Sautter J, Tseng J L, Braguglia D, Aebischer P, Spenger C, Seiler R W, Widmer H R, Zurn A D
Department of Neurosurgery, Inselspital, University of Bern, Switzerland.
Exp Neurol. 1998 Jan;149(1):230-6. doi: 10.1006/exnr.1997.6718.
Neural transplantation as an experimental therapy for Parkinsonian patients has been shown to be effective in several clinical trials. Further benefit, however, may be expected if the grafting is combined with a treatment of neurotrophic factors thus improving the survival and growth of grafted embryonic dopaminergic neurons. Continuous trophic support may be needed and therefore requires the long-term delivery of neurotrophic factors to the brain. We demonstrate here that the implantation of polymer-encapsulated cells genetically engineered to continuously secrete glial cell line-derived neurotrophic factor to the adult rat striatum improves dopaminergic graft survival and function. Near complete compensation of 6-hydroxydopamine-induced rotation was already achieved within 3 weeks postgrafting in rats that received glial cell line-derived neurotrophic factor-releasing capsules in addition to dopaminergic cell grafts of cultured tissue. Rats without trophic factor supply showed only little recovery at the same time point and sham grafted rats showed no recovery. The number of tyrosine hydroxylase-immunoreactive cells per graft was increased 2.6-fold in the presence of glial cell line-derived neurotrophic factor 6 weeks postgrafting. Similarly, tyrosine hydroxylase-immunoreactive fibers around the graft were increased by 53%. Moreover, these fibers showed a preferential growth towards the trophic factor-releasing capsule. Taken together, these results provide evidence that encapsulated genetically engineered cells are an effective means of long-term trophic factor supply into the adult rat brain and that the delivery of glial cell line-derived neurotrophic factor can sustain dopaminergic graft function and survival.
神经移植作为帕金森病患者的一种实验性治疗方法，已在多项临床试验中被证明是有效的。然而，如果将移植与神经营养因子治疗相结合，从而改善移植的胚胎多巴胺能神经元的存活和生长，可能会有进一步的益处。可能需要持续的营养支持，因此需要将神经营养因子长期递送至大脑。我们在此证明，将经过基因工程改造以持续分泌胶质细胞源性神经营养因子的聚合物包裹细胞植入成年大鼠纹状体，可改善多巴胺能移植体的存活和功能。在接受培养组织的多巴胺能细胞移植的同时还接受了胶质细胞源性神经营养因子释放胶囊的大鼠中，移植后3周内已实现对6-羟基多巴胺诱导的旋转的近乎完全补偿。没有营养因子供应的大鼠在同一时间点仅显示出很少的恢复，而假手术移植的大鼠则没有恢复。移植后6周，在存在胶质细胞源性神经营养因子的情况下，每个移植体中酪氨酸羟化酶免疫反应性细胞的数量增加了2.6倍。同样，移植周围的酪氨酸羟化酶免疫反应性纤维增加了53%。此外，这些纤维显示出向营养因子释放胶囊的优先生长。综上所述，这些结果提供了证据，表明包裹的基因工程细胞是向成年大鼠脑内长期供应营养因子的有效手段，并且胶质细胞源性神经营养因子的递送可以维持多巴胺能移植体的功能和存活。
