title: Ferrochelatase is a therapeutic target for ocular neovascularization.
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 angiogenesisin vitroandin vivoFECH is overexpressed in wet AMD eyes and murine choroidal neovascularization; siRNA knockdown ofFechor partial loss of enzymatic function in theFechm1Pasmouse model reduces choroidal neovascularization.FECHdepletion 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.
authors.affiliation: Eugene and Marilyn Glick Eye Institute and Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Halesha D
authors.initials: HD
authors.lastname: Basavarajappa
authors.affiliation: Eugene and Marilyn Glick Eye Institute and Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
authors.forename: Rania S
authors.initials: RS
authors.lastname: Sulaiman
authors.affiliation: Eugene and Marilyn Glick Eye Institute and Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Qi
authors.affiliation: Eugene and Marilyn Glick Eye Institute and Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Trupti
authors.initials: T
authors.lastname: Shetty
authors.affiliation: Eugene and Marilyn Glick Eye Institute and Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Sardar
authors.initials: S
authors.lastname: Sheik Pran Babu
authors.affiliation: Eugene and Marilyn Glick Eye Institute and Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Kamakshi L
authors.initials: KL
authors.lastname: Sishtla
authors.affiliation: College of Pharmacy, Gachon University, Incheon, South Korea.
authors.forename: Bit
authors.initials: B
authors.lastname: Lee
authors.affiliation: Eugene and Marilyn Glick Eye Institute and Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Quigley
authors.affiliation: Eugene and Marilyn Glick Eye Institute and Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Sameerah
authors.initials: S
authors.lastname: Alkhairy
authors.affiliation: Eugene and Marilyn Glick Eye Institute and Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Briggs
authors.affiliation: Eugene and Marilyn Glick Eye Institute and Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Kamna
authors.initials: K
authors.lastname: Gupta
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Buyun
authors.initials: B
authors.lastname: Tang
authors.affiliation: Eugene and Marilyn Glick Eye Institute and Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Shadmand
authors.affiliation: Eugene and Marilyn Glick Eye Institute and Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Maria B
authors.initials: MB
authors.lastname: Grant
authors.affiliation: Eugene and Marilyn Glick Eye Institute and Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Boulton
authors.affiliation: College of Pharmacy, Gachon University, Incheon, South Korea.
authors.forename: Seung-Yong
authors.initials: SY
authors.lastname: Seo
authors.affiliation: Eugene and Marilyn Glick Eye Institute and Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA tcorson@iu.edu.|Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Timothy W
authors.identifier: 0000-0002-1402-7875
authors.initials: TW
authors.lastname: Corson
mesh_terms: D000818:Animals; D005294:Ferrochelatase / Q000378:metabolism*; D006801:Humans; D008268:Macular Degeneration / Q000473:pathology*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D015861:Retinal Neovascularization / Q000503:physiopathology*
chemical_list: D005294:Ferrochelatase
keywords: age‐related macular degeneration; angiogenesis; ferrochelatase; griseofulvin; heme synthesis