Long-term post-mortem studies following neurturin gene therapy in patients with advanced Parkinson's disease
Document Type
Article
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 a-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.
Keywords
Dopaminergic neuron, Gene therapy, Neuroprotection, Neurturin, Parkinson's disease
Publication Date
3-1-2020
Publication Title
Brain
ISSN
00068950
E-ISSN
14602156
Volume
143
Issue
3
First Page
960
Last Page
975
PubMed ID
32203581
Digital Object Identifier (DOI)
10.1093/brain/awaa020
Recommended Citation
Chu, Yaping; Bartus, Raymond T.; Manfredsson, Fredric P.; Warren Olanow, C.; and Kordower, Jeffrey H., "Long-term post-mortem studies following neurturin gene therapy in patients with advanced Parkinson's disease" (2020). Translational Neuroscience. 1432.
https://scholar.barrowneuro.org/neurobiology/1432