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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amphetamine / administration & dosage
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Animals
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Cell Line
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Disease Models, Animal
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Dopamine Agents / administration & dosage
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Enzyme-Linked Immunosorbent Assay / methods
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Gene Expression Regulation / drug effects
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Genetic Therapy / methods*
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Genetic Vectors / physiology
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Glial Cell Line-Derived Neurotrophic Factors / biosynthesis
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Glial Cell Line-Derived Neurotrophic Factors / genetics
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Glial Cell Line-Derived Neurotrophic Factors / therapeutic use*
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Green Fluorescent Proteins / genetics
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Haplorhini
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Humans
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Lentivirus / physiology
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Mice
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Microarray Analysis / methods
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Motor Activity / drug effects
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Neuroprotective Agents / therapeutic use*
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Oxidopamine / toxicity
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Parkinson Disease / complications
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Parkinson Disease / etiology
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Parkinson Disease / therapy*
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Protein Engineering / methods*
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RNA, Messenger / metabolism
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Rats
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Time Factors
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Transfection
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Tyrosine 3-Monooxygenase / metabolism
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Zinc Fingers / genetics
Substances
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Dopamine Agents
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Glial Cell Line-Derived Neurotrophic Factors
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Neuroprotective Agents
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RNA, Messenger
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Green Fluorescent Proteins
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Oxidopamine
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Amphetamine
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Tyrosine 3-Monooxygenase