Wednesday, October 1, 2025 10/1/2025

Analysis of chemical modulators for corneal endothelial dystrophies

Award Number: R01EY032161
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Analysis of chemical modulators for corneal endothelial dystrophies - PROJECT SUMMARY Corneal endothelial dystrophies are a common cause of vision loss and are characterized by a slowly progressive, bilateral dysfunction of the corneal endothelium. The main therapeutic option to restore vision in these patients remains corneal transplantation, as medical management is usually inadequate. Mutations in the SLC4A11 gene are associated with several endothelial dystrophies, including Fuchs endothelial corneal dystrophy (FECD), congenital hereditary endothelial corneal dystrophy (CHED), and Harboyan syndrome. SLC4A11 is a transporter protein that functions to maintain osmotic balance in corneal endothelium, and many point mutations in SLC4A11 found in disease lead to misfolding of the full-length protein. There is recent evidence that assisting mutant SLC4A11 to regain proper folding is a promising therapeutic approach. A prior small-scale, high throughput chemical screen identified the non-steroidal anti-inflammatory drug glafenine for its ability to correct folding defects in misfolded SLC4A11, and following correction the mutant SLC4A11 protein regained functional activity. Though glafenine is not a candidate for clinical use due to anaphylaxis and renal toxicity, its efficacy supports an approach using other small molecule folding correctors to repair defective SLC4A11 in corneal endothelial dystrophies. Our long-term objective is to develop first-in-class therapeutics for patients with vision impairment due to protein misfolding in the cornea. We propose to test the hypothesis that compounds identified through phenotypic screening assays will promote the correct folding of mutant SLC4A11 and restore corneal endothelial cell function. The goals of this proposal are to: Aim 1) Perform focused screening to identify correctors of SLC4A11 folding; Aim 2) Perform large, unbiased chemical library and genetic screening to identify novel targets and mechanisms; and Aim 3) Assess cytotoxic effects of NSAIDs on corneal cells. Using advanced experimental methods, including high-content microscopy-based screening assays and novel CRISPR-based genetic screens, the proposed studies will provide insight into the correction of protein folding defects as a therapeutic strategy for corneal endothelial dystrophies. Results from the study will be used to develop a new, non-surgical treatment option for patients with vision loss due to corneal endothelial dystrophies and establish a novel therapeutic approach to corneal disease.


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: 2025 ( Subtotal = $403,750 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Vision Research	000	5	8/4/2025	NON-COMPETING CONTINUATION	$403,750
														Subtotal = $403,750

Issue Date FY: 2024 ( Subtotal = $403,750 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Vision Research	000	4	7/22/2024	NON-COMPETING CONTINUATION	$403,750
														Subtotal = $403,750

Issue Date FY: 2023 ( Subtotal = $403,750 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Vision Research	000	3	8/14/2023	NON-COMPETING CONTINUATION	$403,750
														Subtotal = $403,750

Issue Date FY: 2022 ( Subtotal = $391,638 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Vision Research	000	2	7/7/2022	NON-COMPETING CONTINUATION	$391,638
														Subtotal = $391,638

Issue Date FY: 2021 ( Subtotal = $403,750 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Vision Research	000	1	9/10/2021	NEW	$403,750
														Subtotal = $403,750

Grand Total All Awards = $2,006,638

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Analysis of chemical modulators for corneal endothelial dystrophies

Award Number: R01EY032161

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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