Selective inhibition of retinal angiogenesis by targeting PI3 kinase.
Ocular neovascularisation is a pathological hallmark of some forms of debilitating blindness including diabetic retinopathy, age related macular degeneration and retinopathy of prematurity. Current therapies for delaying unwanted ocular angiogenesis include laser surgery or molecular inhibition of the pro-angiogenic factor VEGF. However, targeting of angiogenic pathways other than, or in combination to VEGF, may lead to more effective and safer inhibitors of intraocular angiogenesis. In a small chemical screen using zebrafish, we identify LY294002 as an effective and selective inhibitor of both developmental and ectopic hyaloid angiogenesis in the eye. LY294002, a PI3 kinase inhibitor, exerts its anti-angiogenic effect in a dose-dependent manner, without perturbing existing vessels. Significantly, LY294002 delivered by intraocular injection, significantly inhibits ocular angiogenesis without systemic side-effects and without diminishing visual function. Thus, targeting of PI3 kinase pathways has the potential to effectively and safely treat neovascularisation in eye disease.
Alvarez
Yolanda
Y
UCD Schools of Biomolecular and Biomedical Sciences, UCD Conway Institute, University College Dublin, Dublin, Ireland. yolanda.alvarez@ucd.ie
Astudillo
Olaya
O
Jensen
Lasse
L
Reynolds
Alison L
AL
Waghorne
Nora
N
Brazil
Derek P
DP
Cao
Yihai
Y
O'Connor
John J
JJ
Kennedy
Breandán N
BN
D000818:Animals; D002867:Chromones / Q000494:pharmacology; D004596:Electroretinography / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D000860:Hypoxia; D020128:Inhibitory Concentration 50; D009025:Morpholines / Q000494:pharmacology; D009389:Neovascularization, Pathologic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D012160:Retina / Q000196:embryology / Q000473:pathology*; D012171:Retinal Vessels / Q000473:pathology*; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D015027:Zebrafish
D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D042461:Vascular Endothelial Growth Factor A; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases