Corneal Dystrophy‐Causing SLC 4 A 11 Mutants: Suitability for Folding‐Correction Therapy

SLC 4 A 11 mutations cause some cases of the corneal endothelial dystrophies, congenital hereditary endothelial corneal dystrophy type 2 ( CHED 2), Harboyan syndrome ( HS ), and Fuchs endothelial corneal dystrophy ( FECD ). SLC 4 A 11 protein was recently identified as facilitating water flux across membranes. SLC 4 A 11 point mutations usually cause SLC 4 A 11 misfolding and retention in the endoplasmic reticulum ( ER ). We set about to test the feasibility of rescuing misfolded SLC 4 A 11 protein to the plasma membrane as a therapeutic approach. Using a transfected HEK 293 cell model, we measured functional activity present in cells expressing SLC 4 A 11 variants in combinations representing the state found in CHED 2 carriers, affected CHED 2, FECD individuals, and unaffected individuals. These cells manifest respectively about 60%, 5%, and 25% of the water flux activity, relative to the unaffected ( WT alone). ER ‐retained CHED 2 mutant SLC 4 A 11 protein could be rescued to the plasma membrane, where it conferred 25%–30% of WT water flux level. Further, some ER ‐retained CHED 2 mutants expressed at 30°C supported increased water flux compared with 37°C cultures. Caspase activation and cell vitality assays revealed that expression of SLC 4 A 11 mutants in HEK 293 cells does not induce cell death. We conclude that therapeutics able to increase cell surface localization of ER ‐retained SLC 4 A 11 mutants hold promise to treat CHED 2 and FECD patients.