PolyU School of Optometry 45th Anniversary Research Seminar on Secreted Frizzled-Related Protein as a Novel Target for the Treatment of Retinal Angiogenesis

Abnormal blood vessel formation is the leading cause of blindness. The standard of care for ocular angiogenic diseases is dominated by inhibitors targeting vascular endothelial growth factor (VEGF). However, a substantial number of patients do not respond to the treatment or may develop resistance over time, which is, at least, partially due to the compensatory activation of alternative angiogenic pathways in response to anti-VEGF treatment. Using an untargeted Proteomics-based approach, our study reveals a significantly lower level of a secreted frizzled-related protein (SFRP) in the vitreous of PDR patients as compared to that in control patients. We then constructed a fusion protein containing the SFRP and Fc portion of IgG and demonstrated a potent inhibitory effect of SFRP-Fc on retinal microvascular endothelial cell (HREC) proliferation, viability, and tube formation as well as vessel outgrowth from the choroid, aortic ring, and metatarsal explants. SFRP-Fc is also able to prevent and reverse laser-induced choroidal neovascularization (CNV) in mice. We further demonstrated that the C-terminal domain of the SFRP (SFRPC) is responsible for its anti-angiogenic effect. Importantly, SFRPC-Fc synergistically inhibits CNV in combination with the anti-VEGF drug, Aflibercept. Mechanistically, SFRP inhibits angiogenesis by interacting with Caveolin, suppressing its phosphorylation, and altering the endocytosis of cell surface receptors. In summary, this study leads to the discovery of a novel inhibitor of angiogenesis, identified its functional domain, and established its mechanism of action.