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T. L. Favazza, I. Y. Benador, Y. A. Tsabur, A. B. Fulton, R. M. Hansen, J. D. Akula; Early Anti-Angiogenic Intervention in the Immature, Neovascular Retina: A Cautionary Tale. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4458.
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Angiogenic growth factors (e.g., VEGF) are also neurotrophic factors (Saint-Geniez et al., PLoS One, 2008). Thus, we and others have urged considerable caution in the use of such molecules, although promising in age-related macular degeneration and diabetic retinopathy, for prevention of retinopathy of prematurity (ROP). We tested a proprietary, anti-angiogenic molecule in two rat models of ROP and studied functional and vascular outcomes. This drug has been shown to reduce neovascularization (NV) in a choroidal NV model and have low neural toxicity in the mature murine eye.
Retinopathy-inducing oxygen exposures were delivered to Sprague-Dawley rat pups from postnatal day (P) 0-14 ("50/10 model", n=4) or from P7-14 ("75 model", n=4). Room-air-reared controls (n=4) were also studied. Drug or vehicle were injected in contralateral eyes, in a masked fashion, in each rat. Activity in photoreceptor and postreceptor neurons was derived from binocular ERG recordings. Retinae were then flatmounted, and clock hours of NV and percent of the retinal surface lacking capillary perfusion (avascular retina, AR) were quantified. Data were analyzed by two-factor (group, eye) repeated-measures analysis of variance.
Significant attenuation in ERG response amplitudes, both receptor (RmP3, P<0.001), postreceptor (RmP2, P=0.04), and oscillatory potentials (Em, P=0.02) was observed. Retinal sensitivity, Sm, was also significantly (P<0.001) negatively impacted by drug. The negative impact of drug on retinal function was found in both ROP (50/10, 75) and control retinae. The drug did not significantly reduce either NV (P=0.45) or AR (P=0.47) in ROP retinae.
Anti-angiogenic drugs safe in the mature eye may not be safe for the immature retina. Indeed, since neural and vascular dysfunction are associated (Akula et. al., IOVS, 2007; MolVis, 2008), even improvements in vascular outcomes are not assured, as increased damage to retinal neurons may offset the presumed benefit of early anti-angiogenic interventions.
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