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.
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.
Eslamboli
Andisheh
A
Department of Experimental Psychology, University of Cambridge, Cambridge CB2 3EB, United Kingdom. ae228@cam.ac.uk
Georgievska
Biljana
B
Ridley
Rosalind M
RM
Baker
Harry F
HF
Muzyczka
Nicholas
N
Burger
Corinna
C
Mandel
Ronald J
RJ
Annett
Lucy
L
Kirik
Deniz
D
D000818:Animals; D001070:Appetitive Behavior / Q000502:physiology; D002144:Callithrix; D002755:Choice Behavior / Q000502:physiology; D000229:Dependovirus; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D051100:Glial Cell Line-Derived Neurotrophic Factor; D049452:Green Fluorescent Proteins / Q000096:biosynthesis; D008297:Male; D009043:Motor Activity / Q000502:physiology; D017072:Neostriatum / Q000378:metabolism* / Q000473:pathology; D009414:Nerve Growth Factors / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics*; D009416:Nerve Regeneration / Q000502:physiology; D016627:Oxidopamine; D010300:Parkinson Disease / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D010302:Parkinson Disease, Secondary; D010468:Perceptual Disorders / Q000503:physiopathology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine