An Insult-Inducible Vector System Activated by Hypoxia and Oxidative Stress for Neuronal Gene Therapy
- 8 January 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Translational Stroke Research
- Vol. 2 (1), 92-100
- https://doi.org/10.1007/s12975-010-0060-2
Abstract
Gene therapy has demonstrated the protective potential of a variety of genes against stroke. However, conventional gene therapy vectors are limited due to the inability to temporally control their expression, which can sometimes lead to deleterious side effects. Thus, an inducible vector that can be temporally controlled and activated by the insult itself would be advantageous. Using hypoxia responsive elements (HRE) and antioxidant responsive elements (ARE), we have constructed an insult-inducible vector activated by hypoxia and reactive oxygen species (ROS). In COS7 cells, the inducible ARE–HRE-luciferase vectors are highly activated by oxygen deprivation, hydrogen peroxide treatment, and the ROS-induced transcription factor NF-E2-related factor 2 (Nrf2). Using a defective herpes virus, the neuroprotective potential of this inducible vector was tested by over-expressing the transcription factor Nrf2. In primary cortical cultures, expression of the inducible ARE–HRE–Nrf2 protects against oxygen glucose deprivation, similar to that afforded by the constitutively expressed Nrf2. This ARE + HRE vector system is advantageous in that it allows the expression of a transgene to be activated not only during hypoxia but also maintained after reperfusion, thus prolonging the transgene expression during an ischemic insult. This insult-inducible vector system will be a valuable gene therapy tool for activating therapeutic/protective genes in cerebrovascular diseases.Keywords
This publication has 44 references indexed in Scilit:
- Nrf2 activators provide neuroprotection against 6‐hydroxydopamine toxicity in rat organotypic nigrostriatal coculturesJournal of Neuroscience Research, 2009
- Oxidative stress-inducible lentiviral vectors for gene therapyGene Therapy, 2008
- Role of reactive oxygen species in modulation of Nrf2 following ischemic reperfusion injuryNeuroscience, 2007
- Dopamine activates Nrf2‐regulated neuroprotective pathways in astrocytes and meningeal cellsJournal of Neurochemistry, 2007
- Adeno-Associated Viral Vector-Mediated Hypoxia-Inducible Vascular Endothelial Growth Factor Gene Expression Attenuates Ischemic Brain Injury After Focal Cerebral Ischemia in MiceStroke, 2006
- Inflammation in stroke and focal cerebral ischemiaSurgical Neurology, 2006
- A computational model of intracellular oxygen sensing by hypoxia-inducible factor HIF1αJournal of Cell Science, 2006
- Neuropathological and Behavioral Consequences of Adeno-Associated Viral Vector-Mediated Continuous Intrastriatal Neurotrophin Delivery in a Focal Ischemia Model in RatsNeurobiology of Disease, 2002
- Adenovirus-Mediated GDNF and CNTF Pretreatment Protects against Striatal Injury Following Transient Middle Cerebral Artery Occlusion in MiceNeurobiology of Disease, 2001
- Expression of bcl-2 From a Defective Herpes Simplex Virus–1 Vector Limits Neuronal Death in Focal Cerebral IschemiaStroke, 1995