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.