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

• Published in: The Journal of neuroscience Vol. 25; no. 4; pp. 769 - 777
• Main Authors: Eslamboli, Andisheh, Georgievska, Biljana, Ridley, Rosalind M, Baker, Harry F, Muzyczka, Nicholas, Burger, Corinna, Mandel, Ronald J, Annett, Lucy, Kirik, Deniz
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 26-01-2005; Society for Neuroscience
• Subjects: 6-hydroxydopamine; Adeno-associated virus; Animals; Appetitive Behavior - physiology; Basic Medicine; Callithrix; Choice Behavior - physiology; Dependovirus; Disease Models, Animal; dopamine; Dopamine - metabolism; Female; GDNF; gene therapy; Genetic Therapy; Genetic Vectors; Glial Cell Line-Derived Neurotrophic Factor; Green Fluorescent Proteins - biosynthesis; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; monkey; Motor Activity - physiology; Neostriatum - metabolism; Neostriatum - pathology; Nerve Growth Factors - administration & dosage; Nerve Growth Factors - biosynthesis; Nerve Growth Factors - genetics; Nerve Regeneration - physiology; Neurobiology of Disease; Neurosciences; Neurovetenskaper; Oxidopamine; Parkinson Disease - pathology; Parkinson Disease - physiopathology; Parkinson Disease - therapy; Parkinson Disease, Secondary; Perceptual Disorders - physiopathology; Primates; Recombinant Fusion Proteins - biosynthesis; Substantia Nigra - metabolism; Substantia Nigra - pathology; Tyrosine 3-Monooxygenase - metabolism
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/JNEUROSCI.4421-04.2005

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 approximately 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.