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

A Eslamboli, Biljana Georgievska, R M Ridley, H F Baker, N Muzyczka, C Burger, R J Mandel, L Annett, Deniz Kirik

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskriftPeer review

198 Citeringar (SciVal)

Sammanfattning

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.
Originalspråkengelska
Sidor (från-till)769-777
TidskriftJournal of Neuroscience
Volym25
Utgåva4
DOI
StatusPublished - 2005

Ämnesklassifikation (UKÄ)

  • Neurovetenskaper

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