Blockage of PI3K/mTOR Pathways Inhibits Laser-Induced Choroidal Neovascularization and Improves Outcomes Relative to VEGF-A Suppression Alone.
Choroidal neovascularization (CNV) is a major cause of visual loss with age-related macular degeneration (AMD). We evaluated whether blockade of phosphatidyl-inositol-3-kinase (PI3K) and the mammalian target of rapamycin (mTOR), by impairing VEGF-A and other growth factor receptors like platelet-derived growth factor (PDGF), would reduce laser-induced CNV in mice.



Choroidal neovascularization lesions were induced in C57BL/6 mice. Two groups of mice received oral GSK2126458 (3 mg/kg) or vehicle for 14 days following laser, whereas three groups were treated with GSK2126458 (6 μg/eye), aflibercept (2 μL/eye), or vehicle intravitreally on days 0 and 7 after laser. Vascular leakage was measured by fluorescein angiography (FA) on day 14. Choroidal neovascularization membranes were evaluated on choroidal flat mounts following FITC-dextran perfusion, as well as ED1 and isolectin B4 (IB4) immunohistochemistry.



Oral and intravitreal (IVT) GSK2126458 reduced leakage and area of CNV lesions. Greater probability of leaking lesions (∼60%; P < 0.05) was observed in both vehicle groups. Fluorescein isothiocyanate-dextran-labeled total CNV burden area (total lesion area/eye) was reduced ∼67% (P < 0.05) and 35% (P = 0.0528) after oral and IVT GSK2126458 administration. GSK2126458 treatment reduced lesion size by ∼80% (P < 0.05) and 50% (P < 0.05) for oral and IVT control groups. Aflibercept did not alter lesion size (∼27% reduction).



Phosphatidyl-inositol-3-kinase/mTOR is involved in laser-induced CNV angiogenic processes. GSK2126458 effectively reduces CNV size and leakage. Choroidal neovascularization size following IVT GSK2126458 was smaller than after oral administration. Therefore, inhibition of PI3K/mTOR pathways may be more effective due to blockade of action of multiple growth factors.
Schepens Eye Research Institute Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, United States.
Jie
J
Ma
Schepens Eye Research Institute Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, United States.
Yu
Y
Sun
Ophthalmology Discovery Performance Unit, GlaxoSmithKline, King of Prussia, Pennsylvania, United States.
Francisco J
FJ
López
Ophthalmology Discovery Performance Unit, GlaxoSmithKline, Stevenage, United Kingdom 4Ocular Biology and Therapeutics, UCL Institute of Ophthalmology, London, United Kingdom.
Peter
P
Adamson
Quantitative Sciences, RD Alternative Discovery & Development, GlaxoSmithKline, King of Prussia, Pennsylvania, United States.
Edit
E
Kurali
Schepens Eye Research Institute Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, United States.
Kameran
K
Lashkari
D000284:Administration, Oral; D000818:Animals; D020256:Choroidal Neovascularization / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005451:Fluorescein Angiography; D005654:Fundus Oculi; D058449:Intravitreal Injections; D007834:Lasers / Q000009:adverse effects; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011724:Pyridazines; D011804:Quinolines / Q000008:administration & dosage*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000008:administration & dosage*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage*; D013449:Sulfonamides / Q000008:administration & dosage*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D000096926:Benzenesulfonamides
D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011724:Pyridazines; D011804:Quinolines; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins; D013449:Sulfonamides; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A; C533178:aflibercept; C561454:omipalisib; D000096926:Benzenesulfonamides; C546843:mTOR protein, mouse