Ferrochelatase is a therapeutic target for ocular neovascularization

  • Basavarajappa H
  • Sulaiman R
  • Qi X
  • et al.
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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. image New drug targets are needed for blocking pathological blood vessel growth in the eye in diseases such as wet age‐related macular degeneration. The heme synthesis enzyme ferrochelatase is necessary for this process and can be inhibited with therapeutic effect. Ferrochelatase is a target of the antiangiogenic natural product cremastranone. Loss or inhibition of ferrochelatase reduces ocular neovascularization in vitro and in vivo by reducing heme needed for endothelial nitric oxide synthase function. Human and murine eyes undergoing neovascularization upregulate ferrochelatase. The approved drug griseofulvin, which inhibits ferrochelatase as an off‐target effect, is an effective therapy in a preclinical choroidal neovascularization model.

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APA

Basavarajappa, H. D., Sulaiman, R. S., Qi, X., Shetty, T., Sheik Pran Babu, S., Sishtla, K. L., … Corson, T. W. (2017). Ferrochelatase is a therapeutic target for ocular neovascularization. EMBO Molecular Medicine, 9(6), 786–801. https://doi.org/10.15252/emmm.201606561

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