Intravenous glial-derived neurotrophic factor gene therapy of experimental Parkinson's disease with Trojan horse liposomes and a tyrosine hydroxylase promoter.
Intravenous glial-derived neurotrophic factor gene therapy of experimental Parkinson's disease with Trojan horse liposomes and a tyrosine hydroxylase promoter.
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使用特洛伊木马脂质体和酪氨酸羟化酶启动子对实验性帕金森病进行静脉神经胶质源性神经营养因子基因治疗。
DOI：
10.1002/jgm.1152
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发表时间：
2008
期刊：
影响因子：
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通讯作者：
Pardridge,WilliamM
中科院分区：
文献类型：
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作者：
Xia,Chun-Fang;Boado,RubenJ;Zhang,Yun;Chu,Chun;Pardridge,WilliamM
背景实验性帕金森病（PD）大鼠静脉注射胶质源性神经营养因子（GDNF）质粒DNA，使用特洛伊木马脂质体（THL）进行非病毒基因治疗，靶向大鼠转铁蛋白受体（TfR）的单克隆抗体（MAb）。通过将GDNF基因置于大鼠酪氨酸羟化酶（TH）启动子的影响下，将转基因的表达限制在儿茶酚胺能细胞中。方法设计一个13-kb的真核表达质粒，命名为pTHpro-GDNF，其中人前体GDNF cDNA由大鼠TH启动子（pro）的8 kb 5′-侧翼序列驱动，并且3′侧接牛生长激素转录终止序列。将pTHpro-GDNF质粒DNA封装在THL中，靶向TfRMAb，并在实验性PD诱导脑内6-hydroxydopamin. ResultsGDNF基因的表达，TH启动子的影响下，与巨细胞病毒启动子的影响下的GDNF表达相比，在2周后给予大鼠单次静脉注射。GDNF仅在观察到TH基因表达的大鼠器官中升高，包括黑质、肝脏和肾上腺。GDNF基因治疗的单次延迟静脉给药导致阿托吗啡诱导的旋转持续减少，这与纹状体TH酶活性增加19倍相关。剂量反应和时间反应observed. ConclusionsSustainedtherapeutic effects是在实验性PD与GDNF质粒DNA基因治疗的延迟单次静脉给药，使用受体靶向的THL和区域特异性启动子。版权所有© 2007约翰威利父子有限公司。
BackgroundRats with experimental Parkinson's disease (PD) are treated with intravenous glial‐derived neurotrophic factor (GDNF) plasmid DNA, non‐viral gene therapy using Trojan horse liposomes (THLs) targeted with a monoclonal antibody (MAb) to the rat transferrin receptor (TfR). Expression of the transgene is confined to catecholaminergic cells by placement of the GDNF gene under the influence of the rat tyrosine hydroxylase (TH) promoter.MethodsA 13‐kb eukaryotic expression plasmid, designated pTHpro‐GDNF, is engineered in which the human prepro GDNF cDNA is driven by 8 kb of the 5′‐flanking sequence of the rat TH promoter (pro), and is 3′‐flanked by the bovine growth hormone transcription termination sequence. The pTHpro‐GDNF plasmid DNA is encapsulated in THLs targeted with a TfRMAb, and a single intravenous injection is given to rats at 2 weeks after experimental PD is induced by intra‐cerebral 6‐hydroxydopamine.ResultsExpression of the GDNF gene, under the influence of the TH promoter, is restricted compared to GDNF expression under the influence of the cytomegalovirus promoter. GDNF is elevated only in organs of the rat where TH gene expression is observed, including the substantia nigra, liver and adrenal gland. The single, delayed intravenous administration of the GDNF gene therapy causes a lasting reduction in apormorphine‐induced rotation, which is correlated with a 19‐fold increase in striatal TH enzyme activity. Both dose‐response and time‐responses are observed.ConclusionsSustained therapeutic effects are achieved in experimental PD with a delayed single intravenous dosing of GDNF plasmid DNA gene therapy, using receptor‐targeted THLs and a region‐specific promoter. Copyright © 2007 John Wiley & Sons, Ltd.