The browser you are using is not supported by this website. All versions of Internet Explorer are no longer supported, either by us or Microsoft (read more here: https://www.microsoft.com/en-us/microsoft-365/windows/end-of-ie-support).

Please use a modern browser to fully experience our website, such as the newest versions of Edge, Chrome, Firefox or Safari etc.

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

På svenska

Author

  • Ludovic Leriche
  • Tomas Björklund
  • Nathalie Breysse
  • Laurent Besret
  • Marie-Claude Gregoire
  • Thomas Carlsson
  • Frederic Dolle
  • Ronald J. Mandel
  • Nicole Deglon
  • Philippe Hantraye
  • Deniz Kirik
Show all

Summary, in English

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.

Publishing year

2009

Language

English

Pages

1544-1553

Publication/Series

Journal of Neuroscience

Volume

29

Issue

5

Document type

Journal article

Publisher

Society for Neuroscience

Topic

  • Neurosciences

Keywords

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

Status

Published

Research group

  • Brain Repair and Imaging in Neural Systems (BRAINS)

ISBN/ISSN/Other

  • ISSN: 1529-2401