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Halesha Dhurvigere Basavarajappa, Lynn C Shaw, Sergio Li Calzi, Kamakshi Sishtla, Maria B Grant, Timothy William Corson; Ferrochelatase is required for retinal neovascularization. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3639.
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© ARVO (1962-2015); The Authors (2016-present)
Despite the power of anti-vascular endothelial growth factor (VEGF) therapies, there remains a need for novel therapeutic targets in retinopathy of prematurity, a major cause of blindness in infants. We previously identified the heme biosynthesis enzyme ferrochelatase (Fech) as crucial for angiogenesis in vitro and in the laser-induced choroidal neovascularization model. Here, we tested the hypothesis that Fech knockdown would reduce neovascularization in the murine oxygen-induced retinopathy (OIR) model of retinopathy of prematurity.
OIR was induced in neonatal mice by a standard method of exposure to 75% O2 hyperoxia at postnatal day (P) 7 followed by return to normoxia at P12. Fech or non-targeting siRNA or vehicle was injected intravitreally at P12, and retinal wholemounts prepared at P17. Collagen IV staining followed by manual analysis revealed areas of vasoobliteration and neovascularization, which were compared by ANOVA with Tukey’s post hoc tests.
Fech knockdown dose-dependently reduced neovascular area to near zero at high (1.6 µM) concentrations (1.5 ± 0.3% vs. 19.9 ± 0.7% for vehicle control, p=1.02x10-8). Knockdown also modestly but significantly reduced vasoobliteration at all tested concentrations (15.2 ± 1.2% at 1.6 µM siRNA vs. 20.5 ± 0.7% for vehicle control, p=0.006). No disruption of normal vasculature or other acute toxicity was observed.
The knockdown of Fech profoundly decreased neovascularization in the OIR model, without obvious toxic effects. Taken together with the in vitro significance of Fech for angiogenesis and its importance for choroidal neovascularization, inhibition of Fech emerges as a very appealing, VEGF-independent therapeutic avenue for ocular neovascularization.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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