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- Title
An Engineered Zinc Finger Protein Activator of the Endogenous Glial Cell Line-Derived Neurotrophic Factor Gene Provides Functional Neuroprotection in a Rat Model of Parkinson's Disease.
- Authors
Laganiere, Josee; Kells, Adrian P.; Lai, Jeffrey T.; Guschin, Dmitry; Paschon, David E.; Xiangdong Meng; Fong, Lauren K.; Qi Yu; Rebar, Edward J.; Gregory, Philip D.; Bankiewicz, Krystof S.; Forsayeth, John; Zhang, H. Steve
- Abstract
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.
- Subjects
PARKINSON'S disease; ZINC-finger proteins; AMPHETAMINES; NEUROGLIA; GENOMES; LABORATORY mice; PSYCHOLOGY
- Publication
Journal of Neuroscience, 2010, Vol 30, Issue 48, p16469
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.2440-10.2010