July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Semaphorin3A-Trap Accelerates Vascular Regeneration in Ischemic Retinopathy and Reduces Retinal Edema
Author Affiliations & Notes
  • Francois Binet
    Sema Thera - HMR Research Institute, Montreal, Quebec, Canada
  • Normand Beaulieu
    Sema Thera - HMR Research Institute, Montreal, Quebec, Canada
  • Karine Beauchemin
    Sema Thera - HMR Research Institute, Montreal, Quebec, Canada
  • Patricia Laplante
    Sema Thera, Quebec, Canada
    AmorChem, Quebec, Canada
  • John G Clement
    AmorChem, Quebec, Canada
  • Garth Cumberlidge
    Sema Thera, Quebec, Canada
  • Przemyslaw Sapieha
    Sema Thera - HMR Research Institute, Montreal, Quebec, Canada
  • Footnotes
    Commercial Relationships   Francois Binet, Sema Thera (E); Normand Beaulieu, Sema Thera (E); Karine Beauchemin, Sema Thera (E); Patricia Laplante, Amorchem (E), Sema Thera (C); John Clement, Amorchem (E), Sema Thera (C); Garth Cumberlidge, Sema Thera (C); Przemyslaw Sapieha, Sema Thera (C), Sema Thera (P)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 1648. doi:
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      Francois Binet, Normand Beaulieu, Karine Beauchemin, Patricia Laplante, John G Clement, Garth Cumberlidge, Przemyslaw Sapieha; Semaphorin3A-Trap Accelerates Vascular Regeneration in Ischemic Retinopathy and Reduces Retinal Edema. Invest. Ophthalmol. Vis. Sci. 2019;60(9):1648.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Current treatment paradigms for ischemic retinopathies such as diabetic retinopathy call for use of anti-VEGF therapies. While effective at preventing pathological pre-retinal neovascularization, anti-VEGFs prevent all angiogenesis, including desirable revascularization of the ischemic retina. We previously demonstrated in both humans and rodents that under pathological conditions, retinal ganglion cell-derived Semaphorin3A (SEMA3A) is a potent inducer of retinal inflammation, retinal edema, vascular deviation and retinal cell senescence. In the current study, we generated and profiled a library of neutralizing traps against SEMA3A and investigated their ability to trigger vascular regeneration and prevent undesirable neovascularization. We also investigated the efficacy of SEMA3A-Traps at preventing retinal edema in diabetic mice and pathological angiogenesis in laser-induced choroidal neovascularization (CNV).

Methods : We generated over 30 SEMA3A-Traps for intravitreal delivery and profiled their binding affinities to SEMA3A and VEGF. These constructs were tested in various murine models of retinal vasculopathies such as the oxygen-induced retinopathy (OIR) model, the STZ-induced type I diabetes model and the laser-induced choroidal neovascularization (CNV) model.

Results : Profiling of binding affinities to SEMA3A and ability to ameliorate vascular phenotypes in OIR resulted in the selection of a lead Trap (ST-102). In OIR, a single injection of ST-102 suppressed pre-retinal neovascularization by ~54% and accelerated vascular regeneration by ~60% when compared to vehicle controls. Treatment with Aflibercept was efficient at reducing pre-retinal neovascularization (~88% reduction vs control) but suppressed desirable vascular regeneration. In the STZ model, ST-102 reduced vascular edema at 8 weeks (~37% reduction) and 14 weeks (~35% reduction) of diabetes when compared to control. For laser-induced CNV, ST-102 diminished choroidal neovascularization (~64% reduction) vs control.

Conclusions : Our data suggest that targeting SEMA3A with ST-102 in retinal vasculopathies is a promising therapeutic strategy. Accelerating vascular regeneration in the ischemic retina represents a novel approach to countering retinal ischemia and its consequences.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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