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