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Enabling Targeted Protein Degradation of VEGF to Treat Neovascular Age-related Macular Degeneration

Award Number: F32EY037539
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/30/2026
PERIOD OF PERFORMANCE END DATE: 09/29/2027

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Enabling Targeted Protein Degradation of VEGF to Treat Neovascular Age-related Macular Degeneration - PROJECT SUMMARY Neovascular Age-related Macular Degeneration (nAMD) is characterized by pathogenic choroidal neovascularization (CNV) and is a leading cause of blindness in older Americans. The current standard of care, intraocular injection of VEGF inhibitors, presents significant challenges: 25% of patients don’t respond to treatment, many patients experience vision deterioration because challenges associated with receiving frequent invasive intraocular injections lead to undertreatment, and long-term use of VEGF inhibitors may accelerate macular atrophy. This proposal aims to develop and characterize a novel VEGF degrader therapeutic that overcomes these limitations through targeted protein degradation (TPD) technology. In preliminary experiments, we identified a potent VEGF degrader (Degrader 1) which is designed to recruit VEGF to a novel lysosomal trafficking receptor for degradation. This degrader demonstrates exceptional catalytic activity, depleting a 10-fold excess of VEGF within 24 hours in stem cell-derived retinal pigment epithelial (RPE) cells. Importantly, the lysosomal trafficking receptor used has polarized expression on the apical RPE surface and thus has the potential to provide spatial specificity that may prevent the indiscriminate choroidal VEGF inhibition associated with macular atrophy. In this study, we will define Degrader 1's mode of action by: (a) confirming its dependence on the lysosomal trafficking receptor using knockdown and imaging studies; (b) defining its spatial activity on apical versus basal RPE surfaces, (c) evaluating target specificity through proteomics analysis, and (d) assessing therapeutic efficacy in the mouse laser-induced CNV model by comparing Degrader 1 to Aflibercept using fluorescein angiography, OCT, and histology as readouts. Degrader 1 represents a paradigm shift in nAMD treatment with potential advantages of increased potency at lower doses (resulting in reduced treatment frequency), spatial specificity (to prevent macular atrophy), and compatibility with AAV delivery (for long-term expression). If successful, this approach could significantly improve clinical outcomes and quality of life for nAMD patients, providing effective treatment for current non-responders while reducing injection frequency and long-term complications. The University of Wisconsin-Madison is an ideal place for successful completion of both of these aims, as it is a collaborative environment where all of the resources (both technical and intellectual) needed for this project are freely available.


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 = $81,580 )
2026	2026	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Vision Research	000	1	4/7/2026	NEW	$81,580
														Subtotal = $81,580

Grand Total All Awards = $81,580

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Enabling Targeted Protein Degradation of VEGF to Treat Neovascular Age-related Macular Degeneration

Award Number: F32EY037539

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/30/2026

PERIOD OF PERFORMANCE END DATE: 09/29/2027

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