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I. A. Bhutto, D. S. McLeod, S. Y. Kim, S. J. Wiegand, G. A. Lutty; Effects of VEGF Inhibition in the Canine Model of Retinopathy of Prematurity (ROP). Invest. Ophthalmol. Vis. Sci. 2007;48(13):4051.
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The superficial layer of the dog retinal vasculature forms by vasculogenesis, similar to the initial development of the human retinal vasculature. This initial phase in development occurs in the first postnatal week in dog and in utero in human. This study evaluated the effects of VEGF Trap, a receptor-based fusion protein that binds all isoforms of VEGF-A as well as placental growth factor, on retinal vasculogenesis and pathological neovascularization (NV) in canine oxygen-induced retinopathy, a model for human ROP.
One day-old dogs (postnatal day 1, P1) were exposed to 100% O2 for 4 days, during which time vasculogenesis ceases and vaso-obliteration occurs. When the animals are returned to room air, the resultant ischemia initiates a massive vasoproliferative response: florid tufts of intravitreal NV form by P21 and persist to at least P45. VEGF Trap (5, 25, or 250 ug) was injected intravitreally in one eye and a control protein (human Fc) was injected in the fellow eye of air control and oxygen-treated dogs on P6, one day following return to room air. The effect of treatment on the retinal vasculature and preretinal NV was evaluated on P21.
In air controls, the superficial vascular plexus was reduced in eyes injected with 250 or 25 ug VEGF Trap and the deep capillary network was absent. In contrast, eyes that received the 5 ug dose were indistinguishable from control eyes. In animals exposed to hyperoxia, all eyes injected with VEGF Trap exhibited markedly less preretinal NV than Fc-injected fellow eyes, irrespective of the dose of Trap administered. The retinal vascular area also was reduced in eyes injected with 250 or 25 ug of the Trap, but the 5 ug dose did not inhibit revascularization of the retina.
In the context of ROP, the ideal profile of an anti-angiogenic agent would be to inhibit pathologic NV, without altering developmental vasculogenesis or revascularization of the retina following hyperoxia-induced vaso-obliteration. VEGF Trap profoundly inhibited the formation of preretinal NV in the dog model of ROP. However, as reported previously for an antibody directed against VEGFR2, the higher doses of VEGF Trap also inhibited revascularization of retina, resulting in a large avascular periphery. In contrast, the lowest dose of VEGF Trap effectively blocked intravitreal NV, without appreciably affecting vasculogenesis or retinal revascularization. These findings indicate that dose selection is likely to be a critical variable in considering the use of VEGF-targeting agents for the treatment of ROP.
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