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Francois Binet, Normand Beaulieu, Karine Beauchemin, Patricia Laplante, John G Clement, Przemyslaw (Mike) Sapieha; Semaphorin3A Traps for Treatment of Retinal and Choroidal Vasculopathies. Invest. Ophthalmol. Vis. Sci. 2016;57(12):769.
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© ARVO (1962-2015); The Authors (2016-present)
Semaphorin 3A (SEMA3A) is a classical neuronal guidance cue that participates in vessel growth and patterning. Recently, we demonstrated that SEMA3A is upregulated in the vitreous of patients suffering from proliferative diabetic retinopathy where it acts as a chemoattractant to a subset of proangiogenic microglia that mediate pathological pre-retinal angiogenesis. SEMA3A is also elevated in the vitreous of patients with diabetic macular edema where it compromises barrier function. Here we investigated the therapeutic merit of SEMA3A neutralization for retinal and choroidal vasculopathies.
We generated biologic neutralizers of SEMA3A with varying binding affinities to VEGF and tested them in murine models of vasculopathies, including the oxygen-induced retinopathy (OIR) model and the laser-induced choroidal neovascularization model (CNV) of pathological angiogenesis. We also investigated their ability to influence retinal edema in the STZ model of type I diabetes.
Intravitreal injections of the SEMA3A-VEGF trap at P12 in a model of OIR reduced avascular areas at P17 by 32.5±8.6% compared to vehicle treated controls while the SEMA3A-trap alone reduced avascular areas by 62.4±6.7%. Similarly, pathological neovascularization (NV) was reduced by 41.6±15.0% by the SEMA3A-VEGF trap while the SEMA3A-trap alone reduced NV by 58.4±8.5% compared to controls. Moreover, STZ-induced retinal edema assessed at 8 weeks of diabetes was diminished by 37.1± 9.5% by the SEMA3A-VEGF trap, while SEMA3A-trap alone reduced vessel leakage by 33.8±12.0%. The SEMA3A-VEGF trap also reduced retinal edema at 14 weeks of diabetes by 28.4±5.6%, whereas a neutralizing mouse anti-VEGF164 antibody did not significantly lower vessel leakage at the same time-point. Finally, the SEMA3A-VEGF trap reduced laser-burn injury CNV by 34.2±11% at 14 days post-burn.
These data support therapeutic neutralization of SEMA3A either alone or in conjunction with VEGF to treat proliferative retinopathies, CNV and retinal edema. When the vasculopathy is associated with severe ischemia, less potent neutralizers of VEGF allows greater vascular regeneration and greater phenotypic amelioration.
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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