GDNF gene delivery via the p75NTR receptor rescues injured motor neurons
GDNF gene delivery via the p75NTR receptor rescues injured motor neurons
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DOI：
10.1016/j.expneurol.2006.05.027
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发表时间：
2006-11-01
影响因子：
5.3
通讯作者：
Rush, Robert A.
中科院分区：
文献类型：
--
作者：
Barati, Shahram;Hurtado, Plinio R.;Rush, Robert A.
运动神经元的逆行轴突运输机制已被用于将编码胶质细胞系源性神经营养因子（GDNF）的基因递送到中枢神经系统中，以在损伤后提供营养支持。构建了一种非病毒基因递送系统，该系统由结合神经营养受体p75（NTR）的单克隆抗体（MC 192）与多聚赖氨酸偶联组成，并用于通过受体介导的机制递送基因。将MC 192-poly-L-lysine/pGDNF复合物注射到新生大鼠的后肢中，以在坐骨神经切断之前允许运动神经元内的基因表达。在成年大鼠中，将基因递送复合物以凝胶泡沫形式施用于横断的舌下神经上。我们表明，交付的结构是内在的结合p75（NTR），并被运送到大脑和脊髓，绕过血脑屏障。GDNF转基因及其转录物的存在可以在脊髓和脑干中检测到长达8周。GDNF蛋白的表达在新生大鼠损伤后1周可挽救38%的靶运动神经元，而对照组的存活率低于12%。在成年大鼠中，通过引入转基因几乎完全逆转了轴突切断术诱导的神经元死亡（95 +/- 3%）。因此，这种新型基因递送系统的显着功能结果在出生后和成人运动神经元中都得到了证实。(c)2006年爱思唯尔公司All rights reserved.
The retrograde axonal transport mechanism of motor neurons has been exploited to deliver the gene encoding Glial cell line-derived neurotrophic factor (GDNF) into the central nervous system to provide trophic support following injury. A nonviral gene delivery system, consisting of a monoclonal antibody (MC192) that binds the neurotrophic receptor, p75(NTR), Coupled to poly-L-lysine, was constructed and used to deliver the gene via a receptor-mediated mechanism. The MC192-poly-L-lysine/pGDNF complex was injected into the hind limb of newbom rats to allow gene expression within motor neurons prior to sciatic nerve transection. In adult rats, the gene delivery complex was administrated in gel foam placed on a transected hypoglossal nerve. We show that the delivered construct is internalized following binding to p75(NTR) and is transported into the brain and spinal cord, bypassing the blood-brain barrier. The presence of the GDNF transgene and its transcript could be detected for up to 8 weeks in spinal cord and brain stem. Expression of the GDNF protein rescued 38% of the targeted motor neurons 1 week postinjury in newbom rats while the survival rate in control group was below 12%. In adult rats, neuronal death induced by axotomy was almost completely reversed by the introduction of the transgene (95 +/- 3%). Thus, the significant functional outcomes of this novel gene delivery system are demonstrated both in postnatal and adult motor neurons. (c) 2006 Elsevier Inc. All rights reserved.