May 2003
Volume 44, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2003
Hypoxia-regulated Transgene Expression in Experimental Retinal and Choroidal Neovascularisation
Author Affiliations & Notes
  • J. Bainbridge
    Dept of Molecular Genetics, Institute of Ophthalmology, London, United Kingdom
  • A. Mistry
    Dept of Molecular Genetics, Institute of Ophthalmology, London, United Kingdom
  • M. De Alwis
    Dept of Molecular Genetics, Institute of Child Health, London, United Kingdom
  • K. Binley
    Oxford Biomedica, Oxford, United Kingdom
  • S. Naylor
    Oxford Biomedica, Oxford, United Kingdom
  • R.R. Ali
    Oxford Biomedica, Oxford, United Kingdom
  • Footnotes
    Commercial Relationships  J. Bainbridge, None; A. Mistry, None; M. De Alwis, None; K. Binley, Oxford Biomedica E; S. Naylor, Oxford Biomedica E; R.R. Ali, Oxford Biomedica F, C.
Investigative Ophthalmology & Visual Science May 2003, Vol.44, 1081. doi:
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      J. Bainbridge, A. Mistry, M. De Alwis, K. Binley, S. Naylor, R.R. Ali; Hypoxia-regulated Transgene Expression in Experimental Retinal and Choroidal Neovascularisation . Invest. Ophthalmol. Vis. Sci. 2003;44(13):1081.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Abstract: : Purpose: Neovascularisation of the retina and choroid is a central feature of diabetic retinopathy and age-related macular degeneration respectively. These conditions are leading causes of blindness in developed countries for which current treatments are of limited efficacy and associated with significant adverse effects. Gene therapy strategies, using recombinant viral vectors, to achieve local, sustained delivery of angiostatic proteins offers a powerful novel approach for the treatment of these disorders. The application of such strategies, however, may also require regulated gene expression to minimise the potential for unwanted adverse effects. In this study we have evaluated the potential of an optimised hypoxia-responsive promoter (OBHRE) to control gene expression. Methods: Hypoxia activates a signalling cascade that culminates in the stabilisation of the HIF-1 transcription factor and activation of genes such as VEGF and erythropoietin that possess a hypoxia response element (HRE). We have developed an optimised synthetic hypoxia responsive promoter (OBHRE) that is highly activated by hypoxia but has a low basal activity in normoxia (Binley et al., Gene Therapy 1999, Binley et al, Blood 2002). AAV vectors carrying a GFP reporter gene driven by the OBHRE promoter (rAAV.HRE.GFP) were evaluated in a well-characterised murine model of ischaemia-induced VEGF-dependent retinal neovascularisation as well as in a murine model of laser-induced choroidal neovascularisation. Results: In murine ischaemia-induced retinal neovascularisation, intravitreal delivery of rAAV.HRE.GFP results in reporter gene expression specifically at sites of vascular closure during the period of active neovascularisation, and not after vector delivery in normal controls. In murine laser-induced choroidal neovascularisation, subretinal delivery of rAAV.HRE.GFP results in reporter gene expression at sites of active neovascularisation but not elsewhere or after vector delivery in normal controls. Conclusions: OBHRE-driven gene expression offers an attractive strategy for the targeted and regulated delivery of angiostatic proteins to the retina in the management of neovascular disorders.

Keywords: gene transfer/gene therapy • retinal neovascularization • choroid: neovascularization 
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