ASU-Banner Neurodegenerative Disease Research Center, Tempe, Arizona, USA.
School of Life Sciences, Arizona State University, Tempe, Arizona, USA.
Mov Disord. 2023 Sep;38(9):1728-1736. doi: 10.1002/mds.29518. Epub 2023 Aug 6.
Neurturin is a member of the glial cell line-derived neurotrophic factor family of neurotrophic factors and has the potential to protectdegenerating dopaminergic neurons.
Here, we performed post-mortem studies on two patients with advanced Parkinson's disease that survived 10 years following AAV-neurturin gene (Cere120) delivery to verify long-term effects of trophic factor neurturin.
Cere120 was delivered to the putamen bilaterally in one case and to the putamen plus substantia nigra bilaterally in the second. Immunohistochemistry was used to examine neurturin, Rearranged during transfection(RET), phosphor-S6, and tyrosine hydroxylase expressions, inflammatory reactions, and α-synuclein accumulation.
In both patients there was persistent, albeit limited, neurturin expression in the putamen covering 1.31% to 5.92% of the putamen. Dense staining of tyrosine hydroxylase-positive fibers was observed in areas that contained detectable neurturin expression. In substantia nigra, neurturin expression was detected in 11% of remaining melanin-containing neurons in the patient with combined putamenal and nigral gene delivery, but not in the patient with putamenal gene delivery alone. Tyrosine hydroxylase positive neurons were 66% to 84% of remaining neuromelanin neurons in substantia nigra with Cere120 delivery and 23% to 24% in substantia nigra without gene delivery. More RET and phosphor-S6 positive neurons were observed in substantia nigra following nigral Cere120. Inflammatory and Lewy pathologies were similar in substantia nigra with or without Cere120 delivery.
This study provides evidence of long-term persistent transgene expression and bioactivity following gene delivery to the nigrostriatal system. Therefore, future efforts using gene therapy for neurodegenerative diseases should consider means to enhance remaining dopamine neuron function and stop pathological propagation. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
神经胶质细胞源性神经营养因子（GDNF）家族的神经营养因子神经胶质细胞源性神经营养因子（GDNF）家族的神经营养因子神经胶质细胞源性神经营养因子（GDNF）家族的神经营养因子神经胶质细胞源性神经营养因子（GDNF）家族的神经营养因子神经胶质细胞源性神经营养因子（GDNF）家族的神经营养因子有潜力保护退化的多巴胺能神经元。
在这里，我们对两名接受 AAV-neurturin 基因（Cere120）治疗后存活 10 年的晚期帕金森病患者进行了尸检研究，以验证神经营养因子神经胶质细胞源性神经营养因子（GDNF）的长期作用。
在一个病例中双侧纹状体接受 Cere120 治疗，在第二个病例中双侧纹状体和黑质接受 Cere120 治疗。使用免疫组织化学方法检测神经胶质细胞源性神经营养因子（GDNF）、逆转录（RET）、磷酸化 S6 和酪氨酸羟化酶的表达、炎症反应和α-突触核蛋白的积累。
在两名患者中，纹状体中均存在持续但有限的神经胶质细胞源性神经营养因子（GDNF）表达，占纹状体的 1.31%至 5.92%。在含有可检测到的神经胶质细胞源性神经营养因子（GDNF）表达的区域，观察到酪氨酸羟化酶阳性纤维的密集染色。在黑质中，在接受联合纹状体和黑质基因治疗的患者中，有 11%的剩余含黑色素神经元表达神经胶质细胞源性神经营养因子（GDNF），而在仅接受纹状体基因治疗的患者中则没有。在接受 Cere120 治疗的黑质中，酪氨酸羟化酶阳性神经元占剩余神经黑色素神经元的 66%至 84%，而在未接受基因治疗的黑质中占 23%至 24%。在黑质中观察到更多的 RET 和磷酸化 S6 阳性神经元。在黑质中，有无 Cere120 治疗的炎症和路易体病理相似。
这项研究提供了在黑质纹状体系统中进行基因传递后，长期持续的转基因表达和生物活性的证据。因此，未来使用基因治疗神经退行性疾病的努力应考虑增强剩余多巴胺能神经元功能和阻止病理传播的方法。
