Intranigral lentiviral delivery of dominant-negative TNF attenuates neurodegeneration and behavioral deficits in hemiparkinsonian rats.
Intranigral lentiviral delivery of dominant-negative TNF attenuates neurodegeneration and behavioral deficits in hemiparkinsonian rats.
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DOI：
10.1038/mt.2008.146
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发表时间：
2008-09
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--
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神经炎症过程与腹侧中脑多巴胺能神经元的进行性丧失有关，这导致帕金森病，一种迟发性运动障碍，影响2%的70岁以上人口。以前，我们证明，通过黑质输注显性负性肿瘤坏死因子蛋白（XENP 345）在两个帕金森病大鼠模型中抑制促炎细胞因子肿瘤坏死因子可减弱多巴胺能神经元的损失。本研究的目的是开发编码显性阴性肿瘤坏死因子的组成型慢病毒载体，并确定将显性阴性TNF直接递送至啮齿动物黑质的基因治疗方法是否可以预防或减轻神经毒素诱导的多巴胺能神经元损失和相关的行为缺陷。在这里，我们证明了一个单一的注射慢病毒表达显性负性TNF到大鼠黑质管理伴随着纹状体6-羟基多巴胺损伤导致足够高的抑制剂在体内表达，以减轻多巴胺能神经元的损失和行为缺陷造成的纹状体多巴胺耗竭。我们的研究结果表明，显性负性肿瘤坏死因子基因转移作为一种新的神经保护策略，以防止或延迟黑质纹状体通路退化的可行性和有效性，在帕金森病的治疗中具有潜在的未来治疗应用。
Neuroinflammatory processes have been implicated in the progressive loss of ventral midbrain dopaminergic neurons that give rise to Parkinson’s disease, a late-onset movement disorder that affects 2% of the population over age 70. Previously, we demonstrated that inhibition of the pro-inflammatory cytokine Tumor Necrosis Factor through nigral infusion of dominant-negative Tumor Necrosis Factor protein (XENP345) in two rat models of Parkinson’s disease attenuates dopaminergic neuron loss. The objective of this study was to develop a constitutive lentiviral vector encoding dominate-negative Tumor Necrosis Factor and to determine if a gene therapy approach to deliver dominant-negative TNF directly into the rodent substantia nigra could prevent or attenuate neurotoxin-induced dopaminergic neuron loss and associated behavioral deficits. Here we demonstrate that a single injection of lentivirus expressing dominant-negative TNF into rat substantia nigra administered concomitant with a striatal 6- hydroxydopamine lesion resulted in sufficiently high expression of inhibitor in vivo to attenuate both dopaminergic neuron loss and behavioral deficits resulting from striatal dopamine depletion. Our findings demonstrate the feasibility and efficacy of dominant negative Tumor Necrosis Factor gene transfer as a novel neuroprotective strategy to prevent or delay nigrostriatal pathway degeneration with potential future therapeutic applications in the treatment of Parkinson’s disease.
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影响因子：
1.7
作者：
Georgievska, B;Kirik, D;Björklund, A
通讯作者：
Björklund, A
影响因子：
4.1
作者：
McGeer, PL;McGeer, EG
通讯作者：
McGeer, EG
影响因子：
2.1
作者：
Tweedie, David;Sambamurti, Kumar;Greig, Nigel H.
通讯作者：
Greig, Nigel H.
影响因子：
5.3
作者：
Georgievska, B;Kirik, D;Björklund, A
通讯作者：
Björklund, A
影响因子：
5.3
作者：
Taylor, Laura;Jones, Leonard;Blesch, Armin
通讯作者：
Blesch, Armin