Delayed administration of a bio-engineered zinc-finger VEGF-A gene therapy is neuroprotective and attenuates allodynia following traumatic spinal cord injury
Authors: Dale Ando
Michael G Fehlings
Kajana Satkunendrarajah
Gary Lee
Peter Fettes
Yang Liu
Spyridon K Karadimas
S Kaye Spratt
Richard Surosky
Sarah A Figley
Martin Giedlin
Journal: PLoS ONE (2014)
Discipline: Multidisciplinary
Keywords: spinal cord injury; VEGF-A; gene therapy; angiogenesis; neuroprotection
Affiliations: Department of Genetics and Development, Toronto Western Research Institute, and Spinal Program, Krembil Neuroscience Centre, University Health Network, Toronto, Ontario, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada., Department of Genetics and Development, Toronto Western Research Institute, and Spinal Program, Krembil Neuroscience Centre, University Health Network, Toronto, Ontario, Canada., Department of Therapeutic Development, Sangamo BioSciences, Pt. Richmond, California, United States of America., Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada., Department of Genetics and Development, Toronto Western Research Institute, and Spinal Program, Krembil Neuroscience Centre, University Health Network, Toronto, Ontario, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada; Department of Surgery, University of Toronto, Toronto, Ontario, Canada.

Abstract:  Following spinal cord injury (SCI) there are drastic changes that occur in the spinal microvasculature, including ischemia, hemorrhage, endothelial cell death and blood-spinal cord barrier disruption. Vascular endothelial growth factor-A (VEGF-A) is a pleiotropic factor recognized for its pro-angiogenic properties; however, VEGF has recently been shown to provide neuroprotection. We hypothesized that delivery of AdV-ZFP-VEGF--an adenovirally delivered bio-engineered zinc-finger transcription factor that promotes endogenous VEGF-A expression--would result in angiogenesis, neuroprotection and functional recovery following SCI. This novel VEGF gene therapy induces the endogenous production of multiple VEGF-A isoforms; a critical factor for proper vascular development and repair. Briefly, female Wistar rats--under cyclosporin immunosuppression--received a 35 g clip-compression injury and were administered AdV-ZFP-VEGF or AdV-eGFP at 24 hours post-SCI. qRT-PCR and Western Blot analysis of VEGF-A mRNA and protein, showed significant increases in VEGF-A expression in AdV-ZFP-VEGF treated animals (p&lt;0.001 and p&lt;0.05, respectively). Analysis of NF200, TUNEL, and RECA-1 indicated that AdV-ZFP-VEGF increased axonal preservation (p&lt;0.05), reduced cell death (p&lt;0.01), and increased blood vessels (p&lt;0.01), respectively. Moreover, AdV-ZFP-VEGF resulted in a 10% increase in blood vessel proliferation (p&lt;0.001). Catwalk™ analysis showed AdV-ZFP-VEGF treatment dramatically improves hindlimb weight support (p&lt;0.05) and increases hindlimb swing speed (p&lt;0.02) when compared to control animals. Finally, AdV-ZFP-VEGF administration provided a significant reduction in allodynia (p&lt;0.01). Overall, the results of this study indicate that AdV-ZFP-VEGF administration can be delivered in a clinically relevant time-window following SCI (24 hours) and provide significant molecular and functional benefits. 

Retracted: No

PubPeer comments:
 I am really surprised by figure 7 ![file] I am not convinced by the structure pointed as spinal cord. With this magnification, it looks like multiple nerves. I would be very happy if the authors could confirm. Furthermore, the structure pointed in 1 is considered as  striated muscle fibres ![file] For me, this is more likely a nerve. The structure pointed in 2 is considered a cyst. ![file] The problem is that cyst is not a histological diagnosis. What is the exact nature of the lining? Again, the structure pointed in 3 is considered as smooth muscle cells. ![file] For me these cells are likely to be striated muscle cells. A picture with a best magnification should resolve this problem. The structure pointed in 4 is considered as ependyma (which is one-cell thick). ![file] Such is not the case. At last, all the pictures have not been taken with the same magnification (look at the size of the nuclei in the different pictures). So, this means that the squares on the general figure are wrong. ![file] I guess that this figure has not been produced by pathologists. Why? ,