Advanced

Continuous low-level glial cell line-derived neurotrophic factor delivery using recombinant adeno-associated viral vectors provides neuroprotection and induces behavioral recovery in a primate model of Parkinson's disease

Eslamboli, A; Georgievska, Biljana LU ; Ridley, R M; Baker, H F; Muzyczka, N; Burger, C; Mandel, R J; Annett, L and Kirik, Deniz LU (2005) In Journal of Neuroscience 25(4). p.769-777
Abstract
The therapeutic potential of glial cell line-derived neurotrophic factor ( GDNF) for Parkinson's disease is likely to depend on sustained delivery of the appropriate amount to the target areas. Recombinant adeno-associated viral vectors ( rAAVs) expressing GDNF may be a suitable delivery system for this purpose. The aim of this study was to define a sustained level of GDNF that does not affect the function of the normal dopamine (DA) neurons but does provide anatomical and behavioral protection against an intrastriatal 6-hydroxydopamine (6-OHDA) lesion in the common marmoset. We found that unilateral intrastriatal injection of rAAV resulting in the expression of high levels of GDNF ( 14 ng/mg of tissue) in the striatum induced a... (More)
The therapeutic potential of glial cell line-derived neurotrophic factor ( GDNF) for Parkinson's disease is likely to depend on sustained delivery of the appropriate amount to the target areas. Recombinant adeno-associated viral vectors ( rAAVs) expressing GDNF may be a suitable delivery system for this purpose. The aim of this study was to define a sustained level of GDNF that does not affect the function of the normal dopamine (DA) neurons but does provide anatomical and behavioral protection against an intrastriatal 6-hydroxydopamine (6-OHDA) lesion in the common marmoset. We found that unilateral intrastriatal injection of rAAV resulting in the expression of high levels of GDNF ( 14 ng/mg of tissue) in the striatum induced a substantial bilateral increase in tyrosine hydroxylase protein levels and activity as well as in DA turnover. Expression of low levels of GDNF (0.04 ng/mg of tissue), on the other hand, produced only minimal effects on DA synthesis and only on the injected side. In addition, the low level of GDNF provided similar to 85% protection of the nigral DA neurons and their projections to the striatum in the 6-OHDA-lesioned hemisphere. Furthermore, the anatomical protection was accompanied by a complete attenuation of sensorimotor neglect, head position bias, and amphetamine-induced rotation. We conclude that when delivered continuously, a low level of GDNF in the striatum ( approximately threefold above baseline) is sufficient to provide optimal functional outcome. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
adeno-associated virus, gene therapy, 6-hydroxydopamine, GDNF, dopamine, monkey
in
Journal of Neuroscience
volume
25
issue
4
pages
769 - 777
publisher
Society for Neuroscience
external identifiers
  • wos:000226577000001
  • pmid:15673656
  • scopus:12844287442
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.4421-04.2005
language
English
LU publication?
yes
id
2457b4a6-1fc2-4714-98ab-ba548c792f83 (old id 254782)
date added to LUP
2007-08-07 12:51:36
date last changed
2017-11-19 04:08:22
@article{2457b4a6-1fc2-4714-98ab-ba548c792f83,
  abstract     = {The therapeutic potential of glial cell line-derived neurotrophic factor ( GDNF) for Parkinson's disease is likely to depend on sustained delivery of the appropriate amount to the target areas. Recombinant adeno-associated viral vectors ( rAAVs) expressing GDNF may be a suitable delivery system for this purpose. The aim of this study was to define a sustained level of GDNF that does not affect the function of the normal dopamine (DA) neurons but does provide anatomical and behavioral protection against an intrastriatal 6-hydroxydopamine (6-OHDA) lesion in the common marmoset. We found that unilateral intrastriatal injection of rAAV resulting in the expression of high levels of GDNF ( 14 ng/mg of tissue) in the striatum induced a substantial bilateral increase in tyrosine hydroxylase protein levels and activity as well as in DA turnover. Expression of low levels of GDNF (0.04 ng/mg of tissue), on the other hand, produced only minimal effects on DA synthesis and only on the injected side. In addition, the low level of GDNF provided similar to 85% protection of the nigral DA neurons and their projections to the striatum in the 6-OHDA-lesioned hemisphere. Furthermore, the anatomical protection was accompanied by a complete attenuation of sensorimotor neglect, head position bias, and amphetamine-induced rotation. We conclude that when delivered continuously, a low level of GDNF in the striatum ( approximately threefold above baseline) is sufficient to provide optimal functional outcome.},
  author       = {Eslamboli, A and Georgievska, Biljana and Ridley, R M and Baker, H F and Muzyczka, N and Burger, C and Mandel, R J and Annett, L and Kirik, Deniz},
  issn         = {1529-2401},
  keyword      = {adeno-associated virus,gene therapy,6-hydroxydopamine,GDNF,dopamine,monkey},
  language     = {eng},
  number       = {4},
  pages        = {769--777},
  publisher    = {Society for Neuroscience},
  series       = {Journal of Neuroscience},
  title        = {Continuous low-level glial cell line-derived neurotrophic factor delivery using recombinant adeno-associated viral vectors provides neuroprotection and induces behavioral recovery in a primate model of Parkinson's disease},
  url          = {http://dx.doi.org/10.1523/JNEUROSCI.4421-04.2005},
  volume       = {25},
  year         = {2005},
}