Delayed Administration of a Bio-Engineered Zinc-Finger VEGF-A Gene Therapy Is Neuroprotective and Attenuates Allodynia Following Traumatic Spinal Cord Injury

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<0.001 and p<0.05, respectively). Analysis of NF200, TUNEL, and RECA-1 indicated that AdV-ZFP-VEGF increased axonal preservation (p<0.05), reduced cell death (p<0.01), and increased blood vessels (p<0.01), respectively. Moreover, AdV-ZFP-VEGF resulted in a 10% increase in blood vessel proliferation (p<0.001). Catwalk™ analysis showed AdV-ZFP-VEGF treatment dramatically improves hindlimb weight support (p<0.05) and increases hindlimb swing speed (p<0.02) when compared to control animals. Finally, AdV-ZFP-VEGF administration provided a significant reduction in allodynia (p<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.

Soluble epoxide hydrolase inhibition provides multi-target therapeutic effects in rats after spinal cord injury

“…Accumulating evidence has shown correlations between blood vessel density and improvements in recovery following SCI [45][46][47]. EETs signaling may mediate angiogenesis under physiological and CNS diseases conditions [48][49][50][51].…”

Neurotrophic Effects of Mu Bie Zi (Momordica cochinchinensis) Seed Elucidated by High-Throughput Screening of Natural Products for NGF Mimetic Effects in PC-12 Cells

“…Both NGF and MCS can induce morphological changes NF200, which plays a critical role in preventing axonal neuron degeneration after brain [33], or spinal cord injury [34] and used to efficacy of neurological therapies [35, 36]. NGF signaling by a mimetic is likely to induce cellular reorganization/elongation of cytoskeletal microtubules (formation of neuritic shafts) and development of filopodia/lamellipodia with flexible growth cones that extend along a biological matrix (e.g.…”

Immunomodulatory and neuroprotective effect of cryopreserved allogeneic mesenchymal stem cells on spinal cord injury in rats

“…The increase in VEGF occurred only during the chronic phase of spinal cord injury, i.e., in the period during which tissue repair begins. VEGF is known to stimulate angiogenesis, an important process that reduces ischemia and provides the blood supply needed for axon regeneration and motor function recovery (Figley et al, 2014;. A previous study found an increase in the concentration of VEGF in the chronic phase of animals with SCI treated with MSCs .…”

“…A previous study found an increase in the concentration of VEGF in the chronic phase of animals with SCI treated with MSCs . VEGF has direct neuroprotective and neurotrophic actions (Figley et al, 2014;Mead et al, 2014;Shinozaki et al, 2014); therefore, the increase in VEGF expression at 21 days after spinal cord injury in the GMSC may have contributed to a higher number of intact neurons, lower degeneration of white matter, and recovery of motor function.…”