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The Journal of Neuroscience, January 26, 2005, 25(4):769-777; doi:10.1523/JNEUROSCI.4421-04.2005

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Neurobiology of Disease
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

Andisheh Eslamboli,¹ Biljana Georgievska,² Rosalind M. Ridley,¹ Harry F. Baker,¹ Nicholas Muzyczka,³ Corinna Burger,³ Ronald J. Mandel,⁴ Lucy Annett,⁵ and Deniz Kirik²

¹Department of Experimental Psychology, University of Cambridge, Cambridge CB2 3EB, United Kingdom, ²Wallenberg Neuroscience Center, Division of Neurobiology, Biomedical Center A11, 221 84 Lund, Sweden, Departments of ³Molecular Genetics and Microbiology and ⁴Neuroscience, McKnight Brain Institute and Gene Therapy Center, College of Medicine, University of Florida, Gainesville, Florida 32610, and ⁵Psychology Department, University of Hertfordshire, Hatfield, Hertfordshire AL10 9AB, United Kingdom

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 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.

Key words: gene therapy; 6-hydroxydopamine; adeno-associated virus; monkey; GDNF; dopamine

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Received Aug 18, 2004; revised November 29, 2004; accepted November 29, 2004.

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