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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

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Author

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

Summary, in English

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.

Publishing year

2005

Language

English

Pages

769-777

Publication/Series

The Journal of Neuroscience

Volume

25

Issue

4

Document type

Journal article

Publisher

Society for Neuroscience

Topic

  • Neurosciences

Keywords

  • adeno-associated virus
  • gene therapy
  • 6-hydroxydopamine
  • GDNF
  • dopamine
  • monkey

Status

Published

Research group

  • Neurobiology
  • Brain Repair and Imaging in Neural Systems (BRAINS)

ISBN/ISSN/Other

  • ISSN: 1529-2401