Gene Therapy In An Animal Model Of Parkinson

将胎儿腹中脑(VM)组织移植到单侧6-OHDA损伤动物的黑质区域，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。我们研究了编码GDNF的单纯疱疹病毒(HSV)扩增载体(HSVgdnf)是否能在偏侧帕金森病大鼠中诱导类似的修复。成年大鼠麻醉后，单侧前脑束内侧注射6-OHDA。通过测量苯丙胺诱导的旋转来测试损伤的完整性。6-OHDA注射1个月后，将胚胎VM组织移植到黑质损伤区，然后沿黑质至纹状体方向注射HSVgdnf或HSVlac(对照组)。大多数接受移植和注射HSVgdnf的动物在移植后三个月显示苯丙胺诱导的旋转减少。接受HSVlac的动物没有表现出减少旋转。免疫细胞化学显示注射HSVgdnf后黑质和纹状体分别有TH阳性神经元和纤维。在注射HSVlac的移植动物中未观察到免疫反应。这些结果表明，胚胎黑质移植和注射HSVgdnf可以恢复帕金森病动物黑质纹状体DA通路，并支持GDNF对中脑DA神经元的营养作用可能是由HSV扩增载体提供的。

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.