title: Treatment of traumatic brain injury using zinc-finger protein gene therapy targeting VEGF-A.
abstract: Vascular endothelial growth factor (VEGF) plays a role in angiogenesis and has been shown to be neuroprotective following central nervous system trauma. In the present study we evaluated the pro-angiogenic and neuroprotective effects of an engineered zinc-finger protein transcription factor transactivator targeting the vascular endothelial growth factor A (VEGF-ZFP). We used two virus delivery systems, adeno-virus and adeno-associated virus, to examine the effects of early and delayed VEGF-A upregulation after brain trauma, respectively. Male Sprague-Dawley rats were subject to a unilateral fluid percussion injury (FPI) of moderate severity (2.2-2.5 atm) followed by intracerebral microinjection of either adenovirus vector (Adv) or an adeno-associated vector (AAV) carrying the VEGF-ZFP construct. Adv-VEGF-ZFP-treated animals had significantly fewer TUNEL positive cells in the injured penumbra of the cortex (p<0.001) and hippocampus (p=0.001) relative to untreated rats at 72 h post-injury. Adv-VEGF-ZFP treatment significantly improved fEPSP values (p=0.007) in the CA1 region relative to injury alone. Treatment with AAV2-VEGF-ZFP resulted in improved post-injury microvascular diameter and improved functional recovery on the balance beam and rotarod task at 30 days post-injury. Collectively, the results provide supportive evidence for the concept of acute and delayed treatment following TBI using VEGF-ZFP to induce angiogenesis, reduce cell death, and enhance functional recovery.
authors.affiliation: Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ishita
authors.initials: I
authors.lastname: Siddiq
authors.forename: Eugene
authors.initials: E
authors.lastname: Park
authors.forename: Elaine
authors.initials: E
authors.lastname: Liu
authors.forename: S Kaye
authors.initials: SK
authors.lastname: Spratt
authors.forename: Richard
authors.initials: R
authors.lastname: Surosky
authors.forename: Gary
authors.initials: G
authors.lastname: Lee
authors.forename: Dale
authors.initials: D
authors.lastname: Ando
authors.forename: Marty
authors.initials: M
authors.lastname: Giedlin
authors.forename: Gregory M T
authors.initials: GM
authors.lastname: Hare
authors.forename: Michael G
authors.initials: MG
authors.lastname: Fehlings
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Baker
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001930:Brain Injuries / Q000473:pathology / Q000523:psychology / Q000628:therapy*; D056547:CA1 Region, Hippocampal / Q000473:pathology; D002196:Capillaries / Q000473:pathology; D000229:Dependovirus / Q000235:genetics; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D015316:Genetic Therapy; D005822:Genetic Vectors; D020287:In Situ Nick-End Labeling; D017774:Long-Term Potentiation; D008297:Male; D008845:Microinjections; D018919:Neovascularization, Physiologic / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000502:physiology; D016335:Zinc Fingers / Q000235:genetics*
chemical_list: D042461:Vascular Endothelial Growth Factor A