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

Award Number: R01EY033316
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $453,631 )
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Vision Research	000	5	1/12/2026	NON-COMPETING CONTINUATION	$453,631
														Subtotal = $453,631

Issue Date FY: 2025 ( Subtotal = $453,631 )
2025	2025	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Vision Research	000	4	12/20/2024	NON-COMPETING CONTINUATION	$453,631
														Subtotal = $453,631

Issue Date FY: 2024 ( Subtotal = $489,725 )
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Vision Research	001	3	6/28/2024	SUPPLEMENT FOR EXPANSION	$36,094
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Vision Research	000	3	1/4/2024	NON-COMPETING CONTINUATION	$453,631
														Subtotal = $489,725

Issue Date FY: 2023 ( Subtotal = $453,631 )
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Vision Research	001	2	3/6/2023	NON-COMPETING CONTINUATION	$45,363
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Vision Research	000	2	1/5/2023	NON-COMPETING CONTINUATION	$408,268
														Subtotal = $453,631

Issue Date FY: 2022 ( Subtotal = $467,381 )
2022	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Vision Research	000	1	12/16/2021	NEW	$467,381
														Subtotal = $467,381

Grand Total All Awards = $2,317,999

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

Award Number: R01EY033316

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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