Positron emission tomography imaging demonstrates correlation between behavioral recovery and correction of dopamine neurotransmission after gene therapy.
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Date
2009-02-04
Journal Title
Journal ISSN
Volume Title
Publisher
Society for Neuroscience
Abstract
In vivo gene transfer using viral vectors is an emerging therapy for neurodegenerative diseases with a clinical impact recently demonstrated in Parkinson's disease patients. Recombinant adeno-associated viral (rAAV) vectors, in particular, provide an excellent tool for long-term expression of therapeutic genes in the brain. Here we used the [11C]raclopride [(S)-(–)-3,5-dichloro-N-((1-ethyl-2-pyrrolidinyl)methyl)-2-hydroxy-6-methoxybenzamide] micro-positron emission tomography (PET) technique to demonstrate that delivery of the tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GCH1) enzymes using an rAAV5 vector normalizes the increased [11C]raclopride binding in hemiparkinsonian rats. Importantly, we show in vivo by microPET imaging and postmortem by classical binding assays performed in the very same animals that the changes in [11C]raclopride after viral vector-based enzyme replacement therapy is attributable to a decrease in the affinity of the tracer binding to the D2 receptors, providing evidence for reconstitution of a functional pool of endogenous dopamine in the striatum. Moreover, the extent of the normalization in this non-invasive imaging measure was highly correlated with the functional recovery in motor behavior. The PET imaging protocol used in this study is fully adaptable to humans and thus can serve as an in vivo imaging technique to follow TH + GCH1 gene therapy in PD patients and provide an additional objective measure to a potential clinical trial using rAAV vectors to deliver L-3,4-dihydroxyphenylanaline in the brain. © 2009, Society for Neuroscience
Description
Keywords
Positron computed tomography, Dopamine, Gene therapy, Diseases, Simulation, Correlations
Citation
Leriche, L., Bjorklund, T., Breysse, N., Besret, L.,Grégoire , M. C., Carlsson, T., Dollé, F., Mandel, R. J., Déglon, N., Hantrayne, P., & Kirik, D. (2009). Positron emission tomography imaging demonstrates correlation between behavioral recovery and correction of dopamine neurotransmission after gene therapy. Journal of Neuroscience, 29(5), 1544-1553. doi:10.1523/JNEUROSCI.4491-08.2009