An adenoviral vector regulated by hypoxia for the treatment of ischaemic disease and cancer

Binley, Katie; Iqball, Sharifah; Kingsman, Alan J.; Kingsman, Susan M.; Naylor, Stuart

doi:10.1038/sj.gt.3301001

Cited by 79 publications

(50 citation statements)

References 39 publications

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“…Hypoxia-inducible expression of transgenes has been reported in tumor cells and in cardiac myocytes. [4][5][6][7][8][9] Recently, new hypoxia-responsive vectors for tumor-specific gene therapy were developed. 10…”

Section: Expression Of Anti-apoptotic or Neurotrophic Transgene Protementioning

confidence: 99%

Hypoxia-inducible transgene expression in differentiated human NT2N neurons – a cell culture model for gene therapy of postischemic neuronal loss

Cao

Shibata

2001

Gene Ther

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Expression of anti-apoptotic or neurotrophic transgene proteins in hypoxic neurons may provide a novel therapeutic strategy for neuroprotection and alleviation of damage to ischemic brain areas. NT2, a human neoplastic cell line which terminally differentiates into postmitotic neuronsIschemia of the brain due to major vessel thrombosis causes hypoxia in the respective vascular territory and subsequently induces neuronal death which is at least in part caused by apoptosis, especially in the penumbra of the lesion. 1,2 Hypoxia-inducible expression of anti-apoptotic or neurotrophic transgenes in hypoxic neurons may provide a novel therapeutic strategy for neuroprotection and alleviation of damage to ischemic brain areas.Hypoxia has been known as a potent inducer of a large number of genes including those encoding erythropoietin, vascular endothelial growth factor (VEGF), and some glycolytic enzymes, eg phosphoglycerate kinase. These genes have specific regulatory sequences in their promoter regions, known as hypoxia responsive elements (HRE). 3 Under hypoxic conditions, the upregulated hypoxia-inducible transcription factor 1 (HIF-1) binds to the HRE and initiates transcription of 3Ј sequences. This physiological mechanism has been utilized for develop- ment of hypoxia-responsive gene transfer vectors with HRE-based promoters. Hypoxia-inducible expression of transgenes has been reported in tumor cells and in cardiac myocytes. [4][5][6][7][8][9] Recently, new hypoxia-responsive vectors for tumor-specific gene therapy were developed. 10

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Section: Expression Of Anti-apoptotic or Neurotrophic Transgene Protementioning

confidence: 99%

Hypoxia-inducible transgene expression in differentiated human NT2N neurons – a cell culture model for gene therapy of postischemic neuronal loss

Cao

Shibata

2001

Gene Ther

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“…[13][14][15] In this study, we show that the OBHRE promoter is highly active in the tumour microenvironment but is inactive in normal tissues such as liver, spleen, lung and kidney. The high inducibility combined with low basal activity profile of the OBHRE promoter suggested that this system would be useful for the development of tumour-specific gene therapies.…”

Section: Introductionmentioning

confidence: 53%

“…20,21 However, in previous studies, we have shown that the high inducible/low basal activity profile of the OBHRE promoter is maintained in the adenovirus setting in vitro. 13 In this study, we wanted to investigate the activity profile of the OBHRE promoter in vivo. Following intravenous delivery of the Ad.CMVLacZ vector we detected strong b-gal expression, particularly in the liver, which is known to express high levels of the Coxsackie/Adenoviral Receptor (CAR).…”

Section: Hre-mediated Tumour Targetingmentioning

confidence: 99%

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Hypoxia-mediated tumour targeting

et al. 2003

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“…A more recent strategy has been the use of hypoxia-inducible gene therapies where the expression of a cytotoxic gene is modulated by a hypoxia response element (HRE)-based promoter. [3][4][5][6][7][8] To obtain a tight control of expression in low oxygen concentrations, an additional oxygen-regulated component has been tested in some applications. Thus, the oxygen-dependent degradation domain (ODD) from the hypoxia-inducible factor 1a (HIF-1a) protein has been fused in-frame to proteins aimed at tumor cell killing.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-induced human endonuclease G expression suppresses tumor growth in a xenograft model

et al. 2008

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We have developed a hypoxia-inducible gene therapy approach for the expression of the mature form of human endonuclease G to facilitate cell death in hypoxic regions of the tumor. The chimeric therapeutic gene is placed under the control of a hypoxia response element based promoter and contains a translocation motif linked in frame to an oxygen-dependent degradation domain and the endonuclease G gene. Transient expression of the chimeric therapeutic gene in breast and prostate cancer cell lines resulted in efficient cell death under hypoxia-mimetic conditions. Stable MDA-MB-435 cells expressing the chimeric therapeutic gene under 1% O 2 showed an increase in stable HIF-1a protein levels and synthesis of the endonuclease G protein in a time-dependent manner. In normoxic conditions, these stable transgenic cells exhibited no change in growth rate, invasion and motility when compared to parental cells. Moreover, xenografts generated using the transgenic cells exhibited highly significant suppression of tumor growth in a preclinical cancer model compared to the parental cell line. Thus, the hypoxia-modulated endonuclease G expression has the potential to be used as a gene-based-therapy system to kill malignant cells within hypoxic regions of tumors.

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An adenoviral vector regulated by hypoxia for the treatment of ischaemic disease and cancer

Cited by 79 publications

References 39 publications

Hypoxia-inducible transgene expression in differentiated human NT2N neurons – a cell culture model for gene therapy of postischemic neuronal loss

Hypoxia-inducible transgene expression in differentiated human NT2N neurons – a cell culture model for gene therapy of postischemic neuronal loss

Hypoxia-mediated tumour targeting

Hypoxia-induced human endonuclease G expression suppresses tumor growth in a xenograft model

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