Gene Therapy In An Animal Model Of Parkinson

将胎儿腹中脑（VM）组织移植到单侧6-OHDA损伤的动物的黑质区，结合GDNF注射，桥接黑质和纹状体，恢复黑质纹状体酪氨酸羟化酶（TH）免疫反应性。我们调查是否单纯疱疹病毒（HSV）扩增载体编码GDNF（HSVgdnf）诱导类似的恢复偏侧帕金森病大鼠。麻醉成年大鼠，并将6-OHDA单侧注射到内侧前脑束中。通过测量安非他明诱导的旋转来测试病变的完整性。6-OHDA给药后一个月，将胎儿VM组织移植到受损的黑质区域，然后沿从黑质到纹状体的通道沿着注射HSVgdnf或HSVlac（对照）。大多数接受移植和HSVgdnf注射的动物在移植后三个月表现出安非他明诱导的旋转减少。接受HSVlac的动物未显示旋转减少。免疫细胞化学显示TH阳性神经元和纤维的黑质和纹状体，分别移植后HSV gdnf注射。在移植的HSVlac注射动物中未观察到免疫反应性。这些结果表明，胎儿黑质移植和HSVgdnf注射可以恢复帕金森病动物的黑质纹状体DA通路，并支持GDNF对中脑DA神经元的营养活性可以由HSV扩增子载体提供。

Grafting of fetal ventromesencephalic (VM) tissue to the nigral region of unilaterally 6-OHDA-lesioned animals in conjunction with GDNF injection that bridges the nigra and striatum, restores nigrostriatal tyrosine hydroxylase (TH) immunoreactivity. We investigated whether a herpes simplex virus (HSV) amplicon vector encoding GDNF (HSVgdnf) induces a similar restoration in hemiparkinsonian rats. Adult rats were anesthetized and unilaterally injected with 6-OHDA into the medial forebrain bundle. The completeness of lesions was tested by measuring amphetamine-induced rotation. One month after 6-OHDA administration, fetal VM tissues were grafted into the lesioned nigral area followed by injection of HSVgdnf or HSVlac (control) along a tract from nigra to striatum. Most animals that received transplantation and HSVgdnf injection showed a reduction in amphetamine-induced rotation three months after grafting. Animals that received HSVlac showed no reduced rotation. Immunocytochemistry revealed TH-positive neurons and fibers in the nigra and striatum, respectively, after HSVgdnf injection with grafting. No immunoreactivity was observed in grafted, HSVlac injected animals. These results indicate that fetal nigral transplantation and HSVgdnf injection may restore the nigrostriatal DA pathway in the Parkinsonian animals and supports that trophic activity of GDNF on midbrain DA neurons may be provided by HSV amplicon vectors.