In:
The Journal of Neuroscience, Society for Neuroscience, Vol. 30, No. 49 ( 2010-12-08), p. 16469-16474
Kurzfassung:
Loss of dopaminergic neurons is primarily responsible for the onset and progression of Parkinson's disease (PD); thus, neuroprotective and/or neuroregenerative strategies remain critical to the treatment of this increasingly prevalent disease. Here we explore a novel approach to neurotrophic factor-based therapy by engineering zinc finger protein transcription factors (ZFP TFs) that activate the expression of the endogenous glial cell line-derived neurotrophic factor (GDNF) gene. We show that GDNF activation can be achieved with exquisite genome-wide specificity. Furthermore, in a rat model of PD, striatal delivery of an adeno-associated viral vector serotype 2 encoding the GDNF activator resulted in improvements in forelimb akinesia, sensorimotor neglect, and amphetamine-induced rotations caused by 6-hydroxydopamine (6-OHDA) lesion. Our results suggest that an engineered ZFP TF can drive sufficient GDNF expression in the brain to provide functional neuroprotection against 6-OHDA; therefore, targeted activation of the endogenous gene may provide a method for delivering appropriate levels of GDNF to PD patients.
Materialart:
Online-Ressource
ISSN:
0270-6474
,
1529-2401
DOI:
10.1523/JNEUROSCI.2440-10.2010
Sprache:
Englisch
Verlag:
Society for Neuroscience
Publikationsdatum:
2010
ZDB Id:
1475274-8
SSG:
12
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