Abstract

We performed post-mortem studies on two patients with advanced Parkinson’s disease 8 and10 years following AAV2-neurturin (CERE120) gene therapy, the longest post-mortem trophic factor gene therapy cases reported to date. CERE120 was delivered to the putamen bilaterally in one case (10 years post-surgery), and to the putamen plus the substantia nigra bilaterally in the second (8 years post-surgery). In both patients there was persistent, albeit limited, neurturin expression in the putamen covering ∼3–12% of the putamen. In the putamen, dense staining of tyrosine hydroxylase-positive fibres was observed in areas that contained detectable neurturin expression. In the substantia nigra, neurturin expression was detected in 9.8–18.95% and 22.02–39% of remaining melanin-containing neurons in the patient with putamenal and combined putamenal and nigral gene delivery, respectively. Melanized neurons displayed intense tyrosine hydroxylase and RET proto-oncogene expression in nigral neurons in the patient where CERE120 was directly delivered to the nigra. There was no difference in the degree of Lewy pathology in comparison to untreated control patients with Parkinson’s disease, and α-synuclein aggregates were detected in neurons that also stained for neurturin, RET, and tyrosine hydroxylase. These changes were not associated with antiparkinsonian benefits likely due to the limited neurturin expression. This study provides the longest term evidence of persistent transgene expression following gene delivery to the CNS and the first human results when targeting both the terminal fields in the putamen as well as the originating nigral neurons.

中文翻译：

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神经营养素基因治疗后晚期帕金森氏病患者的长期尸检研究。

摘要

我们对两名AAV2-neurturin（CERE120）基因治疗后8和10年晚期帕金森氏病患者进行了死后研究，这是迄今为止报道的最长的死后营养因子基因治疗病例。CERE120在一种情况下（手术后10年）以双边方式递送至壳核，第二例（术后8年）则以双边方式递送至壳核和黑质。在这两名患者中，神经核蛋白在壳核中的表达持续存在，尽管是有限的，约占壳核的3–12％。在壳核中，在含有可检测到的神经营养蛋白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9.8-18.95％和22中检测到神经营养素表达。进行了肺动脉栓塞和联合肺动脉栓塞和黑色素基因递送的患者中，分别剩下02-39％的含黑色素神经元。黑色素化的神经元在CERE120直接递送至黑质的患者的黑质神经元中显示出强烈的酪氨酸羟化酶和RET原癌基因表达。与未经治疗的帕金森氏病对照患者相比，路易氏病理的程度没有差异，并且在神经元中还检测到了α-突触核蛋白聚集体，这些神经元也被神经营养素，RET和酪氨酸羟化酶染色。这些变化与神经帕金森蛋白表达受限可能与抗帕金森病的益处无关。