Abstract
Purpose :
Diabetic retinopathy (DR) is the leading cause of blindness in adults in the Western world, characterized by development of vascular abnormalities and breakdown of blood-retinal barrier with development of diabetic macular edema (DME). VEGF-A is considered the primary factor involved in these processes and current therapies primarily inhibit VEGF-A. In this study we investigated whether VEGF-C and D also contributed to the diabetic pathology, and whether inhibition of VEGF-C/D by a highly selective soluble receptor, VGX-300, could reduce retinal edema and leukocyte adhesion in the streptozotocin (STZ)-induced rat model.
Methods :
Brown Norway rats were given STZ to induce hyperglycemia (blood glucose >250mg/dl) and observed for 2 weeks and 4 months. Rats were administered IgG, aflibercept (VEGF-A inhibitor), VGX-300, or a combination of aflibercept and VGX-300 via intravitreal (IVT) injection every 4 weeks. Rats were sacrificed, perfused with either FITC-dextran or FITC-ConA lectin and retinal flatmounts were prepared. Leukostasis, vascular permeability and apoptosis was quantitated by confocal microscopy and albumin staining. Inner retinal vascular thickness was visualized using IB4 staining on confocal microscopy.
Results :
VGX-300 was as effective as aflibercept in reducing leukocyte adhesion (VGX-300 vs IgG; aflibercept vs IgG; VGX-300+aflibercept vs. IgG; P<0.05 per group; no differences between VGX-300 vs. aflibercept). Vascular leakage, as measured by extravasated albumin and FITC-dextran, was significantly reduced (P<0.05) in all treatment groups compared to IgG control. IB4 staining of the inner retinal vascular layer (an indirect indicator of inner retinal edema) indicated significant reductions in retinal thickness in the VGX-300, aflibercept and combination groups compared to IgG control.
Conclusions :
Selective inhibition of VEGF-C/D by VGX-300 is an effective therapeutic modality for treatment of diabetic retinal edema in the rat model, and equivalent to inhibition of VEGF-A by aflibercept. While targeting VEGF-A is effective in treating DR complications; many patients experience a sub-response to selective anti-VEGF-A monotherapy. Targeting VEGF-C/D may be an effective strategy to address sub-optimal responses to VEGF-A inhibitors in DME.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.