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Inhibition of retinal neovascularisation by gene transfer of soluble VEGF receptor sFlt-1
J W B Bainbridge1, A Mistry, M De Alwis
1Department of Molecular Genetics, Institute of Ophthalmology, University College London, London, UK.
Abstract:
Retinal angiogenesis is a central feature of the leading causes of blindness. Current treatments for these conditions are of limited efficacy and cause significant adverse effects. In this study, we evaluated the angiostatic effect of gene transfer of the soluble VEGF receptor sFlt-1 in a mouse model of ischaemia-induced retinal neovascularisation using adenovirus and adeno-associated virus (AAV) vectors. We induced proliferative retinopathy in mice by exposure to 75% oxygen from postnatal day 7 (p7) to p12 and injected intravitreally recombinant viral vectors expressing the reporter green fluorescent protein (GFP) or vectors expressing the VEGF inhibitor sFlt-1. Efficient adenovirus-mediated GFP expression was evident in cells of the corneal endothelium and iris pigment epithelium. AAV-mediated GFP expression was evident in ganglion cells and cells of the inner nuclear layer of the retina. Vector-mediated sFlt-1 expression was confirmed by ELISA of pooled homogenised whole eyes. Injection of either vector expressing sFlt-1 resulted in a reduction in the number of neovascular endothelial cells by 56% and 52% for adenovirus and AAV vectors, respectively (P < 0.05). Local gene transfer of sFlt-1 consistently inhibits experimental retinal neovascularisation by approximately 50% and offers a powerful novel approach to the clinical management of retinal neovascular disorders.
Insights
Gene transfer of soluble VEGF receptor sFlt-1 effectively inhibited retinal neovascularization by approximately 50% in a mouse model. This approach offers a promising new strategy for treating blinding neovascular eye diseases.
Area of Science:
- Ophthalmology
- Gene Therapy
- Vascular Biology
Background:
- Retinal angiogenesis contributes to major causes of blindness.
- Current treatments for these conditions have limited efficacy and adverse effects.
Purpose of the Study:
- To evaluate the angiostatic effect of gene transfer of soluble VEGF receptor sFlt-1.
- To assess the efficacy of adenovirus and adeno-associated virus (AAV) vectors for delivering sFlt-1 in a mouse model of retinal neovascularization.
Main Methods:
- Proliferative retinopathy was induced in mice via oxygen exposure.
- Intravitreal injection of recombinant viral vectors expressing green fluorescent protein (GFP) or sFlt-1 was performed.
- sFlt-1 expression was confirmed by ELISA; neovascularization was quantified.
Main Results:
- Adenovirus and AAV vectors mediated efficient gene expression in specific retinal cells.
- Vector-mediated sFlt-1 expression significantly reduced neovascular endothelial cells by 56% (adenovirus) and 52% (AAV).
- Both vectors demonstrated a statistically significant reduction (P < 0.05) in experimental retinal neovascularization.
Conclusions:
- Local gene transfer of sFlt-1 effectively inhibits experimental retinal neovascularization by approximately 50%.
- This gene therapy approach represents a novel and powerful strategy for managing retinal neovascular disorders.