Gene Therapy In An Animal Model Of Parkinson

将胎儿腹中脑（VM）组织移植到单侧6-羟色胺损伤动物的黑质区，并结合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）的免疫反应性。我们研究了编码GDNF的单纯疱疹病毒（HSV）扩增子载体（HSVgdnf）是否能在半帕金森大鼠中诱导类似的恢复。成年大鼠麻醉后单侧前脑内侧束注射6-羟多巴胺。通过测量安非他明引起的旋转来检测病变的完整性。6-OHDA给药1个月后，将胎儿VM组织移植到受损的黑质区，然后沿黑质至纹状体的通道注射hssvgdnf或hssvlac（对照组）。大多数接受移植和注射HSVgdnf的动物在移植后3个月显示安非他明诱导的旋转减少。接受HSVlac治疗的动物旋转没有减少。免疫细胞化学显示，注射HSVgdnf后，黑质和纹状体分别出现th阳性神经元和th阳性纤维。移植、注射hslac的动物无免疫反应性。这些结果表明，胚胎神经移植和注射HSV GDNF可恢复帕金森病动物黑质纹状体DA通路，并支持GDNF对中脑DA神经元的营养活性可能是由HSV扩增子载体提供的。

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.