A hypoxia-inducible vigilant vector system for activating therapeutic genes in ischemia

Tang, Yao; Tang, Yi; Zhang, Y. Clare; Agarwal, Anupam; Kasahara, Hideko; Qian, Keping; Shen, Leping; Phillips, M. Ian

doi:10.1038/sj.gt.3302513

Cited by 31 publications

(21 citation statements)

References 40 publications

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“…51 Plasmid systems that upregulate HO-1 expression during hypoxia are also cardioprotective. 52 Several studies investigating the protective effects of HIF-1 have focused on the role of HO-1 in this response. Zhu et al 53 studied protection against I/R in the retina, and found that repeated exposure to hypoxia over 12 days led to sustained increases in HIF-1a and HO-1 protein expression, which was associated with significant protection.…”

Section: Role Of Ho-1 In Mediating the Protective Effect Of Hif-1 Agamentioning

confidence: 99%

Role of hypoxia-inducible factor in cell survival during myocardial ischemia–reperfusion

2008

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Hypoxia-inducible factor (HIF) is the principal transcription factor involved in the regulation of transcriptional responses to hypoxia. During hypoxia, HIF-a levels accumulate and trigger an increase in expression of genes involved in glycolysis, glucose metabolism, mitochondrial function, cell survival, apoptosis, and resistance to oxidative stress. In this regard, HIF activation plays an essential role in triggering cellular protection and metabolic alterations from the consequences of oxygen deprivation. This suggests that HIF activation should confer protection against ischemia-reperfusion (I/R) injury, although this protection might require HIF activation before the onset of lethal ischemia. Studies using enhanced expression of HIF-1a suggest that its upregulation may be a beneficial therapeutic modality in the treatment or prevention of ischemic injury. HIF-regulated gene expression may mediate the late phase of preconditioning, and constitutive HIF activity may influence the expression of genes that are required for the cell to be able to respond to acute preconditioning. This article reviews the current literature on the role of HIF in balancing protection and cell death in the face of ischemia and I/R injury.

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Section: Role Of Ho-1 In Mediating the Protective Effect Of Hif-1 Agamentioning

confidence: 99%

Role of hypoxia-inducible factor in cell survival during myocardial ischemia–reperfusion

2008

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“…This can be achieved by designing promoters that can be activated by orally administered drugs such as doxycyclin 101 or, alternatively, with the use of a promoter element responsive to physiological stimuli such as hypoxia 44,102 or shear stress. 103 Combining these approaches with tissue-specific promoters such as the endothelium-specific Tie-2 and smooth muscle cell-specific SM22␣ allows spatial control of the transgene expression in combination with temporal control.…”

Section: Development Of Regulatable Vector Systemsmentioning

confidence: 99%

Antioxidant Gene Therapy for Cardiovascular Disease

et al. 2008

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Abstract-Excessive production of reactive oxygen species has been implicated to play an important role in a number of cardiovascular pathologies, including hypertension, atherosclerosis, myocardial infarction, ischemia/reperfusion injury, and restenosis after angioplasty or venous bypass grafting. The formation of reactive oxygen species is balanced out by antioxidant defenses, and augmenting this defense by antioxidant therapies could therefore provide a potential means to treat conditions in which the formation of reactive oxygen species exceeds the capability of natural protective mechanisms. In this review, we summarize the studies in which antioxidant gene therapy has been used successfully to treat cardiovascular diseases. We also discuss the current limitations of antioxidant gene therapy and envision future therapeutic targets and methodological approaches for an improved outcome. (Circulation. 2008;117:2142-2150.)

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“…Under normoxic conditions HIF-1α is rapidly degraded to undetectable levels due to hydroxylation of the oxygen-dependent degradation domain (ODD), which tags HIF-1α for proteasome-based destruction. Fusion of the ODD of HIF-1α to the Gal4 DNA-binding (DBD Gal4 ) and p65 transactivation domains (Gal4-ODDp65) resulted in an oxygen-sensitive transactivator, which undergoes normoxia-dependent ODD-mediated degradation but induces expression of chimeric promoters containing O Gal4 operator sites under hypoxic conditions [19]. In a mouse model for myocardial infarction, DBD Gal4 -ODD-p65 mediated heme oxygenase-1 expression in response to ischemia, limiting apoptosis in the infarcted area and improving cardiac functions by increasing the availability of local oxygen availability.…”

Section: Hypoxia-controlled Transgene Expressionmentioning

confidence: 99%

“…Pioneering examples of semi-synthetic mammalian gene network design include regulatory cascades and circuitries responsive to multi-level control by a combination of synthetic and physiologic signals, which enable discrete inducer-specific expression levels [15,[18][19][20], epigenetic transcription imprinting locking transgene transcription at desired levels without sustained inducer administration [17], and molecular expression memories generating expression levels which depend on the expression history of the circuitry [17].…”

Section: Introductionmentioning

confidence: 99%

Pharmacologic transgene control systems for gene therapy

Weber

Fussenegger

2006

The Journal of Gene Medicine

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Pharmacologic transgene-expression dosing is considered essential for future gene therapy scenarios. Genetic interventions require precise transcription or translation fine-tuning of therapeutic transgenes to enable their titration into the therapeutic window, to adapt them to daily changing dosing regimes of the patient, to integrate them seamlessly into the patient's transcriptome orchestra, and to terminate their expression after successful therapy. In recent years, decisive progress has been achieved in designing high-precision trigger-inducible mammalian transgene control modalities responsive to clinically licensed and inert heterologous molecules or to endogenous physiologic signals. Availability of a portfolio of compatible transcription control systems has enabled assembly of higher-order control circuitries providing simultaneous or independent control of several transgenes and the design of (semi-)synthetic gene networks, which emulate digital expression switches, regulatory transcription cascades, epigenetic expression imprinting, and cellular transcription memories. This review provides an overview of cutting-edge developments in transgene control systems, of the design of synthetic gene networks, and of the delivery of such systems for the prototype treatment of prominent human disease phenotypes.

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A hypoxia-inducible vigilant vector system for activating therapeutic genes in ischemia

Cited by 31 publications

References 40 publications

Role of hypoxia-inducible factor in cell survival during myocardial ischemia–reperfusion

Role of hypoxia-inducible factor in cell survival during myocardial ischemia–reperfusion

Antioxidant Gene Therapy for Cardiovascular Disease

Pharmacologic transgene control systems for gene therapy

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