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Shira Toledano, Huayi Lu, Agustina Palacio, Ofra Kessler, Shlomit Schaal, Gera Neufeld, Yoreh Barak; Semaphorin-3C Resistant To Cleavage By Furins Inhibits Choroidal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4423.
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© ARVO (1962-2015); The Authors (2016-present)
Choroidal neovascularization (CNV) is a major blinding consequence of several retinal diseases including the exudative form of age-related macular degeneration (AMD). Anti-VEGF agents are widely used to treat AMD, however the high rate of non-responders calls for the exploration of anti-angiogenic agents that act independently from the VEGF pathway. This study was designed to investigate whether a point mutated form of the anti-angiogenic semaphorin-3C which was rendered resistant to cleavage by furin like pro-protein convertases (FR-Sema3C) can be used to effectively inhibit laser induced CNV formation in a mouse model.
CNV was induced in the eyes of C57B mice (n=15) by laser photocoagulation followed by an intravitreal injection of either 100 ng FR-Sema3C, 5µg EYLEA® (aflibercept) or vehicle as a control. After a week flat whole mounts of retinas where used to determine CNV development and size. Results were assessed by the staining of blood vessels with dextran green and by calculation of the area of stained blood vessels using Image-J morphometric software. The effects of FR-sema3C injection on the visual function of healthy mice were assessed using a non-invasive OptoMotry© optokinetic testing system.
FR-Sema3C (100 ng) injected into the vitreous cavity of mice reduced the area of laser induced CNV by 44% as compared to controls (121063± 16957μm2 for controls (n=48) vs 53383±5779μm2 (n=40), P<0.001). This efficacy was similar to that of EYLEA (40%, 48713± 7255μm2 (n=40), P<0.0001). The optokinetic essays indicated that at this dose FR-sema3C does not compromise visual acuity. FR-Sema3C also inhibited significantly laser induced CNV using lower doses (10 and 50 ng per injection) although the inhibition was less effective than at 100 ng per injection (142578± 23886μm2 for controls (n=16) vs 100 ng (53153± 10094μm2 (n=24), P<0.001) ,50 ng (93836± 12890μm2 (n=24), P<0.05) and 10 ng (95042± 16348μm2 (n=24), P<0.05).
FR-Sema3C inhibits laser induced CNV formation in the mouse model as efficiently as EYLEA and seems to be devoid of toxic effects. FR-sema3C mechanism of action is independent of VEGF. This suggests that FR-Sema3C may be considered as a possible therapeutic agent for the treatment of exudative AMD that is refractory to current VEGF targeting agents.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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