1. 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.
- Author
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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, and Zhang, H. Steve
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PARKINSON'S disease , *ZINC-finger proteins , *AMPHETAMINES , *NEUROGLIA , *GENOMES , *LABORATORY mice , *PSYCHOLOGY - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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