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Adeno-associated viral vector serotypes 1 and 5 targeted to the neonatal rat and pig striatum induce widespread transgene expression in the forebrain

Kornum, Birgitte R.; Stott, Simon LU ; Mattsson, Bengt LU ; Wisman, Liselijn LU ; Ettrup, Anders; Hermening, Stephan LU ; Knudsen, Gitte M. and Kirik, Deniz LU (2010) In Experimental Neurology 222(1). p.70-85
Abstract
Viral vector-mediated gene transfer has emerged as a powerful means to target transgene expression in the central nervous system. Here we characterized the efficacy of serotypes 1 and 5 recombinant adeno-associated virus (rAAV) vectors encoding green fluorescent protein (GFP) after stereotaxic delivery to the neonatal rat and minipig striatum. The efficiency of GFP expression and the phenotype of GFP-positive cells were assessed within the forebrain at different time points up to 12 months after surgery. Both rAAV1-GFP and rAAV5-GFP delivery resulted in transduction of the striatum as well as striatal input and output areas, including large parts of the cortex. In both species, rAAV5 resulted in a more widespread transgene expression... (More)
Viral vector-mediated gene transfer has emerged as a powerful means to target transgene expression in the central nervous system. Here we characterized the efficacy of serotypes 1 and 5 recombinant adeno-associated virus (rAAV) vectors encoding green fluorescent protein (GFP) after stereotaxic delivery to the neonatal rat and minipig striatum. The efficiency of GFP expression and the phenotype of GFP-positive cells were assessed within the forebrain at different time points up to 12 months after surgery. Both rAAV1-GFP and rAAV5-GFP delivery resulted in transduction of the striatum as well as striatal input and output areas, including large parts of the cortex. In both species, rAAV5 resulted in a more widespread transgene expression compared to rAAV1. In neonatal rats, rAAV5 also transduced several other areas such as the olfactory bulbs, hippocampus, and septum. Phenotypic analysis of the GFP-positive cells, performed using immunohistochemistry and confocal microscopy, showed that most of the GFP-positive cells by either serotype were NeuN-positive neuronal profiles. The rAAV5 vector further displayed the ability to transduce non-neuronal cell types in both rats and pigs, albeit at a low frequency. Our results show that striatal delivery of rAAV5 vectors in the neonatal brain represents a useful tool to express genes of interest both in the basal ganglia and the neocortex. Furthermore, we apply, for the first time, viral vector-mediated gene transfer to the pig brain providing the opportunity to study effects of genetic manipulation in this non-primate large animal species. Finally, we generated an atlas of the Gottingen minipig brain for guiding future studies in this large animal species. (C) 2009 Elsevier Inc. All rights reserved. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Pig, Rat, Neonate, Cortex, Striatum, In vivo gene transfer, Adeno-associated viral vectors, Swine, Stereology, Confocal microscopy
in
Experimental Neurology
volume
222
issue
1
pages
70 - 85
publisher
Academic Press
external identifiers
  • wos:000275306600010
  • scopus:77649338568
ISSN
0014-4886
DOI
10.1016/j.expneurol.2009.12.009
language
English
LU publication?
yes
id
6003875d-9072-47e5-9543-8ba2542b3e84 (old id 1589590)
date added to LUP
2010-04-20 09:58:11
date last changed
2018-05-29 09:49:44
@article{6003875d-9072-47e5-9543-8ba2542b3e84,
  abstract     = {Viral vector-mediated gene transfer has emerged as a powerful means to target transgene expression in the central nervous system. Here we characterized the efficacy of serotypes 1 and 5 recombinant adeno-associated virus (rAAV) vectors encoding green fluorescent protein (GFP) after stereotaxic delivery to the neonatal rat and minipig striatum. The efficiency of GFP expression and the phenotype of GFP-positive cells were assessed within the forebrain at different time points up to 12 months after surgery. Both rAAV1-GFP and rAAV5-GFP delivery resulted in transduction of the striatum as well as striatal input and output areas, including large parts of the cortex. In both species, rAAV5 resulted in a more widespread transgene expression compared to rAAV1. In neonatal rats, rAAV5 also transduced several other areas such as the olfactory bulbs, hippocampus, and septum. Phenotypic analysis of the GFP-positive cells, performed using immunohistochemistry and confocal microscopy, showed that most of the GFP-positive cells by either serotype were NeuN-positive neuronal profiles. The rAAV5 vector further displayed the ability to transduce non-neuronal cell types in both rats and pigs, albeit at a low frequency. Our results show that striatal delivery of rAAV5 vectors in the neonatal brain represents a useful tool to express genes of interest both in the basal ganglia and the neocortex. Furthermore, we apply, for the first time, viral vector-mediated gene transfer to the pig brain providing the opportunity to study effects of genetic manipulation in this non-primate large animal species. Finally, we generated an atlas of the Gottingen minipig brain for guiding future studies in this large animal species. (C) 2009 Elsevier Inc. All rights reserved.},
  author       = {Kornum, Birgitte R. and Stott, Simon and Mattsson, Bengt and Wisman, Liselijn and Ettrup, Anders and Hermening, Stephan and Knudsen, Gitte M. and Kirik, Deniz},
  issn         = {0014-4886},
  keyword      = {Pig,Rat,Neonate,Cortex,Striatum,In vivo gene transfer,Adeno-associated viral vectors,Swine,Stereology,Confocal microscopy},
  language     = {eng},
  number       = {1},
  pages        = {70--85},
  publisher    = {Academic Press},
  series       = {Experimental Neurology},
  title        = {Adeno-associated viral vector serotypes 1 and 5 targeted to the neonatal rat and pig striatum induce widespread transgene expression in the forebrain},
  url          = {http://dx.doi.org/10.1016/j.expneurol.2009.12.009},
  volume       = {222},
  year         = {2010},
}