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Study of gene therapy on hypoalgesia in sensory neuropathy using neurotrophic factors

神经营养因子对感觉神经病痛觉减退的基因治疗研究

基本信息

批准号：
17590906
负责人：
MURAKAMI Tatsufumi
金额：
$ 2.24万
依托单位：
Kawasaki Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590906/
关键词：
diabetic neuropathy sensory neuropathy gene therapy electroporation hypoalgesia VEGF P1GF2 Neuropilin-1 感覚性ニィーロパチー PIGF2 PGF

项目摘要

VEGF120 does not bind to neuropilin-1 (nrp-1) but binds to fetal liver kinase (flk-1) and fms-like tyrosine kinase (flt-1) receptors, while VEGF164 binds these receptors. To examine the effect of VEGF120 overexpression on sensory deficits, VEGF120 plasmid was injected into bilateral TA muscles of diabetic mice with hypoalgesia followed by electroporation. After electro-gene transfer, the nociceptive threshold on the dorsum of the hindpaw was measured bilaterally. VEGF120 gene transfer by electroporation did not significantly reduce the nociceptive threshold. To confirm the overexpression of VEGF, we measured VEGF levels in TA muscles of diabetic mice at 2 weeks after VEGF120 plasmid injection with electroporation by ELISA. There was a significant increase in the VEGF level in these samples compared with samples from diabetic mice at 2 weeks after control plasmid injection with electroporation.Placental growth factor2 (P1GF2) has neurotrophic activity in dorsal root ganglion (DRG) neurons through nrp-1 receptor in vitro. To examine the efficiency of P1GF2 therapy for diabetic neuropathy, intramuscular P1GF2 gene transfer by electroporation was performed to treat sensory neuropathy in diabetic mice. P1GF2 was overexpressed in the TA muscles of diabetic mice with hypoalgesia, using a P1GF2 plasmid injection with electroporation. Two weeks after electro-gene transfer into the bilateral TA muscles, the elevated nociceptive threshold was significantly decreased in all treated mice. No increase in the number of endoneurial vessels in the sciatic nerve was found in the P1GF2 plasmid-electroporated mice. Taken together, these findings suggest that VEGF164 and P1GF2 electro-gene therapy significantly recovered the sensory deficits, i.e. hypoalgesia, in the diabetic mice through nrp-1 receptor in DRG neurons.

VEGF120不与神经粘蛋白-1(NRP-1)结合，但与胎肝激酶(Flk-1)和FMS样酪氨酸激酶(Flt-1)受体结合，而VEGF164与这些受体结合。为探讨VEGF120过表达对感觉障碍的影响，将VEGF120质粒注入糖尿病痛觉减退小鼠双侧TA肌内，然后电穿孔。电基因转移后，测量双侧后足背的伤害性阈值。电穿孔转导VEGF120基因不能显著降低小鼠的伤害性阈值。为证实血管内皮生长因子的过度表达，我们用ELISA法检测了电穿孔注射VEGF120后2周糖尿病小鼠TA肌中的血管内皮生长因子水平。对照组注射电穿孔后2周，这些标本中的血管内皮生长因子水平较糖尿病小鼠显著升高。体外培养的背根神经节神经元中，定位生长因子2(P1GF2)通过NRP-1受体具有神经营养活性。为探讨P1GF2对糖尿病神经病变的治疗效果，采用电穿孔法肌肉注射P1GF2基因治疗糖尿病小鼠感觉神经病变。通过电穿孔注射P1GF2质粒，在痛觉减退的糖尿病小鼠的TA肌中过表达P1GF2。将电子基因导入双侧TA肌两周后，所有治疗组小鼠提高的伤害性阈值均显著降低。电穿孔P1GF2基因的小鼠坐骨神经内神经血管数未见增加。综上所述，这些结果表明VEGF164和P1GF2电基因治疗通过DRG神经元上的NRP-1受体显著恢复了糖尿病小鼠的感觉障碍，即痛觉减退。