Peripherally delivered glutamic acid decarboxylase gene therapy for spinal cord injury pain
Peripherally delivered glutamic acid decarboxylase gene therapy for spinal cord injury pain
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DOI：
10.1016/j.ymthe.2004.04.017
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发表时间：
2004-07-01
影响因子：
12.4
通讯作者：
Fink, DJ
中科院分区：
文献类型：
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作者：
Liu, J;Wolfe, D;Fink, DJ
脊髓损伤(SCI)后神经性疼痛是传统医学治疗难以解决的难题。为了确定脊髓释放γ-氨基丁酸(GABA)是否可以减轻脊髓损伤后低于水平的中枢神经病理性疼痛，我们构建了基于复制不能的单纯疱疹病毒(HSV)载体，编码人类谷氨酸脱羧酶(GAD67)的一个亚型。皮下接种体外或体内转导的背根神经节(DRG)神经元产生GAD并结构性地释放GABA。T13脊髓半横断引起中枢神经病理性疼痛，表现为机械性痛觉过敏和热痛敏。将载体接种到双脚皮下可减少低于水平的脊髓损伤疼痛的两种表现；鞘内注射荷包牡丹碱或苯氯芬的剂量不影响正常或受伤的未接种动物的阈值，这种载体介导的效应可部分逆转。载体介导的GABA释放减弱了脊髓半横断引起的脊髓降钙素基因相关肽免疫反应性的增加。这些结果提示单纯疱疹病毒介导的DRG基因转移可用于治疗不完全性脊髓损伤后的低度中枢神经病理性疼痛。
Neuropathic pain after spinal cord injury (SCI) represents a difficult problem that is commonly refractory to conventional medical management. To determine if spinal release of gamma-amino butyric acid (GABA) could reduce below-level central neuropathic pain after SCI, we constructed a replication-incompetent herpes simplex virus (HSV)-based vector encoding one isoform of human glutamic acid decarboxylase (GAD67). Dorsal root ganglion (DRG) neurons transduced in vitro or in vivo by subcutaneous inoculation produced GAD and released GABA constitutively. T13 spinal cord hemisection resulted in central neuropathic pain manifested by mechanical allodynia and thermal hyperalgesia. Subcutaneous inoculation of the vector into both feet reduced both manifestations of below-level SCI pain; the vector-mediated effect was partially reversed by intrathecal bicuculline or phaclofen at doses that did not affect thresholds in normal or injured uninoculated animals. Vector-mediated GABA release attenuated the increase in spinal calcitonin gene-related peptide immunoreactivity caused by cord hemisection. These results suggest that HSV-mediated gene transfer to DRG could be used to treat below-level central neuropathic pain after incomplete SCI.