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
(2005) In The 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:
https://lup.lub.lu.se/record/254782
- author
- Eslamboli, A ; Georgievska, Biljana LU ; Ridley, R M ; Baker, H F ; Muzyczka, N ; Burger, C ; Mandel, R J ; Annett, L and Kirik, Deniz LU
- organization
- publishing date
- 2005
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- adeno-associated virus, gene therapy, 6-hydroxydopamine, GDNF, dopamine, monkey
- in
- The Journal of Neuroscience
- volume
- 25
- issue
- 4
- pages
- 769 - 777
- publisher
- Society for Neuroscience
- external identifiers
-
- wos:000226577000001
- pmid:15673656
- scopus:12844287442
- pmid:15673656
- 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
- 2016-04-01 16:09:00
- date last changed
- 2023-10-31 00:48:03
@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}}, keywords = {{adeno-associated virus; gene therapy; 6-hydroxydopamine; GDNF; dopamine; monkey}}, language = {{eng}}, number = {{4}}, pages = {{769--777}}, publisher = {{Society for Neuroscience}}, series = {{The 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}}, doi = {{10.1523/JNEUROSCI.4421-04.2005}}, volume = {{25}}, year = {{2005}}, }