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Optimized adeno-associated viral vector-mediated striatal DOPA delivery restores sensorimotor function and prevents dyskinesias in a model of advanced Parkinson's disease.

Björklund, Tomas LU ; Carlsson, Thomas LU ; Cederfjäll, Erik LU ; Carta, Manolo LU and Kirik, Deniz LU (2010) In Brain 133(Pt 2). p.496-511
Abstract
Viral vector-mediated gene transfer utilizing adeno-associated viral vectors has recently entered clinical testing as a novel tool for delivery of therapeutic agents to the brain. Clinical trials in Parkinson's disease using adeno-associated viral vector-based gene therapy have shown the safety of the approach. Further efforts in this area will show if gene-based approaches can rival the therapeutic efficacy achieved with the best pharmacological therapy or other, already established, surgical interventions. One of the strategies under development for clinical application is continuous 3,4-dihydroxyphenylalanine delivery. This approach has been shown to be efficient in restoring motor function and reducing established dyskinesias in rats... (More)
Viral vector-mediated gene transfer utilizing adeno-associated viral vectors has recently entered clinical testing as a novel tool for delivery of therapeutic agents to the brain. Clinical trials in Parkinson's disease using adeno-associated viral vector-based gene therapy have shown the safety of the approach. Further efforts in this area will show if gene-based approaches can rival the therapeutic efficacy achieved with the best pharmacological therapy or other, already established, surgical interventions. One of the strategies under development for clinical application is continuous 3,4-dihydroxyphenylalanine delivery. This approach has been shown to be efficient in restoring motor function and reducing established dyskinesias in rats with a partial lesion of the nigrostriatal dopamine projection. Here we utilized high purity recombinant adeno-associated viral vectors serotype 5 coding for tyrosine hydroxylase and its co-factor synthesizing enzyme guanosine-5'-triphosphate cyclohydrolase-1, delivered at an optimal ratio of 5 : 1, to show that the enhanced 3,4-dihydroxyphenylalanine production obtained with this optimized delivery system results in robust recovery of function in spontaneous motor tests after complete dopamine denervation. We found that the therapeutic efficacy was substantial and could be maintained for at least 6 months. The tyrosine hydroxylase plus guanosine-5'-triphosphate cyclohydrolase-1 treated animals were resistant to developing dyskinesias upon peripheral l-3,4-dihydroxyphenylalanine drug challenge, which is consistent with the interpretation that continuous dopamine stimulation resulted in a normalization of the post-synaptic response. Interestingly, recovery of forelimb use in the stepping test observed here was maintained even after a second lesion depleting the serotonin input to the forebrain, suggesting that the therapeutic efficacy was not solely dependent on dopamine synthesis and release from striatal serotonergic terminals. Taken together these results show that vector-mediated continuous 3,4-dihydroxyphenylalanine delivery has the potential to provide significant symptomatic relief even in advanced stages of Parkinson's disease. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Brain
volume
133
issue
Pt 2
pages
496 - 511
publisher
Oxford University Press
external identifiers
  • wos:000274777700015
  • pmid:20129936
  • scopus:77249179185
ISSN
1460-2156
DOI
10.1093/brain/awp314
language
English
LU publication?
yes
id
649649e1-7ec1-4d1e-b0b0-7e5b656aa27f (old id 1552968)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/20129936?dopt=Abstract
date added to LUP
2010-03-02 15:12:22
date last changed
2018-05-29 11:01:39
@article{649649e1-7ec1-4d1e-b0b0-7e5b656aa27f,
  abstract     = {Viral vector-mediated gene transfer utilizing adeno-associated viral vectors has recently entered clinical testing as a novel tool for delivery of therapeutic agents to the brain. Clinical trials in Parkinson's disease using adeno-associated viral vector-based gene therapy have shown the safety of the approach. Further efforts in this area will show if gene-based approaches can rival the therapeutic efficacy achieved with the best pharmacological therapy or other, already established, surgical interventions. One of the strategies under development for clinical application is continuous 3,4-dihydroxyphenylalanine delivery. This approach has been shown to be efficient in restoring motor function and reducing established dyskinesias in rats with a partial lesion of the nigrostriatal dopamine projection. Here we utilized high purity recombinant adeno-associated viral vectors serotype 5 coding for tyrosine hydroxylase and its co-factor synthesizing enzyme guanosine-5'-triphosphate cyclohydrolase-1, delivered at an optimal ratio of 5 : 1, to show that the enhanced 3,4-dihydroxyphenylalanine production obtained with this optimized delivery system results in robust recovery of function in spontaneous motor tests after complete dopamine denervation. We found that the therapeutic efficacy was substantial and could be maintained for at least 6 months. The tyrosine hydroxylase plus guanosine-5'-triphosphate cyclohydrolase-1 treated animals were resistant to developing dyskinesias upon peripheral l-3,4-dihydroxyphenylalanine drug challenge, which is consistent with the interpretation that continuous dopamine stimulation resulted in a normalization of the post-synaptic response. Interestingly, recovery of forelimb use in the stepping test observed here was maintained even after a second lesion depleting the serotonin input to the forebrain, suggesting that the therapeutic efficacy was not solely dependent on dopamine synthesis and release from striatal serotonergic terminals. Taken together these results show that vector-mediated continuous 3,4-dihydroxyphenylalanine delivery has the potential to provide significant symptomatic relief even in advanced stages of Parkinson's disease.},
  author       = {Björklund, Tomas and Carlsson, Thomas and Cederfjäll, Erik and Carta, Manolo and Kirik, Deniz},
  issn         = {1460-2156},
  language     = {eng},
  number       = {Pt 2},
  pages        = {496--511},
  publisher    = {Oxford University Press},
  series       = {Brain},
  title        = {Optimized adeno-associated viral vector-mediated striatal DOPA delivery restores sensorimotor function and prevents dyskinesias in a model of advanced Parkinson's disease.},
  url          = {http://dx.doi.org/10.1093/brain/awp314},
  volume       = {133},
  year         = {2010},
}