些结果，胶质细胞源性神经营养因子（GDNF）被评估为帕金森病的6-羟基多巴胺模型中的神经保护分子。将携带GDNF或突变GDNF的cDNA的慢病毒载体单侧注射到C57 BL/6 j小鼠的黑质上方。两周后，用6-羟基多巴胺将动物同侧损伤到纹状体。与对照组相比，GDNF注射组中阿扑吗啡诱导的旋转显著降低。此外，GDNF有效地保护69.5%的酪氨酸羟化酶阳性细胞在黑质对B-羟基多巴胺诱导的毒性相比，33.1%的对照突变GDNF。这些数据表明，慢病毒载体构成了一个强大的基因传递系统，用于筛选帕金森氏病小鼠模型中的治疗分子。(C)北京大学出版社.
Local delivery of therapeutic molecules represents one of the limiting factors for the treatment of neurodegenerative disorders. In vivo gene transfer using viral vectors constitutes a powerful strategy to overcome this limitation. The aim of the present study was to validate the lentiviral vector as a gene delivery system in the mouse midbrain in the perspective of screening biotherapeutic molecules in mouse models of Parkinson's disease. A preliminary study with a LacZ-encoding vector injected above the substantia nigra of C57BL/6j mice indicated that lentiviral vectors can infect approximately 40,000 cells and diffuse over long distances. Based on these results, glial cell line-derived neurotrophic factor (GDNF) was assessed as a neuroprotective molecule in a 6-hydroxydopamine model of Parkinson's disease. Lentiviral vectors carrying the cDNA for GDNF or mutated GDNF were unilaterally injected above the substantia nigra of C57BL/6j mice. Two weeks later, the animals were lesioned ipsilaterally with 6-hydroxydopamine into the striatum. Apomorphine-induced rotation was significantly decreased in the GDNF-injected group compared to control animals. Moreover, GDNF efficiently protected 69.5% of the tyrosine hydroxylase-positive cells in the substantia nigra against B-hydroxydopamine-induced toxicity compared to 33.1% with control mutated GDNF. These data indicate that lentiviral vectors constitute a powerful gene delivery system for the screening of therapeutic molecules in mouse models of Parkinson's disease. (C) 2000 Academic Press.