Behrstock S, Ebert A, McHugh J, Vosberg S, Moore J, Schneider B, Capowski E, Hei D, Kordower J, Aebischer P, Svendsen C N
Waisman Center and Department of Anatomy, University of Wisconsin-Madison, WI 53705, USA.
Gene Ther. 2006 Mar;13(5):379-88. doi: 10.1038/sj.gt.3302679.
Glial cell line-derived neurotrophic factor (GDNF) has been shown to increase the survival and functioning of dopamine neurons in a variety of animal models and some recent human trials. However, delivery of any protein to the brain remains a challenge due to the blood/brain barrier. Here we show that human neural progenitor cells (hNPC) can be genetically modified to release glycosylated GDNF in vitro under an inducible promoter system. hNPC-GDNF were transplanted into the striatum of rats 10 days following a partial lesion of the dopamine system. At 2 weeks following transplantation, the cells had migrated within the striatum and were releasing physiologically relevant levels of GDNF. This was sufficient to increase host dopamine neuron survival and fiber outgrowth. At 5 weeks following grafting there was a strong trend towards functional improvement in transplanted animals and at 8 weeks the cells had migrated to fill most of the striatum and continued to release GDNF with transport to the substantia nigra. These cells could also survive and release GDNF 3 months following transplantation into the aged monkey brain. No tumors were found in any animal. hNPC can be genetically modified, and thereby represent a safe and powerful option for delivering growth factors to specific targets within the central nervous system for diseases such as Parkinson's.
胶质细胞系源性神经营养因子（GDNF）已在多种动物模型及近期的一些人体试验中被证明可提高多巴胺能神经元的存活率及功能。然而，由于血脑屏障的存在，向大脑递送任何蛋白质仍然是一项挑战。在此我们表明，人类神经祖细胞（hNPC）可通过基因改造，在诱导型启动子系统下于体外释放糖基化的GDNF。在多巴胺系统部分损伤10天后，将hNPC-GDNF移植到大鼠纹状体中。移植后2周，细胞已在纹状体内迁移，并释放出生理相关水平的GDNF。这足以提高宿主多巴胺能神经元的存活率及纤维生长。移植后5周，移植动物有功能改善的强烈趋势，而在8周时，细胞已迁移至填充大部分纹状体，并继续释放GDNF且转运至黑质。将这些细胞移植到老年猴脑内3个月后，它们仍可存活并释放GDNF。在任何动物中均未发现肿瘤。hNPC可进行基因改造，因此对于向中枢神经系统内特定靶点递送生长因子以治疗帕金森氏症等疾病而言，是一种安全且有效的选择。
