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M. M. Hamilton, D. E. Einfeld, C. R. King, L. L. Wei; Alternate Serotype and Combination Anti-Angiogenic Therapy in the Eye. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5359.
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Over the past few years, there have emerged more advanced treatments for ocular neovascular diseases, in particular for wet age-related macular degeneration (AMD). Two anti-VEGF methods for the treatment of wet AMD have been FDA approved and demonstrate that inhibition of VEGF in the eye is possible, safe, and effective. However, despite the clear efficacy and safety of these treatments, there continues to be a medical need for less frequent and non-invasive intraocular delivery into the eye. One novel strategy is to use gene delivery systems, alternate serotypes of adenovirus, that enable the synthesis of anti-angiogenic agents in the eye over several months to deliver combination anti-angiogenic genes to the eye. The purpose of this study was to identify a platform of gene delivery to the eye that reduces the necessity of repeat intraocular injections and test whether combination therapy provides an improved therapeutic drug.
To assess the transgene expression, C57BL/6 mice received a single, intravitreal (IVT) injection of Ad5 or Ad35-based vectors expressing human PEDF or soluble Flt-1 alone or in combination. At specified time points following vector administration, animals were sacrificed, eyes harvested and assayed for PEDF or sFlt-1 levels. In vivo biological activity was then investigated using a laser-induced mouse model of choroidal neovascularization (CNV). On Day 0, mice received a single, IVT injection of Ad5.PEDF or Ad5.sFlt-1 alone or in combination followed by laser induction of CNV on Day 14. Fourteen days following laser induction, animals were perfused with fluorescein-labeled dextran, eyes harvested, and CNV lesion size quantitated in choroidal flat mounts.
Preliminary studies demonstrate that: 1) gene expression is prolonged following a single, IVT injection of an Ad35 construct; and 2) that combination therapy using PEDF and sFlt-1 transgenes inhibits choroidal neovascularization in a mouse laser-induced CNV model better than each agent alone.
These initial studies show that transgene levels are prolonged in the eye following a single, IVT injection of an alternate adenovector serotype, Ad35. Moreover, the combination of PEDF and sFlt-1 (specific for VEGF) blocks abnormal blood vessel growth in a laser-induced mouse model of choroidal neovascularization better than each agent alone. These early studies support further work to test Ad35.PEDF and Ad35.sFlt-1 vectors and provide the scientific rationale that PEDF in combination with an anti-VEGF approach warrants consideration for clinical testing.
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