Ferrochelatase is a therapeutic target for ocular neovascularization

Halesha D. Basavarajappa, Rania S. Sulaiman, Xiaoping Qi, Trupti Shetty, Sardar Sheik Pran Babu, Kamakshi L. Sishtla, Bit Lee, Judith Quigley, Sameerah Alkhairy, Christian M. Briggs, Kamna Gupta, Buyun Tang, Mehdi Shadmand, Maria B. Grant, Michael E. Boulton, Seung Yong Seo, Timothy Corson

Research output: Contribution to journalArticle

12 Citations (Scopus)

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 Fechm1Pas 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.

Original languageEnglish (US)
JournalEMBO Molecular Medicine
DOIs
StateAccepted/In press - 2017

Fingerprint

Ferrochelatase
Choroidal Neovascularization
Macular Degeneration
Griseofulvin
Therapeutics
Vascular Endothelial Growth Factor Receptor-2
Eye Diseases
Nitric Oxide Synthase Type III
Heme
Vascular Endothelial Growth Factor A
Small Interfering RNA
Enzymes
Pharmaceutical Preparations
Population

Keywords

  • Age-related macular degeneration
  • Angiogenesis
  • Ferrochelatase
  • Griseofulvin
  • Heme synthesis

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

Basavarajappa, H. D., Sulaiman, R. S., Qi, X., Shetty, T., Sheik Pran Babu, S., Sishtla, K. L., ... Corson, T. (Accepted/In press). Ferrochelatase is a therapeutic target for ocular neovascularization. EMBO Molecular Medicine. https://doi.org/10.15252/emmm.201606561

Ferrochelatase is a therapeutic target for ocular neovascularization. / Basavarajappa, Halesha D.; Sulaiman, Rania S.; Qi, Xiaoping; Shetty, Trupti; Sheik Pran Babu, Sardar; Sishtla, Kamakshi L.; Lee, Bit; Quigley, Judith; Alkhairy, Sameerah; Briggs, Christian M.; Gupta, Kamna; Tang, Buyun; Shadmand, Mehdi; Grant, Maria B.; Boulton, Michael E.; Seo, Seung Yong; Corson, Timothy.

In: EMBO Molecular Medicine, 2017.

Research output: Contribution to journalArticle

Basavarajappa, HD, Sulaiman, RS, Qi, X, Shetty, T, Sheik Pran Babu, S, Sishtla, KL, Lee, B, Quigley, J, Alkhairy, S, Briggs, CM, Gupta, K, Tang, B, Shadmand, M, Grant, MB, Boulton, ME, Seo, SY & Corson, T 2017, 'Ferrochelatase is a therapeutic target for ocular neovascularization', EMBO Molecular Medicine. https://doi.org/10.15252/emmm.201606561
Basavarajappa HD, Sulaiman RS, Qi X, Shetty T, Sheik Pran Babu S, Sishtla KL et al. Ferrochelatase is a therapeutic target for ocular neovascularization. EMBO Molecular Medicine. 2017. https://doi.org/10.15252/emmm.201606561
Basavarajappa, Halesha D. ; Sulaiman, Rania S. ; Qi, Xiaoping ; Shetty, Trupti ; Sheik Pran Babu, Sardar ; Sishtla, Kamakshi L. ; Lee, Bit ; Quigley, Judith ; Alkhairy, Sameerah ; Briggs, Christian M. ; Gupta, Kamna ; Tang, Buyun ; Shadmand, Mehdi ; Grant, Maria B. ; Boulton, Michael E. ; Seo, Seung Yong ; Corson, Timothy. / Ferrochelatase is a therapeutic target for ocular neovascularization. In: EMBO Molecular Medicine. 2017.
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AU - Boulton, Michael E.

AU - Seo, Seung Yong

AU - Corson, Timothy

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