Corneal Dystrophies Caused by SLC4A11 Mutation: A Promising New Paradigm Shift in Therapy Using an Ophthalmic Nonsteroidal Anti-Inflammatory Eye Drops

Introduction:

Corneal endothelial cell loss is often associated with blinding endothelial corneal dystrophies: relatively seen more frequently dominantly inherited (5%) FECD (Fuchs Endothelial Corneal Dystrophy) and rare recessive CHED1. Mutations of SLC4A11, an abundant corneal solute transporter, cause CHED and some cases of FECD. SLC4A11 is a unique member of the SLC4 family of bicarbonate transport proteins localized at the basolateral surface of corneal endothelial cells that contributes to osmotically-driven water flux from the stroma to aqueous humour to maintain corneal fluid-balance2.

While mutations and loss of functional SLC4A11 are reported to be associated with degeneration and death of endothelial cells, the detailed physiological roles of SLC4A11 still remain unknown. Seventy-eight different mutations, including 42- missense, 9- nonsense, 4- splice sites, and 23 insertion-deletion mutations, have been scattered across the gene reported in families with CHED from Indian populations3. Current therapeutic interventions Penetrating keratoplasty, Descemet's Stripping Automated Endothelial Keratoplasty (DSAEK), and Descemet's Membrane Endothelial Keratoplasty (DMEK) face problems such as shortage of donor corneas, complex surgical procedure, and incidence of graft failure in acute and chronic phases4, 5.

When studied in model cells, the most common molecular phenotype of mutant membrane proteins is mild misfolding. This biosynthetic defect renders the protein incapable of transit from the endoplasmic reticulum (ER) site of synthesis to its normal cellular location. Note that SLC4A11 localization in corneas of endothelial dystrophy patients has not been examined; the conclusion of ER retention presently rests on data from cell culture models. Correcting such biosynthetic defects is an attractive therapeutic approach for some genetic diseases affecting membrane proteins, best exemplified by the efficacy of the drug, Lumacaftor, in rescuing the cell-surface misfolded cystic fibrosis transmembrane conductance regulator (CFTR), the protein product of the cystic fibrosis (CF) gene.

Thus, there is an urgent need to find alternative therapy, which is reliable, simple and affordable. A lot of interest has being taken now a day in opting for a non-invasive way of modality over invasive ones. In SLC4A11 mutation corneal dystrophies, one such topic of interest is the hypothesized role of Non-Steroidal Anti-Inflammatory Drugs (NSAID's) as a medical management of corneal endothelial dystrophies.