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.
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.
authors.affiliation: Sangamo BioSciences, Point Richmond Tech Center, Richmond, California 94804, USA.
authors.forename: Josee
authors.initials: J
authors.lastname: Laganiere
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Kells
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Lai
authors.forename: Dmitry
authors.initials: D
authors.lastname: Guschin
authors.forename: David E
authors.initials: DE
authors.lastname: Paschon
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Meng
authors.forename: Lauren K
authors.initials: LK
authors.lastname: Fong
authors.forename: Qi
authors.initials: Q
authors.lastname: Yu
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Rebar
authors.forename: Philip D
authors.initials: PD
authors.lastname: Gregory
authors.forename: Krystof S
authors.initials: KS
authors.lastname: Bankiewicz
authors.forename: John
authors.initials: J
authors.lastname: Forsayeth
authors.forename: H Steve
authors.initials: HS
authors.lastname: Zhang
mesh_terms: D000661:Amphetamine / Q000008:administration & dosage; D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000008:administration & dosage; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000502:physiology; D051098:Glial Cell Line-Derived Neurotrophic Factors / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use*; D049452:Green Fluorescent Proteins / Q000235:genetics; D000882:Haplorhini; D006801:Humans; D016086:Lentivirus / Q000502:physiology; D051379:Mice; D046228:Microarray Analysis / Q000379:methods; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000150:complications / Q000209:etiology / Q000628:therapy*; D015202:Protein Engineering / Q000379:methods*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D014162:Transfection; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D015259:Dopamine Agents; D051098:Glial Cell Line-Derived Neurotrophic Factors; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D049452:Green Fluorescent Proteins; D016627:Oxidopamine; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase