Abstract
Purpose :
Norrin/Fzd4 signaling is indispensable for retinal vascular development and vessel function in humans and rodent models. These studies examined whether a novel Norrin mimetic could promote the regeneration of damaged blood vessels and their functions in diabetic retinopathy animal models.
Methods :
We generated an antibody-based bi-specific Norrin mimetic (SZN-413) that targets Fzd4 and low-density lipoprotein receptor-related proteins and evaluated its effects on damaged retinal vessels in mice and rabbit models. In an oxygen-induced retinopathy (OIR) mouse model, SZN-413 was delivered intravitreally (IVT) and the avascular (AV) area and neovascularization (NV) area were measured 5 days later. Furthermore, the impact on vascular leakage by SZN-413 was examined in a VEGF-induced retinal vascular leakage rabbit model, in which the level of fluorescein leakage was measured 3 days after IVT delivery of VEGF together with SZN-413 or vehicle. ANOVA was used for statistical analysis.
Results :
Results: In the OIR mouse model, nanogram quantities of SZN-413 significantly reduced the NV area size (p<0.001) to a level comparable to the group treated with 60 ug aflibercept. SZN-413 also showed a dramatic reduction in AV area size compared to vehicle (p<0.001) and compared to aflibercept (p<0.01). In the VEGF-induced retinal vascular leakage rabbit model, SZN-413 significantly reduced retinal vascular leakage by 78%, compared to the vehicle-treated group (p<0.01). No observable abnormalities were detected in ocular exams in these studies.
Conclusions :
The novel Norrin mimetic, SZN-413, demonstrated anti-NV properties and reduced the avascular area in OIR mice, and reduced VEGF-driven retinal vascular leakage in rabbits. The results strongly suggests that the pathological cellular responses can be modulated by SZN-413, with possible therapeutic implications for diabetic retinopathy.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.