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

In English

Författare

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

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.

Publiceringsår

2009

Språk

Engelska

Sidor

1544-1553

Publikation/Tidskrift/Serie

Journal of Neuroscience

Volym

29

Issue

5

Dokumenttyp

Artikel i tidskrift

Förlag

Society for Neuroscience

Ämne

  • Neurosciences

Nyckelord

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

Status

Published

Forskningsgrupp

  • Brain Repair and Imaging in Neural Systems (BRAINS)

ISBN/ISSN/Övrigt

  • ISSN: 1529-2401