Towards a neuroprotective gene therapy for Parkinson's disease:: use of adenovirus, AAV and lentivirus vectors for gene transfer of GDNF to the nigrostriatal system in the rat Parkinson model
Towards a neuroprotective gene therapy for Parkinson's disease:: use of adenovirus, AAV and lentivirus vectors for gene transfer of GDNF to the nigrostriatal system in the rat Parkinson model
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DOI：
10.1016/s0006-8993(00)02915-2
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发表时间：
2000-12-15
期刊：
影响因子：
2.9
通讯作者：
Mandel, RJ
中科院分区：
文献类型：
--
作者：
Björklund, A;Kirik, D;Mandel, RJ
在过去几年里。由腺病毒(Ad)、腺相关病毒(AAV)或慢病毒(LV)衍生的重组病毒载体已发展成为将基因转移到成人中枢神经系统的高效载体。在最近的实验中，在帕金森病大鼠模型中，所有三种载体系统都被证明在黑质纹状体系统中以生物学相关的水平长期运送胶质细胞系衍生神经营养因子(GDNF)。因此，将GDNF编码载体注射到纹状体或黑质可以获得黑质纹状体系统中GDNF的区域限制性过表达，从而足以阻止毒素诱导的黑质多巴胺神经元的变性。尤其是纹状体注射GDNF载体，不仅能有效地挽救黑质细胞体，而且能保护帕金森模型大鼠的黑质纹状体投射和功能性纹状体多巴胺神经支配。使用AAV-GDNF和LV-GDNF载体的长期实验表明。此外，持续给予3-6个月的GDNF可以促进6-OHDA损伤大鼠和MPTP损伤猴子的再生和显著的功能恢复。新型AAV和LV载体在啮齿动物和灵长类帕金森模型中的令人印象深刻的效果表明，现在探索这些载体系统作为帕金森病患者神经保护治疗工具的时机可能已经成熟。(C)2000 Elsevier Science B.V.保留所有权利。
During the last few years. recombinant viral vectors derived from adenovirus (Ad), adeno-associated virus (AAV) or lentivirus (LV) have been developed into highly effective vehicles for gene transfer to the adult central nervous system. In recent experiments, in the rat model of Parkinson's disease, all three vector systems have been shown to be effective for long-term delivery of glial cell line-derived neurotrophic factor (GDNF) at biologically relevant levels in the nigrostriatal system. Injection of the GDNF encoding vectors into either striatum or substantia nigra thus makes it possible to obtain a regionally restricted over-expression of GDNF within the nigrostriatal system that is sufficient to block the toxin-induced degeneration of the nigral dopamine neurons. Injection of GDNF vectors in the striatum, in particular, is effective not only in rescuing the cell bodies in the substantia nigra, but also in preserving the nigrostriatal projection and a functional striatal dopamine innervation in the rat Parkinson model. Long-term experiments using AAV-GDNF and LV-GDNF vectors show. moreover, that sustained GDNF delivery over 3-6 months can promote regeneration and significant functional recovery in both 6-OHDA-lesioned rats and MPTP-lesioned monkeys. The impressive efficacy of the novel AAV and LV vectors in rodent and primate Parkinson models suggests that the time may now be ripe to explore these vector systems as tools for neuroprotective treatments in patients with Parkinson's disease. (C) 2000 Elsevier Science B.V. All rights reserved.