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.

Grant Number: 5R01EY032161-05
NIH Institute/Center: NIH
Principal Investigator: Matilda Chan