Abstract
Ocular neovascularization underlies major blinding eye diseases such as “wet” age‐related macular degeneration (AMD). Despite the successes of treatments targeting the vascular endothelial growth factor (VEGF) pathway, resistant and refractory patient populations necessitate discovery of new therapeutic targets. Using a forward chemical genetic approach, we identified the heme synthesis enzyme ferrochelatase (FECH) as necessary for angiogenesis in vitro and in vivo. FECH is overexpressed in wet AMD eyes and murine choroidal neovascularization; siRNA knockdown of Fech or partial loss of enzymatic function in the Fech m1Pas mouse model reduces choroidal neovascularization. FECH depletion modulates endothelial nitric oxide synthase function and VEGF receptor 2 levels. FECH is inhibited by the oral antifungal drug griseofulvin, and this compound ameliorates choroidal neovascularization in mice when delivered intravitreally or orally. Thus, FECH inhibition could be used therapeutically to block ocular neovascularization.
Highlights
Ocular neovascularization is a characteristic of blinding eye diseases like retinopathy of prematurity, proliferative diabetic retinopathy, and “wet” age-related macular degeneration (AMD; Das & McGuire, 2003)
To identify potentially novel protein modulators of angiogenesis, we used photoaffinity chromatography to search for targets of the naturally occurring antiangiogenic compound, cremastranone (Fig 1A), which has selective antiproliferative effects on endothelial cells (Lee et al, 2014)
Understanding the molecular events of pathological angiogenesis is key to developing novel therapeutics for neovascular eye diseases such as proliferative diabetic retinopathy, retinopathy of prematurity, and wet AMD
Summary
Ocular neovascularization is a characteristic of blinding eye diseases like retinopathy of prematurity, proliferative diabetic retinopathy, and “wet” age-related macular degeneration (AMD; Das & McGuire, 2003). All are characterized by abnormal angiogenesis (neovascularization) in the posterior segment of the eye (in the retina or choroid), leading to vascular leakage that can result in hemorrhage, edema, and retinal detachment, with vision loss as a direct result This neovascularization is driven by a number of factors, prominent among which is vascular endothelial growth factor (VEGF; Penn et al, 2008). Management of neovascular eye diseases has been revolutionized by the advent of anti-VEGF biologics such as ranibizumab, bevacizumab, and aflibercept (Folk & Stone, 2010; Prasad et al, 2010; Hanout et al, 2013) Despite these considerable advances, treatment options remain limited for a substantial fraction of patients who are non-responsive or refractory to antiVEGF therapy (Lux et al, 2007); no agents acting downstream of the VEGF receptor interaction are yet approved for targeted therapy of these diseases (Abouammoh & Sharma, 2011; Lally et al, 2012). We describe here for the first time FECH’s role as a druggable mediator of angiogenesis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
