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Novel anti-VEGF chimeric molecules delivered by AAV vectors for inhibition of retinal neovascularization

Gene Therapy volume 16, pages 10–16 (2009)Cite this article

Abstract

Vascular endothelial growth factor (VEGF) is important in pathological neovascularization, which is a key component of diseases such as the wet form of age-related macular degeneration, proliferative diabetic retinopathy and cancer. One of the most potent naturally occurring VEGF binders is VEGF receptor Flt-1. We have generated two novel chimeric VEGF-binding molecules, sFLT01 and sFLT02, which consist of the second immunoglobulin (IgG)-like domain of Flt-1 fused either to a human IgG1 Fc or solely to the CH3 domain of IgG1 Fc through a polyglycine linker 9Gly. In vitro analysis showed that these novel molecules are high-affinity VEGF binders. We have demonstrated that adeno-associated virus serotype 2 (AAV2)-mediated intravitreal gene delivery of sFLT01 efficiently inhibits angiogenesis in the mouse oxygen-induced retinopathy model. There were no histological observations of toxicity upon persistent ocular expression of sFLT01 for up to 12 months following intravitreal AAV2-based delivery in the rodent eye. Our data suggest that AAV2-mediated intravitreal gene delivery of our novel molecules may be a safe and effective treatment for retinal neovascularization.

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Acknowledgements

We thank Sirkka Kyostio-Moore and for helpful discussions; Michelle Deng for valuable comments on the paper; Shelley Nass and Denise Woodcock for virus production and Bob Brown for support with illustrations.

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Authors and Affiliations

  1. Department of Molecular Biology, Genzyme Corporation, Framingham, MA, USA

    P Pechan, H Rubin, M Lukason, J Ardinger, E DuFresne, S C Wadsworth & A Scaria

  2. Department of Ophthalmology, University of Florida, Gainesville, FL, USA

    W W Hauswirth

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  1. P Pechan
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  2. H Rubin
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  3. M Lukason
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  8. A Scaria
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Correspondence to A Scaria.

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Pechan, P., Rubin, H., Lukason, M. et al. Novel anti-VEGF chimeric molecules delivered by AAV vectors for inhibition of retinal neovascularization. Gene Ther 16, 10–16 (2009). https://doi.org/10.1038/gt.2008.115

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