An engineered transcription factor which activates VEGF-A enhances recovery after spinal cord injury.
Spinal cord injury (SCI) leads to local vascular disruption and progressive ischemia, which contribute to secondary degeneration. Enhancing angiogenesis through the induction of vascular endothelial growth factor (VEGF)-A expression therefore constitutes an attractive therapeutic approach. Moreover, emerging evidence suggests that VEGF-A may also exhibit neurotrophic, neuroprotective, and neuroproliferative effects. Building on this previous work, we seek to examine the potential therapeutic benefits of an engineered zinc finger protein (ZFP) transcription factor designed to activate expression of all isoforms of endogenous VEGF-A (ZFP-VEGF). Administration of ZFP-VEGF resulted in increased VEGF-A mRNA and protein levels, an attenuation of axonal degradation, a significant increase in vascularity and decreased levels of apoptosis. Furthermore, ZFP-VEGF treated animals showed significant improvements in tissue preservation and neurobehavioural outcomes. These data suggest that activation of VEGF-A via the administration of an engineered ZFP transcription factor holds promise as a therapy for SCI and potentially other forms of neurotrauma.
Liu
Yang
Y
Department of Genetics and Development, Toronto Western Research Institute, and Spinal Program, Krembil Neuroscience Centre, University Health Network, Ontario, Canada.
Figley
Sarah
S
Spratt
S Kaye
SK
Lee
Gary
G
Ando
Dale
D
Surosky
Richard
R
Fehlings
Michael G
MG
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001808:Blood Vessels / Q000166:cytology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000494:pharmacology / Q000627:therapeutic use; D018919:Neovascularization, Physiologic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000235:genetics; D013119:Spinal Cord Injuries / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D014157:Transcription Factors / Q000235:genetics* / Q000494:pharmacology; D015533:Transcriptional Activation / Q000235:genetics; D016896:Treatment Outcome; D015854:Up-Regulation / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism; D014855:Wallerian Degeneration / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D016335:Zinc Fingers / Q000235:genetics
D012333:RNA, Messenger; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat