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

被引:185
作者
Eslamboli, A
Georgievska, B
Ridley, RM
Baker, HF
Muzyczka, N
Burger, C
Mandel, RJ
Annett, L
Kirik, D
机构
[1] Univ Cambridge, Dept Expt Psychol, Cambridge CB2 3EB, England
[2] Biomed Ctr A11, Div Neurobiol, Wallenberg Neurosci Ctr, S-22184 Lund, Sweden
[3] Univ Florida, Coll Med, McKnight Brain Inst, Dept Mol Genet & Microbiol, Gainesville, FL 32610 USA
[4] Univ Florida, Coll Med, McKnight Brain Inst, Dept Neurosci, Gainesville, FL 32610 USA
[5] Univ Florida, Coll Med, Gene Therapy Ctr, Gainesville, FL 32610 USA
[6] Univ Hertfordshire, Dept Psychol, Hatfield AL10 9AB, Herts, England
基金
英国惠康基金;
关键词
gene therapy; 6-hydroxydopamine; adeno-associated virus; monkey; GDNF; dopamine;
D O I
10.1523/JNEUROSCI.4421-04.2005
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:769 / 777
页数:9
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