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Yu Sun, Jie Ma, Gianna C Teague, Francisco J Lopez, Peter S Adamson, Edit Kurali, Kameran Lashkari; A Highly Potent Inhibitor of PI3K and the Mammalian Target of Rapamycin, GSK2126458, Inhibits Laser-Induced Choroidal Neovascularization . Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2364.
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© ARVO (1962-2015); The Authors (2016-present)
Choroidal neovascularization (CNV) is the major cause of severe visual loss in subjects with AMD. A significant number of patients with wet AMD exhibit some degree of resistance to anti-VEGF monotherapy. The PI3K/Akt/mTOR pathway plays an important role in downstream cellular processes from the VEGF receptor, including growth, survival and angiogenesis. In this study, we investigated whether blockade of phosphatidylinositol-3-kinase (PI3K) and mTOR pathway using a highly potent blocker, GSK2126458, was able to effectively inhibit laser-induced CNV lesions.
Laser-induced CNV was created in C57BL/6 mice using a 532 nm laser under direct observation with the Micron III fundus camera. Mice were treated with daily oral gavage of GSK2126458 or vehicle for 14 days after laser injury. Alternatively, mice received intravitreal injections of GSK2126458, Eylea™ (aflibercept) or vehicle on day 0 and 7 after laser injury. CNV areas and extent of leakage were determined by fluorescein angiography followed by intracardiac perfusion of FITC-dextran in gelatin (10%) on day 14. Choroidal flatmounts were examined by immunohistochemistry for Iba-1 expression
Fluorescence intensities of laser-induced CNV lesions in mice treated with oral GSK2126458 were significantly lower than control vehicle. Vehicle-treated group exhibited significantly increased number of leaking lesions (≈ 88%) and larger CNV areas. Intravitreal injections of GSK2126458 had strong inhibitory effects on CNV leakage (21%) and size (~ 6000 µm2/eye), and significantly lower than Eylea™ (36%, ~6500 µm2/eye) and vehicle (47%, ~7000 µm2/eye) groups.
The PI3K/mTOR pathway participates in laser-induced CNV formation. GSK2126458 a highly potent inhibitor of the PI3K/mTOR pathway is more effective than Eylea™ in inhibiting laser-induced CNV lesions through its downstream signaling effects when given orally. Compared to Eylea™, intravitreal GSK2126458 showed a trend toward more effective blockade of CNV lesions. Our findings suggest that inhibition of the PI3K/mTOR pathway may be an advantageous approach for inhibiting CNV lesions on its own right and potentially in CNV clinically resistant to VEGF monotherapy.
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