Ophthalmic Nonsteroidal Anti-Inflammatory Drugs as a Therapy for Corneal Dystrophies Caused by SLC4A11 Mutation

Abstract

Citation: Alka K, Casey JR. Ophthalmic nonsteroidal anti-inflammatory drugs as a therapy for corneal dystrophies caused by SLC4A11 mutation. Invest Ophthalmol Vis Sci. 2018;59:4258-4267. https://doi.org/ 10.1167/iovs.18-24301 PURPOSE. SLC4A11 is a plasma membrane protein of corneal endothelial cells. Some mutations of the SLC4A11 gene result in SLC4A11 protein misfolding and failure to mature to the plasma membrane. This gives rise to some cases of Fuchs' endothelial corneal dystrophy (FECD) and congenital hereditary endothelial dystrophy (CHED). We screened ophthalmic nonsteroidal anti-inflammatory drugs (NSAIDs) for their ability to correct SLC4A11 folding defects.METHODS. Five ophthalmic NSAIDs were tested for their therapeutic potential in some genetic corneal dystrophy patients. HEK293 cells expressing CHED and FECD-causing SLC4A11 mutants were grown on 96-well dishes in the absence or presence of NSAIDs. Ability of NSAIDs to correct mutant SLC4A11 cell-surface trafficking was assessed with a bioluminescence resonance energy transfer (BRET) assay and by confocal microscopy. The ability of mutant SLC4A11-expressing cells to mediate water flux (SLC4A11 mediates water flux across the corneal endothelial cell basolateral membrane as part of the endothelial water pump) was measured upon treatment with ophthalmic NSAIDs.RESULTS. BRET-assays revealed significant rescue of SLC4A11 mutants to the cell surface by 4 of 5 NSAIDs tested. The NSAIDs, diclofenac and nepafenac, were effective in moving endoplasmic reticulum-retained missense mutant SLC4A11 to the cell surface, as measured by confocal immunofluorescence. Among intracellular-retained SLC4A11 mutants, 20 of 30 had significant restoration of cell surface abundance upon treatment with diclofenac. Diclofenac restored mutant SLC4A11 water flux activity to the level of wild-type SLC4A11 in some cases.CONCLUSIONS. These results encourage testing diclofenac eye drops as a treatment for corneal dystrophy in patients whose disease is caused by some SLC4A11 missense mutations.

Ammonia sensitive SLC4A11 mitochondrial uncoupling reduces glutamine induced oxidative stress

“…1B) and PS120 fibroblasts stably transfected with HA-tagged SLC4A11 (Fig. 1C), consistent with previous reports of multiple cytoplasmic locations in addition to the plasma membrane [11,24]. TEM immunochemistry of isolated mitochondria from PS120-hSLC4A11-HA cells (Fig.…”

The therapeutic importance of acid-base balance

“…CA inhibitors applied as eye drops have long been used to treat glaucoma by virtue of their ability to reduce the production of aqueous humor, although even their localized ophthalmic use has been documented to lead to the side-effect of systemic MAc in some prone individuals [144] , [145] . Corneal edema that results from the expression of mutant misfolded SLC4A11 may be amenable to correction by small molecule folding chaperones [146] . NHE1 blockers are cytoprotective in a rat model of diabetic cataract formation and retinopathy [147] .…”

Energy Shortage in Human and Mouse Models ofSLC4A11-Associated Corneal Endothelial Dystrophies

“…Approximately 94 SLC4A11 mutations have been identified in individuals with CHED. 4,6,9,[31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] Although a large number of these mutations result in SLC4A11 protein misfolding and failure to mature to the plasma membrane, 5,6,[49][50][51] some mutations affect SLC4A11 transporter function without impacting membrane trafficking 17,52,53 or cause aberrant SLC4A11 pre-mRNA splicing and subsequent reduced SLC4A11 expression. 47 Collectively, these observations support the hypothesis that loss of SLC4A11 function is the primary pathogenetic mechanism in CHED rather than mutant SLC4A11 protein misfolding/mislocalization in the endoplasmic reticulum (ER).…”