Ophthalmic NSAIDs for Corneal Dystrophy Caused by SLC4A11 Mutation
By Lynda Seminara Selected By: Deepak P. Edward, MD
Journal Highlights
JAMA Dermatology
Published online Aug. 29, 2018
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Some mutations of the SLC4A11 gene cause misfolding of the SLC4A11 protein, which may lead to Fuchs endothelial corneal dystrophy (FECD) or congenital hereditary endothelial dystrophy (CHED). Alka and Casey tested 5 ophthalmic nonsteroidal anti-inflammatory drugs (NSAIDs) for their ability to correct SLC4A11 folding defects. They found that 4 of the 5 NSAIDs provided significant rescue of SLC4A11 mutants to the cell surface. In addition, 2 of the drugs restored osmotically driven water flux of SLC4A11 mutants. The 5 drugs studied were bromfenac, diclofenac, flurbiprofen, ketorolac tromethamine, and nepafenac.
HEK293 cells expressing CHED- and FECD-causing SLC4A11 mutants were grown in 96-well dishes, with or without an NSAID. Except for ketorolac, the tested drug concentrations were twice the EC50. The amount of ketorolac was much lower (0.25 μM) because concentrations >5 μM are toxic to HEK293 cells.
Using bioluminescence resonance energy transfer (BRET) and confocal microscopy, the authors tested each NSAID’s ability to correct mutant SLC4A11 cell-surface trafficking. Upon treatment, they also tested the ability of mutant SLC4A11-expressing cells to mediate water flux, which may mimic water flux across the corneal endothelial cell basolateral membrane.
BRET assays showed significant rescue of SLC4A11 mutants to the cell surface by 4 of the 5 NSAIDs. Diclofenac and nepafenac were the most effective for moving endoplasmic reticulum–retained missense mutant SLC4A11 to the cell surface. In 20 of 30 intracellular-retained SLC4A11 mutants, diclofenac significantly restored cell-surface abundance. In some cases, diclofenac restored mutant SLC4A11 water flux activity to the level of wild-type SLC4A11. Ketorolac had no effect on cell-surface abundance. Of the 3 mutants examined for cell-surface abundance (L843P, G709E, and E143K), L843P had the greatest improvement in trafficking.
This research suggests that topical ophthalmic NSAIDs possess sufficient permeability to reach the corneal endothelium. The authors encourage testing of diclofenac eyedrops to treat corneal dystrophy in patients with certain SLC4A11 missense mutations. Wide use of NSAIDs for FECD or CHED would require robust data from well-designed clinical trials in which appropriate dosing regimens are established.
The original article can be found here.