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

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2024 · $36,094

## Abstract

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
immunohistochemical 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.

## Key facts

- **NIH application ID:** 11089079
- **Project number:** 3R01EY033316-03S1
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Stephane Angers
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $36,094
- **Award type:** 3
- **Project period:** 2022-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11089079

## Citation

> US National Institutes of Health, RePORTER application 11089079, Investigation of a first-in-class Frizzled4/LRP5 agonist in retinal disease models (3R01EY033316-03S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11089079. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*