June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
Chemical Screens in Zebrafish Identify Novel Inhibitors of Retinal Neovascularisation in Mouse
Author Affiliations & Notes
  • Breandan Kennedy
    UCD School of Biomolecular and Biomedical Science & UCD Conway Institute, University College Dublin, Dublin, Ireland
  • Yolanda Alvarez
    UCD School of Biomolecular and Biomedical Science & UCD Conway Institute, University College Dublin, Dublin, Ireland
  • Miriam Tosetto
    St. Vincent’s University Hospital,, University College Dublin, Dublin, Ireland
  • Claire Kilty
    UCD School of Biomolecular and Biomedical Science & UCD Conway Institute, University College Dublin, Dublin, Ireland
  • Temitope Sasore
    UCD School of Biomolecular and Biomedical Science & UCD Conway Institute, University College Dublin, Dublin, Ireland
  • Carmel McVicar
    Centre for Vision and Vascular Science,, Queen’s University, Belfast, United Kingdom
  • Alan Stitt
    Centre for Vision and Vascular Science,, Queen’s University, Belfast, United Kingdom
  • Jacintha O'Sullivan
    Department of Surgery,, Trinity College Dublin, Dublin, Ireland
  • Alison Reynolds
    UCD School of Biomolecular and Biomedical Science & UCD Conway Institute, University College Dublin, Dublin, Ireland
  • Footnotes
    Commercial Relationships Breandan Kennedy, University College Dublin (P); Yolanda Alvarez, UNiversity College Dublin (P); Miriam Tosetto, None; Claire Kilty, University College Dublin (P); Temitope Sasore, None; Carmel McVicar, None; Alan Stitt, GlaxoSmithKline (F); Jacintha O'Sullivan, UCD (P); Alison Reynolds, PCT/IE2012/000002 (P)
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 4617. doi:https://doi.org/
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Breandan Kennedy, Yolanda Alvarez, Miriam Tosetto, Claire Kilty, Temitope Sasore, Carmel McVicar, Alan Stitt, Jacintha O'Sullivan, Alison Reynolds; Chemical Screens in Zebrafish Identify Novel Inhibitors of Retinal Neovascularisation in Mouse. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4617. doi: https://doi.org/.

      Download citation file:


      © ARVO (1962-2015); The Authors (2016-present)

      ×
  • Supplements
Abstract

Purpose: Ocular neovascularisation is a pathological feature of human eye diseases including diabetic retinopathy and age-related macular degeneration. Using an unbiased approach we sought to uncover novel anti-angiogenic drugs by screening a chemical library in Tg(fli1:EGFP) transgenic zebrafish and identifying “hits” which inhibit development of the intraocular vasculature.

Methods: Zebrafish were treated from 1-5 days post fertilisation with compounds from the Chembridge Diverset library, and the number of primary vessels in the hyaloid vasculature quantified. Hit compounds were tested in human dermal-derived microvascular endothelial cells (HMVEC) for affects on proliferation, migration and tubule formation. Selected compounds were tested in the mouse oxygen-induced retinopathy model to evaluate efficacy in a mammalian model of ocular neovascularisation.

Results: In zebrafish, several isoquinoline compounds displayed significant and reproducible anti-angiogenic activity, decreasing the number of primary hyaloid branches, without gross effects on ocular morphology or function. These effects were validated in human cells with endothelial tubule formation inhibited by ~24%, without significant effects on cell migration or proliferation. In the mouse oxygen-induced retinopathy (OIR) model, the highest ranking hit 2-[(E)-2-(Quinolin-2-yl)vinyl]phenol significantly inhibits ocular neovascularisation, increasing the avascular retinal area by 2.4 +/- 0.08 fold (p-value <0.0001) compared to controls.

Conclusions: Chemical screens in zebrafish identify novel small molecules which show potential as therapeutics for ocular neovascularisation associated with blindness. Anti-angiogenic activity has been confirmed in human cells and in a mouse model of retinal neovascularisation.

Keywords: 700 retinal neovascularization  
×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×