Investigation of a first-in-class Frizzled4/LRP5 agonist in retinal disease models

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PROJECT SUMMARY/ABSTRACT The blood-retina barrier (BRB) protects the retina by limiting extravasation of solutes and immune cells and by providing active transport mechanisms for required nutrients and hormones. BRB dysfunction is implicated in retinal diseases including diabetic retinopathy, choroidal neovascularization, retinal occlusive diseases, uveitis, macular telangiectasia, familial exudative vitreoretinopathy, retinopathy of prematurity, and Coat’s disease. Although the key role of canonical Norrin and WNT7A/B signaling in inducing and maintaining blood-CNS barriers has been identified, highly potent and therapeutically amenable agonists of these pathways that could promote or restore BRB function are lacking. Signal initiation by Norrin requires the receptor Frizzled4 (FZD4) and two co-receptors, low-density-lipoprotein receptor-related protein 5 (LRP5) and tetraspanin-12 (TSPAN12). Here, we use an entirely novel agonist to activate canonical (i.e., beta-catenin-dependent) signaling in endothelial cells. The agonist is a human antibody modality that functionally mimics Norrin and WNT7A/B. The mechanism of action and its efficacy in distinct types of BRB defects are not known. We will conduct cell-based experiments to test the hypothesis that the agonist activates signaling by inducing complex formation of receptor and co-receptor molecules. To understand which types of BRB defects can be restored by the agonist, we will use multiple mouse models with BRB defects that have distinct characteristics. We will determine the efficacy in restoring the BRB in each model, perform transcriptomic experiments and immuno- histochemical analyses to identify mechanism of BRB restoration, and quantify vascular density. BRB defects, e.g., in macular edema, are treated with anti-VEGF or anti-inflammatory drugs. However, anti-VEGF therapies are not effective in all patients, and other patients may develop resistance. The novel agonist used here has an entirely different pharmacodynamic profile compared to anti-VEGF and anti-inflammatory drugs. Therefore, it is important to evaluate this drug candidate for its therapeutic potential.