Treatment of traumatic brain injury using zinc-finger protein gene therapy targeting VEGF-A

J Neurotrauma. 2012 Nov 20;29(17):2647-59. doi: 10.1089/neu.2012.2444. Epub 2012 Nov 9.


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.

MeSH terms

  • Animals
  • Blotting, Western
  • Brain Injuries / pathology
  • Brain Injuries / psychology
  • Brain Injuries / therapy*
  • CA1 Region, Hippocampal / pathology
  • Capillaries / pathology
  • Dependovirus / genetics
  • Excitatory Postsynaptic Potentials / physiology
  • Genetic Therapy*
  • Genetic Vectors
  • In Situ Nick-End Labeling
  • Long-Term Potentiation
  • Male
  • Microinjections
  • Neovascularization, Physiologic / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Recovery of Function
  • Vascular Endothelial Growth Factor A / genetics*
  • Vascular Endothelial Growth Factor A / physiology
  • Zinc Fingers / genetics*


  • Vascular Endothelial Growth Factor A