25-07-08(14:41:52)
Authors:
Tomas Björklund1, Ludovic Leriche2, Nathalie Breysse1, Laurent Besret2 , Marie-Claude Grégoire2, Thomas Carlsson1, Frédéric Dollé3, Ronald J Mandel4, Nicole Déglon2, Philippe Hantraye2 and Deniz Kirik1
Institutions:
1 B.R.A.I.N.S Unit, BMC D11, Department of Experimental Medical Science, Lund University, Sweden; 2 URA CEA/CNRS 2210, MIRCen, France; 3 Laboratoire d’Imagerie Moléculaire Expérimentale, CEA, Orsay, France; 4 Department of Neuroscience, McKnight Brain Institute and Gene Therapy Centre, University of Florida, USA
Title of abstract : PET imaging demonstrates correlation between correction of dopamine neurotransmission and behavioral recovery following gene therapy
Abstract text:
It has been hypothesized that complications related to oral administration of L-DOPA in Parkinson’s disease (PD) may, at least in part, be due to the intermittent, pulsatile supply of L-DOPA provided by peripheral administration. Thus, we are currently developing a novel gene therapy strategy to provide long-term continuous DOPA administration using recombinant adeno-associated viral vector serotype 5 (rAAV5) to over-express tyrosine hydroxylase (TH) and GTP-cyclohydrolase (GCH1) enzymes. Here we provide the first demonstration that ectopic dopamine synthesis after rAAV mediated DOPA delivery can reconstitute a functional pool of dopamine (DA) in the parkinsonian striatum. To determine this, we utilized a novel quantification method to determine binding potential (BP), binding affinity (1/KdVr) and receptor density (Bmax) of striatal D2 receptors from a single [11C]raclopride PET scan. We found that continuous in vivo L-DOPA delivery normalizes the lesion-induced increase in raclopride binding affinity in the DA-delpeted striatum. Neither 6-OHDA lesion nor DOPA delivery affected the Bmax in this experimental paradigm. Although DA levels were reconstituted only to 12% of levels in the intact striatum (9.4 pmol/mg), the synaptic concentration was sufficient to restore motor function in drug-naïve motor tests such as cylinder, staircase and stepping tests. Further we found that the binding affinity is a good predictor of DA synthesis and behavioral recovery after rAAV mediated continuous DOPA delivery. These results strengthen the evidence that this gene therapy strategy holds great promise for the treatment of PD patients, especially those in the complication phase. [11C]raclopride PET is a well suited, non-invasive, method to study the efficacy of rAAV-TH-GCH1 gene transfer and provides a useful surrogate marker to predict the therapeutical benefits in future patient trials.
