Sphingosine-1-phosphate receptor 2 inhibition ameliorates familial exudative vitreoretinopathy models

Familial exudative vitreoretinopathy (FEVR) is an inherited childhood blinding disorder with close to 85% of molecularly determined cases due to rare variants in the genes encoding members of the frizzled 4 (FZD4) receptor complex. FEVR causes blindness due to complications arising from developmental peripheral non-perfusion of the retina. We sought to find a small molecule that could ameliorate FEVR models. In this study, we determine that the sphingosine1-phosphate receptor 2 (S1PR2) antagonist JTE-013 can ameliorate cellular and mouse models of FEVR. Using human primary retinal microvascular endothelial cells (hRMECs), we show that either knockdown of FZD4 expression using shRNA or expression of a known FEVR-causing dominant negative allele of FZD4 decreases the ability of hRMECs to tubularize. The addition of JTE-013 to both hRMEC models of FEVR resulted in the restoration of tubularization. In the well-established Fzd4^-/- mouse model of FEVR, dosing animals with JTE-013 ameliorated the retinal vascularization defects in these mice. The implications of these findings are (i) a major contributor to abnormal retinal angiogenesis in FEVR is likely through a decrease in vascular formation/integrity, and (ii) treatment with a well-characterized S1PR2 inhibitor restores normal vascularization in cell and mouse models of FEVR. To our knowledge, this is the first study to implicate S1PR signaling in FEVR and to show that a small drug-like molecule can restore normal vascularization and prevent blinding complications.