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

Leriche, Ludovic; Björklund, Tomas LU ; Breysse, Nathalie LU ; Besret, Laurent; Gregoire, Marie-Claude; Carlsson, Thomas LU ; Dolle, Frederic; Mandel, Ronald J.; Deglon, Nicole and Hantraye, Philippe, et al. (2009) In Journal of Neuroscience 29(5). p.1544-1553
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 [C-11] raclopride [(S)-(-)-3,5-dichloro-N-((1-ethyl-2-pyrrolidinyl) methyl)-2-hydroxy6-methoxybenzamide] micro-positron emission tomography (PET) technique to demonstrate that delivery of the tyrosine hydroxylase (TH) andGTPcyclohydrolase 1 (GCH1) enzymes using an rAAV5 vector normalizes the increased [C-11] raclopride binding in hemiparkinsonian rats. Importantly, we show in vivo by microPET imaging... (More)
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 [C-11] raclopride [(S)-(-)-3,5-dichloro-N-((1-ethyl-2-pyrrolidinyl) methyl)-2-hydroxy6-methoxybenzamide] micro-positron emission tomography (PET) technique to demonstrate that delivery of the tyrosine hydroxylase (TH) andGTPcyclohydrolase 1 (GCH1) enzymes using an rAAV5 vector normalizes the increased [C-11] 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 [C-11] raclopride after viral vector-based enzyme replacement therapy is attributable to a decrease in the affinity of the tracer binding to the D-2 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 patientsandprovideanadditionalobjectivemeasuretoapotentialclinicaltrialu singrAAVvectorstodeliverL-3,4-dihydroxyphenylanalineinthebrain. (Less)
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published
subject
keywords
tomography, positron emission, GTP cyclohydrolase-1, tyrosine hydroxylase, Parkinson's disease, recombinant adeno-associated viral vector, compartmental modeling, molecular imaging
in
Journal of Neuroscience
volume
29
issue
5
pages
1544 - 1553
publisher
Society for Neuroscience
external identifiers
  • wos:000263072400030
  • scopus:59649116335
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.4491-08.2009
language
English
LU publication?
yes
id
3273bd56-1177-4aa2-997d-e308ab2c8c74 (old id 1311398)
date added to LUP
2009-03-18 08:51:44
date last changed
2017-06-04 04:13:28
@article{3273bd56-1177-4aa2-997d-e308ab2c8c74,
  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 [C-11] raclopride [(S)-(-)-3,5-dichloro-N-((1-ethyl-2-pyrrolidinyl) methyl)-2-hydroxy6-methoxybenzamide] micro-positron emission tomography (PET) technique to demonstrate that delivery of the tyrosine hydroxylase (TH) andGTPcyclohydrolase 1 (GCH1) enzymes using an rAAV5 vector normalizes the increased [C-11] 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 [C-11] raclopride after viral vector-based enzyme replacement therapy is attributable to a decrease in the affinity of the tracer binding to the D-2 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 patientsandprovideanadditionalobjectivemeasuretoapotentialclinicaltrialu singrAAVvectorstodeliverL-3,4-dihydroxyphenylanalineinthebrain.},
  author       = {Leriche, Ludovic and Björklund, Tomas and Breysse, Nathalie and Besret, Laurent and Gregoire, Marie-Claude and Carlsson, Thomas and Dolle, Frederic and Mandel, Ronald J. and Deglon, Nicole and Hantraye, Philippe and Kirik, Deniz},
  issn         = {1529-2401},
  keyword      = {tomography,positron emission,GTP cyclohydrolase-1,tyrosine hydroxylase,Parkinson's disease,recombinant adeno-associated viral vector,compartmental modeling,molecular imaging},
  language     = {eng},
  number       = {5},
  pages        = {1544--1553},
  publisher    = {Society for Neuroscience},
  series       = {Journal of Neuroscience},
  title        = {Positron Emission Tomography Imaging Demonstrates Correlation between Behavioral Recovery and Correction of Dopamine Neurotransmission after Gene Therapy},
  url          = {http://dx.doi.org/10.1523/JNEUROSCI.4491-08.2009},
  volume       = {29},
  year         = {2009},
}