MFAP4 – a novel potential target for treatment of vascular leakage in diabetic retinopathy

Abstract

Purpose : Development of new treatment strategies for diabetic retinopathy (DR) is required to improve the disease management due to a large fraction of anti-VEGF poor responders. Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix protein and a ligand for v3 and v5 integrins. We have previously shown that anti-MFAP4 antibodies (anti-MFAP4) effectively block pathological angiogenesis and inflammation in a mouse model of laser-induced choroidal neovascularization. Here we investigate the efficacy of anti-MFAP4 in a rat model of DR and cellular sources of MFAP4 expression, and assess tolerability in rabbits.

Methods : In vivo effects of anti-MFAP4 antibodies were investigated in streptozotocin (STZ)-treated rats. MFAP4 mRNA expression was measured by qPCR in primary retinal endothelial cell (REC) and retinal pigmented epithelium ARPE-19 cells in vitro +/- growth factor treatment. Tolerability of anti-MFAP4 antibodies were tested by intraocular injection into New Zealand White Rabbits and imaged after 7 days by OCT and fundus angiography on a Heidelberg Spectralis.

Results : Anti-MFAP4 antibody significantly reduced retinal vascular permeability induced by STZ (p<0.001) and to the same level as anti-VEGF. Both RECs and ARPE-19 cells expressed the MFAP4 transcript. MFAP4 expression was not induced by either VEGF or TGF-2 stimulation in RECs but highly upregulated by ARPE-19 cells by TGF-2 stimulation in a time- and dose-dependent manner. Injection of anti-MFAP4 was well tolerated in rabbits for 7 days, with no signs of inflammation, retinal hyperemia or toxicity.

Conclusions : We demonstrated that retinal vascular permeability in vivo was significantly affected by anti-MFAP4 treatment. Both RECs and retinal pigmented epithelial cells express MFAP4, and MFAP4 expression is highly upregulated in the latter upon stimulation by fibrotic signalling. Our results support that anti-MFAP4 has potential in treatment DR.

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