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Korean J Spine Search


Hypoxia-inducible Specific Gene Expression System in Rat Spinal Cord Injury Model
Joon-ho Chung, M.D.1, Dong-Keun Hyun, M.D.1, Min-hyung Lee, Ph.D.3, Byung-Hyune Choi, Ph.D.2, Hyung-Chun Park, M.D.1, Yoon Ha, M.D.1,2
1Department of Neurosurgery, 2Neuro-Repair Center, 3Clinical Research Center, Inha University College of Medicine, Incheon, Korea
흰쥐의 척수 손상 모델에서 저산소증으로 유발되는 특정 유전자 발현 체계에 관한 연구
인하대학교 의과대학 신경외과학교실
s: The aim of this study is to establish a controllable and safe gene therapy tool for treating spinal cord injury(SCI) using hypoxia-inducible gene expression system.
Background: It is generally believed that gene therapy is one of the promising tools to treat the spinal cord injury. However, it has a risk of uncontrollable expression of the target genes particularly in normal tissues. Hypoxia(or ischemia) is a main cause of pathophysiological events in the injured neuronal system including the spinal cord. Therefore, a safe gene expression system depending on the hypoxic condition will be a useful tool for the gene therapy to treat spinal cord injury.

Using the Erythropoietin(Epo) enhancer and hypoxia-inducible factor 1(HIF-1) responsive gene(RTP801) promoter, the plasmids(pEpo-SV40-Luc, pRTP801-Luc) were constructed. In vitro, mouse neuroblastoma cells(N2A) were transfected by the plasmids and cultured in hypoxic(PO2 7.6mmHg) or normoxic(PO2 152mmHg) conditions. In vivo, the plasmids were adminis- tered into the rat spinal cord injured by a vascular clip(pressure, 50gm) for 15 min. The luciferase gene expression was measured by the luciferase assay. The VEGF expression plasmid under the Epo enhancer(pEpo-SV40-VEGF) was constructed to evaluate the therapeutic effect of VEGF in rat SCI model. The plasmid was administered directly into the injured spinal cord of the rat, and behavioral improvement was evaluated by Basso, Beattie, and Bresnahan(BBB) Locomotion Test Score.

In N2A cells, the luciferase activity of the test plasmids was higher in hypoxic condition than in normoxic condition. In rat SCI model, the luciferase activity of pEpo-SV-Luc or pRTP801-Luc was higher than that of the control(pSV-Luc). The behavior of the rat which was injured spinal cord, and treated by pEpo-SV-VEGF showed better improvement than that of the control. All the results are statistically significant(p<0.01, non-paired student t-test).

Hypoxia-inducible gene expression system by using Epo enhancer or RTP801 promoter showed specific expre- ssion of the genes in hypoxic condition or in injured spinal cord. Therefore, this system could be a safe treatment of technique of the gene therapy for spinal cord injury.
Keywords: Gene therapy.VEGF.RTP801 promoter.Epo enhancer.Hypoxia

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