Agonism of the liver X receptor improves dry eye pathology in vitro and in vivo

Abstract

Purpose : To evaluate pharmacologic liver X receptor agonism in human corneal epithelial cells and in a murine model for dry eye disease.

Methods : Human corneal epithelial (HCE-T) cells were seeded in 8-chamber slides grown to confluency. Cells were pre-treated with DMSO (vehicle) and or ouabagenin (0.05 µM in DMSO). One hour later, cells were exposed to hyperosmolar conditions by supplementation with a dose-range of NaCl (0 - 75 mM). after 24 h, tight junction organization was quantified by anti-zona occludens 1 (ZO-1) immunostaining. For in vivo studies, the liver X receptor agonist, T-0901317, was encapsulated into poly (lactide-co-glycolide) nanoparticles (PLGA NP). Dry eye disease was induced using the SiccaSystem® desiccating stress environment combined with transdermal administration of scopolamine to inhibit lacrimal gland exocrine function for a period of 14 d. Concomitantly, mice were treated three times daily by topical application (10 µl) with either empty PLGA NP or T-0901317-encapsulating PLGA NP. Corneal fluorescein staining was performed to assess corneal damage.

Results : Hyperosmolar stress resulted in ~30% decreased ZO-1 immunoreactivity (P < 0.05) and significantly reduced tight junction organization index (TiJOR). Treatment with ouabagenin fully protected against loss of ZO-1 immunoreactivity and disorganization of cellular tight junctions. Desiccating stress/ scopolamine-induced corneal damage was significantly lower in T-0901317-encapsulating PLGA NP-treated eyes (median score: 1, range 0 – 3) compared with vehicle-treated eyes (median score: 2, range 1 – 4; n= 16; P < 0.05).

Conclusions : LXR agonists, oubagenin and T-0901317, improve dry eye disease pathology in vitro and in vivo. These data support feasibility of the ongoing development of LXR agonists for the treatment of dry eye disease.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.