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

Investigative Ophthalmology & Visual Science
Kumari Alka, Joseph R Casey

Abstract

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. 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. BRET-assays revealed significant rescue of SLC4A11 mutants to the cell surface by 4 of 5 NSAIDs tested. The NSAIDs, diclofenac and nepafenac, were e...Continue Reading

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Citations

Jul 29, 2020·Investigative Ophthalmology & Visual Science·Wenlin ZhangAnthony J Aldave
Jan 5, 2019·Molecular Diagnosis & Therapy·Jie ZhangDipika V Patel
Jul 6, 2019·Scientific Reports·Darpan MalhotraJoseph R Casey
Sep 7, 2019·Experimental Eye Research·Susumu HaraKohji Nishida
Oct 12, 2020·Biochemical Pharmacology·Bianca N QuadeRossana Occhipinti
Sep 10, 2021·Investigative Ophthalmology & Visual Science·Moonjung Choi, Joseph A Bonanno

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