PMID- 21902538
OWN - NLM
STAT- MEDLINE
DCOM- 20120116
LR  - 20121115
IS  - 1557-9042 (Electronic)
IS  - 0897-7151 (Linking)
VI  - 28
IP  - 9
DP  - 2011 Sep
TI  - Gene therapy for traumatic central nervous system injury and stroke using an 
      engineered zinc finger protein that upregulates VEGF-A.
PG  - 1863-79
LID - 10.1089/neu.2011.1896 [doi]
AB  - Recent studies have identified anti-apoptotic functions for vascular endothelial 
      growth factor (VEGF) in the central nervous system (CNS). However, VEGF therapy 
      has been hampered by a tendency to promote vascular permeability, edema, and 
      inflammation. Recently, engineered zinc finger proteins (ZFPs) that upregulate 
      multiple forms of VEGF in their natural biological ratios, have been developed to 
      overcome these negative side effects. We used retinal trauma and ischemia models, 
      and a cortical pial strip ischemia model to determine if VEGF upregulating ZFPs 
      are neuroprotective in the adult CNS. Optic nerve transection and ophthalmic 
      artery ligation lead to the apoptotic degeneration of retinal ganglion cells 
      (RGCs) and are, respectively, two highly reproducible models for CNS trauma or 
      ischemia. Adeno-associated vectors (AAV) vectors encoding VEGF-ZFPs 
      (AAV-VEGF-ZFP) significantly increased RGC survival by  approximately twofold at 14 days after 
      optic nerve transection or ophthalmic artery ligation. Furthermore, AAV-VEGF-ZFP 
      enhanced recovery of the pupillary light reflex. RECA-1 immunostaining 
      demonstrated no appreciable differences between retinas treated with AAV-VEGF-ZFP 
      and controls, suggesting that AAV-VEGF-ZFP treatment did not affect retinal 
      vasculature. Following pial strip of the forelimb motor cortex, brains treated 
      with an adenovirus encoding VEGF ZFPs (AdV-ZFP) showed higher neuronal survival, 
      accelerated wound contraction, and reduced lesion volume between 1 and 6 weeks 
      after injury. Behavioral testing using the cylinder test for vertical exploration 
      showed that AdV-VEGF-ZFP treatment enhanced contralateral forelimb function 
      within the first 2 weeks after injury. Our results indicate that VEGF ZFP therapy 
      is neuroprotective following traumatic injury or stroke in the adult mammalian 
      CNS.
FAU - D'Onofrio, Philippe M
AU  - D'Onofrio PM
AD  - Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
FAU - Thayapararajah, Mahinthan
AU  - Thayapararajah M
FAU - Lysko, Meghan D
AU  - Lysko MD
FAU - Magharious, Mark
AU  - Magharious M
FAU - Spratt, S Kaye
AU  - Spratt SK
FAU - Lee, Gary
AU  - Lee G
FAU - Ando, Dale
AU  - Ando D
FAU - Surosky, Richard
AU  - Surosky R
FAU - Fehlings, Michael G
AU  - Fehlings MG
FAU - Koeberle, Paulo D
AU  - Koeberle PD
LA  - eng
PT  - Journal Article
DEP - 20110908
PL  - United States
TA  - J Neurotrauma
JT  - Journal of neurotrauma
JID - 8811626
RN  - 0 (Vascular Endothelial Growth Factor A)
SB  - IM
MH  - Animals
MH  - Behavior, Animal/physiology
MH  - Brain Injuries/genetics/*therapy
MH  - Genetic Therapy/*methods
MH  - Optic Nerve Injuries/genetics/therapy
MH  - Protein Engineering
MH  - Rats
MH  - Recovery of Function/genetics
MH  - Stroke/genetics/*therapy
MH  - Treatment Outcome
MH  - Up-Regulation/*genetics
MH  - Vascular Endothelial Growth Factor A/*genetics/metabolism
MH  - Zinc Fingers/*genetics
EDAT- 2011/09/10 06:00
MHDA- 2012/01/17 06:00
CRDT- 2011/09/10 06:00
PHST- 2011/09/10 06:00 [entrez]
PHST- 2011/09/10 06:00 [pubmed]
PHST- 2012/01/17 06:00 [medline]
AID - 10.1089/neu.2011.1896 [doi]
PST - ppublish
SO  - J Neurotrauma. 2011 Sep;28(9):1863-79. doi: 10.1089/neu.2011.1896. Epub 2011 Sep 
      8.