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Reversal of motor impairments in parkinsonian rats by continuous intrastriatal delivery of L-dopa using rAAV-mediated gene transfer.

Kirik, Deniz LU ; Georgievska, Biljana LU ; Burger, Corinna; Winkler, Christian; Muzyczka, Nicholas; Mandel, Ronald J and Björklund, Anders LU (2002) In Proceedings of the National Academy of Sciences 99(7). p.4708-4713
Abstract
Intrastriatal delivery of the tyrosine hydroxylase gene by viral vectors is being explored as a tool for local delivery of L-dopa in animals with lesions of the nigrostriatal pathway. The functional effects reported using this approach have been disappointing, probably because the striatal L-dopa levels attained have been too low. In the present study, we have defined a critical threshold level of L-dopa, 1.5 pmol/mg of tissue, that has to be reached to induce any significant functional effects. Using new generation high-titer recombinant adeno-associated virus vectors, we show that levels of striatal L-dopa production exceeding this threshold can be obtained provided that tyrosine hydroxylase is coexpressed with the cofactor synthetic... (More)
Intrastriatal delivery of the tyrosine hydroxylase gene by viral vectors is being explored as a tool for local delivery of L-dopa in animals with lesions of the nigrostriatal pathway. The functional effects reported using this approach have been disappointing, probably because the striatal L-dopa levels attained have been too low. In the present study, we have defined a critical threshold level of L-dopa, 1.5 pmol/mg of tissue, that has to be reached to induce any significant functional effects. Using new generation high-titer recombinant adeno-associated virus vectors, we show that levels of striatal L-dopa production exceeding this threshold can be obtained provided that tyrosine hydroxylase is coexpressed with the cofactor synthetic enzyme, GTP-cyclohydrolase-1. After striatal transduction with this combination of vectors, substantial functional improvement in both drug-induced and spontaneous behavior was observed in rats with either complete or partial 6-hydroxydopamine lesions of the nigrostriatal pathway. However, complete reversal of motor deficits occurred only in animals in which part of the striatal dopamine innervation was left intact. Spared nigrostriatal fibers thus may convert L-dopa to dopamine and store and release dopamine in a more physiologically relevant manner in the denervated striatum to mediate better striatal output-dependent motor function. We conclude that intrastriatal L-dopa delivery may be a viable strategy for treatment and control of adverse side effects associated with oral L-dopa therapy such as on-off fluctuations and drug-induced dyskinesias in patients with Parkinson's disease. (Less)
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published
subject
keywords
Gene Transfer, Horizontal, Levodopa : administration & dosage, Levodopa : metabolism, Parkinson Disease : therapy, Rats, Sprague-Dawley, Support, Non-U.S. Gov't, U.S. Gov't, P.H.S., Tyrosine 3-Monooxygenase : genetics, Gene Therapy, GTP Cyclohydrolase : genetics, Female, Dependovirus : genetics, Corpus Striatum : metabolism, Animal
in
Proceedings of the National Academy of Sciences
volume
99
issue
7
pages
4708 - 4713
publisher
National Acad Sciences
external identifiers
  • wos:000174856000102
  • pmid:11917105
  • scopus:0037007106
ISSN
1091-6490
DOI
10.1073/pnas.062047599
language
English
LU publication?
yes
id
c9cf82a6-6abf-4217-8283-f73c528ac5bb (old id 107342)
date added to LUP
2007-07-16 12:57:39
date last changed
2017-08-13 03:35:33
@article{c9cf82a6-6abf-4217-8283-f73c528ac5bb,
  abstract     = {Intrastriatal delivery of the tyrosine hydroxylase gene by viral vectors is being explored as a tool for local delivery of L-dopa in animals with lesions of the nigrostriatal pathway. The functional effects reported using this approach have been disappointing, probably because the striatal L-dopa levels attained have been too low. In the present study, we have defined a critical threshold level of L-dopa, 1.5 pmol/mg of tissue, that has to be reached to induce any significant functional effects. Using new generation high-titer recombinant adeno-associated virus vectors, we show that levels of striatal L-dopa production exceeding this threshold can be obtained provided that tyrosine hydroxylase is coexpressed with the cofactor synthetic enzyme, GTP-cyclohydrolase-1. After striatal transduction with this combination of vectors, substantial functional improvement in both drug-induced and spontaneous behavior was observed in rats with either complete or partial 6-hydroxydopamine lesions of the nigrostriatal pathway. However, complete reversal of motor deficits occurred only in animals in which part of the striatal dopamine innervation was left intact. Spared nigrostriatal fibers thus may convert L-dopa to dopamine and store and release dopamine in a more physiologically relevant manner in the denervated striatum to mediate better striatal output-dependent motor function. We conclude that intrastriatal L-dopa delivery may be a viable strategy for treatment and control of adverse side effects associated with oral L-dopa therapy such as on-off fluctuations and drug-induced dyskinesias in patients with Parkinson's disease.},
  author       = {Kirik, Deniz and Georgievska, Biljana and Burger, Corinna and Winkler, Christian and Muzyczka, Nicholas and Mandel, Ronald J and Björklund, Anders},
  issn         = {1091-6490},
  keyword      = {Gene Transfer,Horizontal,Levodopa : administration & dosage,Levodopa : metabolism,Parkinson Disease : therapy,Rats,Sprague-Dawley,Support,Non-U.S. Gov't,U.S. Gov't,P.H.S.,Tyrosine 3-Monooxygenase : genetics,Gene Therapy,GTP Cyclohydrolase : genetics,Female,Dependovirus : genetics,Corpus Striatum : metabolism,Animal},
  language     = {eng},
  number       = {7},
  pages        = {4708--4713},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {Reversal of motor impairments in parkinsonian rats by continuous intrastriatal delivery of L-dopa using rAAV-mediated gene transfer.},
  url          = {http://dx.doi.org/10.1073/pnas.062047599},
  volume       = {99},
  year         = {2002},
}