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Continuous DOPA synthesis from a single AAV: dosing and efficacy in models of Parkinson's disease.

Cederfjäll, Erik LU ; Nilsson, Nathalie LU ; Sahin, Gurdal LU ; Chu, Yaping; Nikitidou, Elisabeth LU ; Björklund, Tomas LU ; Kordower, Jeffrey H and Kirik, Deniz LU (2013) In Scientific Reports 3.
Abstract
We used a single adeno-associated viral (AAV) vector co-expressing tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GCH1) to investigate the relationship between vector dose, and the magnitude and rate of recovery in hemi-parkinsonian rats. Intrastriatal injections of >1E10 genomic copies (gc) of TH-GCH1 vector resulted in complete recovery in drug-naïve behavior tests. Lower vector dose gave partial to no functional improvement. Stereological quantification revealed no striatal NeuN+ cell loss in any of the groups, whereas a TH-GCH1 dose of >1E11 gc resulted in cell loss in globus pallidus. Thus, a TH-GCH1 dose of 1E10 gc gave complete recovery without causing neuronal loss. Safety and efficacy was also studied in non-human... (More)
We used a single adeno-associated viral (AAV) vector co-expressing tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GCH1) to investigate the relationship between vector dose, and the magnitude and rate of recovery in hemi-parkinsonian rats. Intrastriatal injections of >1E10 genomic copies (gc) of TH-GCH1 vector resulted in complete recovery in drug-naïve behavior tests. Lower vector dose gave partial to no functional improvement. Stereological quantification revealed no striatal NeuN+ cell loss in any of the groups, whereas a TH-GCH1 dose of >1E11 gc resulted in cell loss in globus pallidus. Thus, a TH-GCH1 dose of 1E10 gc gave complete recovery without causing neuronal loss. Safety and efficacy was also studied in non-human primates where the control vector resulted in co-expression of the transgenes in caudate-putamen. In the TH-GCH1 group, GCH1 expression was robust but TH was not detectable. Moreover, TH-GCH1 treatment did not result in functional improvement in non-human primates. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Scientific Reports
volume
3
publisher
Nature Publishing Group
external identifiers
  • wos:000321425700005
  • pmid:23831692
  • scopus:84880302312
ISSN
2045-2322
DOI
10.1038/srep02157
language
English
LU publication?
yes
id
a6107052-8c2f-4120-8f89-5c0e9e93870f (old id 3956118)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/23831692?dopt=Abstract
date added to LUP
2013-08-02 11:02:05
date last changed
2019-05-14 02:49:34
@article{a6107052-8c2f-4120-8f89-5c0e9e93870f,
  abstract     = {We used a single adeno-associated viral (AAV) vector co-expressing tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GCH1) to investigate the relationship between vector dose, and the magnitude and rate of recovery in hemi-parkinsonian rats. Intrastriatal injections of >1E10 genomic copies (gc) of TH-GCH1 vector resulted in complete recovery in drug-naïve behavior tests. Lower vector dose gave partial to no functional improvement. Stereological quantification revealed no striatal NeuN+ cell loss in any of the groups, whereas a TH-GCH1 dose of >1E11 gc resulted in cell loss in globus pallidus. Thus, a TH-GCH1 dose of 1E10 gc gave complete recovery without causing neuronal loss. Safety and efficacy was also studied in non-human primates where the control vector resulted in co-expression of the transgenes in caudate-putamen. In the TH-GCH1 group, GCH1 expression was robust but TH was not detectable. Moreover, TH-GCH1 treatment did not result in functional improvement in non-human primates.},
  articleno    = {2157},
  author       = {Cederfjäll, Erik and Nilsson, Nathalie and Sahin, Gurdal and Chu, Yaping and Nikitidou, Elisabeth and Björklund, Tomas and Kordower, Jeffrey H and Kirik, Deniz},
  issn         = {2045-2322},
  language     = {eng},
  publisher    = {Nature Publishing Group},
  series       = {Scientific Reports},
  title        = {Continuous DOPA synthesis from a single AAV: dosing and efficacy in models of Parkinson's disease.},
  url          = {http://dx.doi.org/10.1038/srep02157},
  volume       = {3},
  year         = {2013},
}