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Adenoviral GDNF gene therapy against motoneuron death

腺病毒 GDNF 基因治疗对抗运动神经元死亡

基本信息

批准号：
10670616
负责人：
WATABE Kazuhiko
金额：
$ 2.05万
依托单位：
TOKYO METROPOLITAN ORGANIZATION FOR MEDICAL RESEARCH (1999)Tokyo Metropolitan Institute for Neuroscience (1998)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

Glial cell line-derived neurotrophic factor (GDNF) has been shown to protect cranial and spinal motoneurons, that suggests potential uses of GDNF in the treatment of spinal cord injury and motor neuron diseases. We examined neuroprotective effect of human GDNF encoded by an adenovirus vector (AxCAhGDNF) on the death of lesioned adult rat facial and spinal motoneurons. The facial nerve or the seventh cervical segment (C7) ventral and dorsal roots and dorsal root ganglia of adult Fisher 344 rats were avulsed and removed from the stylomastoid or vertebral foramen, respectively, and AxCAhGDNF, AxCALacZ (adenovirus encoding b-galactosidase gene) or PBS was inoculated in the lesioned foramen. One week after the avulsion and treatment with AxCALacZ, the animals showed expression of beta-galactosidase activity in lesioned facial and spinal motoneurons. Animals avulsed and treated with AxCAhGDNF showed intense immunolabeling for GDNF in lesioned facial and spinal motoneurons and expression of virus-induced human GDNF mRNA transcripts in the lesioned brain stem and spinal cord tissues. Nissl-stained cell counts revealed that the treatment with AxCAhGDNF significantly prevented the loss of lesioned motoneurons 2 to 8 weeks after avulsion, as compared to AxCALacZ or PBS treatment. Furthermore, the AxCAhGDNF treatment ameliorated choline acetyltransferase immunoreactivity and suppressed the induction of nitric oxide synthase activity in the lesioned motoneurons after avulsion. These results indicate that the adenovirus-mediated gene transfer of GDNF may prevent the degeneration of motoneurons in adult humans with motoneuron injury and motor neuron diseases.

胶质细胞源性神经营养因子（GDNF）具有保护脑和脊髓运动神经元的作用，提示GDNF在治疗脊髓损伤和运动神经元疾病中具有潜在的应用价值。我们研究了腺病毒载体（AxCAhGDNF）编码的人GDNF对损伤的成年大鼠面部和脊髓运动神经元死亡的神经保护作用。将成年Fisher 344大鼠的面神经或第七颈段（C7）腹根和背根以及背根神经节分别从茎乳孔或椎孔撕脱并移除，并在损伤的孔中接种AxCAhGDNF、AxCALacZ（编码b-半乳糖苷酶基因的腺病毒）或PBS。撕脱和AxCALacZ治疗后一周，动物在受损的面部和脊髓运动神经元中显示β-半乳糖苷酶活性的表达。动物撕脱和治疗AxCAhGDNF显示出强烈的免疫标记GDNF在受损的面部和脊髓运动神经元和表达病毒诱导的人GDNF mRNA转录在受损的脑干和脊髓组织。Nissl染色细胞计数显示，与AxCALacZ或PBS治疗相比，AxCAhGDNF治疗显著防止了撕脱后2至8周受损运动神经元的丢失。此外，AxCAhGDNF治疗改善胆碱乙酰转移酶的免疫反应性和抑制诱导的一氧化氮合酶活性在撕脱伤后受损的运动神经元。这些结果表明，腺病毒介导的GDNF基因转移可以防止成年人运动神经元损伤和运动神经元疾病的运动神经元变性。