Factor XIIa inhibition protects against VEGF-induced neuroretinal dysfunction in mice

Abstract

Purpose : Factor XIIa (FXIIa), the primary activator of the kallikrein kinin system (KKS), has been identified in the vitreous of patients with diabetic macular edema (DME). We have previously shown that intravitreal injection of VEGF or bradykinin (BK) induced alterations in electroretinogram (ERG) amplitude and reduced visual function measured by optokinetics in mice. The current study investigates the effects of a novel, selective, oral FXIIa inhibitor KV998086 on VEGF-induced effect on ERG.

Methods : Male C57bl6/J wild-type mice at 8 weeks of age received intravitreal injections (IVI, 1µL/eye) of VEGF (100ng/eye), FXIIa (50ng/eye), BK (20mM) or PBS control. Retinal neuronal function was assessed using full field dark-adapted scotopic ERG at 24 hours following IVI. Scotopic ERG responses were recorded by a DiagnoSys Celeris system at 10 cd-s/m² flash intensity. A subset of mice received FXIIa inhibitor, KV998086, administered by 1003D Alzet minipump (14.2mg/kg/d) initiated at 24 hours prior to IVI of VEGF.

Results : ERG amplitudes in mice were increased at 24 hours post IVI of FXIIa (n=11) for A-wave by 40.6% (p<0.01) and B-wave by 52.4% (p<0.01) and IVI of BK increased A-wave by 55.3% (p=0.01) and B-wave by 60.3% (p<0.05) compared to IVI of PBS (n=9). At 48h post IVI of FXIIa, both A-wave (39.9%, p<0.01) and B-wave (38.9%, p<0.01) remained increased compared with PBS controls. ERG amplitudes in mice were increased at 24 hours post IVI of VEGF (n=8) for A-wave by 50.2% (p<0.01) and B-wave by 51.5% (p<0.01) compared to PBS. KV998086 administered at 14.2 mg/kg/day s.c. in mice (n=11) decreased VEGF induced ERG amplitude by 84.1% for A-wave (p<0.01) and 81.9% for B-wave (p<0.05) compared to VEGF alone. KV998086 has an IC₅₀ for FXIIa of 7.3 nM and 9.4 nM for human and mouse, respectively, with selectivity greater than > 1000-fold compared to a panel of other serine proteases. In mice receiving KV998086 at 14.2 mg/kg/day, steady state plasma concentration was 450±54 ng/ml.

Conclusions : Intravitreal injection of FXIIa, BK, and VEGF caused abnormalities in scotopic ERG amplitude at 24 hours post injection in male C57bl6/J wild-type mice. Systemic administration of the FXIIa inhibitor KV998086 blocked the effects of IVI of VEGF on ERG. These data suggest that systemic administration of a FXIIa inhibitor may provide protective effects on neuroretinal function in DME.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.