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

• Published in: The Journal of neuroscience Vol. 30; no. 49; pp. 16469 - 16474
• Main Authors: Laganiere, Josee, Kells, Adrian P, Lai, Jeffrey T, Guschin, Dmitry, Paschon, David E, Meng, Xiangdong, Fong, Lauren K, Yu, Qi, Rebar, Edward J, Gregory, Philip D, Bankiewicz, Krystof S, Forsayeth, John, Zhang, H Steve
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 08-12-2010
• Subjects: Amphetamine - administration & dosage; Animals; Cell Line; Disease Models, Animal; Dopamine Agents - administration & dosage; Enzyme-Linked Immunosorbent Assay - methods; Gene Expression Regulation - drug effects; Genetic Therapy - methods; Genetic Vectors - physiology; Glial Cell Line-Derived Neurotrophic Factors - biosynthesis; Glial Cell Line-Derived Neurotrophic Factors - genetics; Glial Cell Line-Derived Neurotrophic Factors - therapeutic use; Green Fluorescent Proteins - genetics; Haplorhini; Humans; Lentivirus - physiology; Mice; Microarray Analysis - methods; Motor Activity - drug effects; Neuroprotective Agents - therapeutic use; Oxidopamine - toxicity; Parkinson Disease - complications; Parkinson Disease - etiology; Parkinson Disease - therapy; Protein Engineering - methods; Rats; RNA, Messenger - metabolism; Time Factors; Transfection; Tyrosine 3-Monooxygenase - metabolism; Zinc Fingers - genetics
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.2440-10.2010

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.