Treatment of traumatic brain injury using zinc-finger protein gene therapy targeting VEGF-A
| Autor: | Ishita Siddiq, Dale Ando, Michael G. Fehlings, Marty Giedlin, Eugene Park, Gregory M. T. Hare, Gary Lee, Elaine Liu, Andrew J. Baker, S. Kaye Spratt, Richard T. Surosky |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Vascular Endothelial Growth Factor A Pathology medicine.medical_specialty Microinjections Traumatic brain injury Angiogenesis viruses Genetic enhancement Central nervous system Blotting Western Genetic Vectors Long-Term Potentiation Neovascularization Physiologic Pharmacology medicine.disease_cause Neuroprotection Rats Sprague-Dawley chemistry.chemical_compound In Situ Nick-End Labeling Medicine Animals Adeno-associated virus CA1 Region Hippocampal business.industry Excitatory Postsynaptic Potentials Zinc Fingers Genetic Therapy Recovery of Function Dependovirus medicine.disease Capillaries Rats Vascular endothelial growth factor Vascular endothelial growth factor A medicine.anatomical_structure chemistry Brain Injuries Neurology (clinical) business |
| Zdroj: | Journal of neurotrauma. 29(17) |
| ISSN: | 1557-9042 |
| Popis: | 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 (p0.001) 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. |
| Databáze: | OpenAIRE |
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