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M. Ju, C. Mailhos, M. Ganley, T. Dowie, G. Cook, P. Calias, A.P. Adams, N. Lange, G.S. Robinson, D.T. Shima; Pegaptanib in Combination With Verteporfin–Based PDT Increases Regression of Murine Ocular Neovascularization . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4175.
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© ARVO (1962-2015); The Authors (2016-present)
Macugen® (pegaptanib sodium injection) and photodynamic therapy (PDT) are the only FDA–approved treatments for neovascular age–related macular degeneration (AMD). In this study we used murine models of ocular neo–vascularizaton to determine the benefits of using combined therapy consisting of Macugen® and PDT.
Following in vitro PDT exposure, the chemical integrity of pegaptanib was analyzed by HPLC analysis and pegaptanib biological activity was determined in a VEGF–induced tissue factor gene expression assay. Corneal neovascularization(CoNV) was induced by removing corneal and limbal epithelia. Pegaptanib was administered intraperitoneally at a dose of 50mg/kg for 10 days starting 10 days post injury (D10 to D19). Verteporfin was administered by intravenous injection at a dose of 1 mg/kg on D10. Then mouse corneas were exposed to 50J/cm2 laser energy using 689 nm wavelength laser light at 200 mW/cm2. PDT–induced vessel obliteration was determined 24hrs after PDT (D11). Corneal vessel regression was determined 10 days after PDT (D20). The percent vascularized cornea was assessed through PECAM–1 staining and fluorescein ConA infusion. A murine choroidal neovascularization (CNV) model was generated using diode laser photocoagulation (75–µm spot size, 0.1–second duration, 90mW, Oculight SL laser, CA).
Neither pegaptanib integrity nor pegaptanib function was affected by either verteporfin or laser irradiation. In the murine CoNV model, there was a 37% reduction in neo–vessel area 24 hours post PDT. By 10 days post PDT, there was only a 27% reduction in vessel area compared with D20 controls. In contrast, a 52% reduction in neo–vessel area was observed following the combined treatment with pegaptanib sodium and PDT as compared to D20 controls. In the mouse CNV model, PDT alone decreased existing choroidal neovascularization by 23%, while the combined treatment of pegaptanib and PDT resulted in a 51% decrease in the choroidal neovascular lesion size.
Vessel re–growth is a major drawback when PDT is used as a treatment for AMD. Anti–VEGF therapy is effective in preventing neo–vessel growth but has less effect on vessel regression. In two animal models of ocular NV, the combined use of pegaptanib sodium and PDT was more effective at inhibiting and regressing NV than using either separately. These results suggest that the combined use of pegaptanib sodium and PDT merits further investigation as a first–line treatment for AMD.
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