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The Journal of Neuroscience, February 4, 2009, 29(5):1544-1553; doi:10.1523/JNEUROSCI.4491-08.2009

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Neurobiology of Disease
Positron Emission Tomography Imaging Demonstrates Correlation between Behavioral Recovery and Correction of Dopamine Neurotransmission after Gene Therapy

Ludovic Leriche,^1,2 * Tomas Björklund,^3 * Nathalie Breysse,^3 * Laurent Besret,^1,2 Marie-Claude Grégoire,^1,2 Thomas Carlsson,³ Frédéric Dollé,⁴ Ronald J. Mandel,⁵ Nicole Déglon,^1,2 Philippe Hantraye,^1,2 * and Deniz Kirik^3,6 *

¹Centre National de la Recherche Scientifique, Unité de Recherche Associée 2210, 91401 Orsay, France, ²Commissariat à l'Énergie Atomique (CEA), Biomedical Imaging Institute, Molecular Imaging Research Center, 92265 Fontenay-aux-Roses, France, ³Brain Repair and Imaging in Neural Systems, Department of Experimental Medical Science, Lund University, SE-221 84, Lund, Sweden, ⁴CEA, Biomedical Imaging Institute, Service Hospitalier Frédéric Joliot, 91406 Orsay, France, ⁵Department of Neuroscience, McKnight Brain Institute and Gene Therapy Centre, College of Medicine, University of Florida, Gainesville, Florida 32610, and ⁶Lund University Bio-Imaging Center, Faculty of Medicine, SE-221 84 Lund, Sweden

Correspondence should be addressed to Dr. Deniz Kirik, Department of Experimental Medical Science, Brain Repair and Imaging in Neural Systems, Lund University, BMC D11, SE-221 84, Lund, Sweden. Email: deniz.kirik{at}med.lu.se

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.

Key words: Parkinson's disease; recombinant adeno-associated viral vector; tyrosine hydroxylase; GTP cyclohydrolase-1; positron emission tomography; molecular imaging; compartmental modeling

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Received Sept. 19, 2008; revised Nov. 29, 2008; accepted Dec. 16, 2008.

Correspondence should be addressed to Dr. Deniz Kirik, Department of Experimental Medical Science, Brain Repair and Imaging in Neural Systems, Lund University, BMC D11, SE-221 84, Lund, Sweden. Email: deniz.kirik{at}med.lu.se

This article has been cited by other articles:

				A. Bjorklund, T. Bjorklund, and D. Kirik Gene Therapy for Dopamine Replacement in Parkinsons Disease Science Translational Medicine, October 14, 2009; 1(2): 2ps2 - 2ps2. [Full Text] [PDF]

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