Calcium-sensing receptor (CaSR) modulates ocular surface chloride transport and its inhibition promotes ocular surface hydration.

PURPOSE: Ocular surface hydration is critical for eye health and its impairment can lead to dry eye disease. Extracellular calcium-sensing receptor (CaSR) is regulator of ion transport in epithelial cells expressing cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel. CFTR is also a major ion channel in ocular surface epithelia, however the roles of CaSR in ocular surface are not well studied. This study aims to investigate expression and functional roles of CaSR in ocular surface. METHODS: CaSR immunostaining was performed in mouse and human cornea and conjunctiva. Ocular surface potential difference (OSPD) and tear fluid volume measurements were performed in mice with topically applied cinacalcet (CaSR activator) and NPS-2143 (CaSR inhibitor). RESULTS: CaSR is expressed in corneal and conjunctival epithelia of mice and humans. Topically administered CaSR activator cinacalcet inhibits cAMP agonist forskolin-induced Cl- secretion and CFTR activity up to 90 %. CaSR inhibitor NPS-2143 stimulates CFTR-mediated Cl- secretion in mouse ocular surface, after which cAMP agonist forskolin had minimal additional secretory effects. Single dose NPS-2143 treatment (as an eye drop) increases tear fluid volume in mice by ∼60 % compared to vehicle treatment. NPS-2143 effect on tear volume lasts at least 8 h after single dose. CONCLUSIONS: CaSR is a key regulator of ocular surface ion transport and CaSR inhibition promotes Cl- and tear secretion in the ocular surface. If they are found to be effective in in dry eye models, CaSR inhibitors (currently in clinical development) can potentially be repurposed as novel prosecretory treatments for dry eye disease.

Incidence and Mitigation of Corneal Pseudomicrocysts Induced by Antibody-Drug Conjugates (ADCs).

Purpose of Review: This study is to highlight the incidence of corneal pseudomicrocysts in FDA-approved antibody-drug conjugates (ADCs), and success of preventive therapies for pseudomicrocysts and related ocular surface adverse events (AEs). Recent Findings: ADCs are an emerging class of selective cancer therapies that consist of a potent cytotoxin connected to a monoclonal antibody (mAb) that targets antigens expressed on malignant cells. Currently, there are 11 FDA-approved ADCs with over 164 in clinical trials. Various AEs have been attributed to ADCs, including ocular surface AEs (keratitis/keratopathy, dry eye, conjunctivitis, blurred vision, corneal pseudomicrocysts). While the severity and prevalence of ADC-induced ocular surface AEs are well reported, the reporting of corneal pseudomicrocysts is limited, complicating the development of therapies to prevent or treat ADC-related ocular surface toxicity. Summary: Three of 11 FDA-approved ADCs have been implicated with corneal pseudomicrocysts, with incidence ranging from 41 to 100% of patients. Of the six ADCs that reported ocular surface AEs, only three had ocular substudies to investigate the benefit of preventive therapies including topical steroids, vasoconstrictors, and preservative-free lubricants. Current preventive therapies demonstrate limited efficacy at mitigating pseudomicrocysts and other ocular surface AEs.

Ocular Surface Ion Transport and Dry Eye Disease.

Purpose of Review: To review the role of ocular surface epithelial (corneal and conjunctival) ion transporters in the pathogenesis and treatment of dry eye disease (DED). Recent Findings: Currently, anti-inflammatory agents are the mainstay of DED treatment, though there are several agents in development that target ion transport proteins on the ocular surface, acting by pro-secretory or anti-absorptive mechanisms to increase the tear fluid Film volume. Activation or inhibition of selected ion transporters can alter tear fluid osmolality, driving water transport onto the ocular surface via osmosis. Several ion transporters have been proposed as potential therapeutic targets for DED, including the cystic fibrosis transmembrane conductance regulator (CFTR), calcium-activated chloride channels (CaCCs), and the epithelial sodium channel (ENaC). Summary: Ocular surface epithelial cell ion transporters are promising targets for pro-secretory and anti-absorptive therapies of DED.

Microbiological alterations in the conjunctiva of hot tub-soaking ophthalmologists (MACHO): a randomized double-blind clinical trial.

Background: To determine if there is a difference in the quantity of microbial flora of the conjunctiva in individuals practicing head submersion ("dunk") versus no head submersion ("no-dunk") during hot tub use. Methods: In this double-blind randomized clinical trial, healthy volunteers aged ≥ 18 years were recruited. Participants were randomized to head submersion versus no head submersion during a 15-minute hot tub soak. Study personnel, masked to the dunk or no-dunk group assignment, obtained conjunctival cultures before and immediately after hot tub use. De-identified specimens were submitted to the clinical microbiology laboratory for culture and analysis. The main outcome measure was the difference in the quantity of organisms cultured from the conjunctiva before and after hot tub exposure, as determined using a defined ordinal scale. A two-tailed Student's t-test was performed to compare the total microbial colony counts between the two arms. Simpson's diversity was used to measure the changes in organism diversity between the arms. Results: Of 36 enrolled subjects, 19 were randomly assigned to the dunk and 17 were assigned to the no-dunk groups. Water samples obtained from all hot tubs were culture negative. Eleven of 19 eyes (58%) from the dunk group and eight of 17 eyes (47%) from the no-dunk group had negative conjunctival bacterial cultures before and after hot tub exposure. However, six of 19 eyes (32%) and four of 17 eyes (24%) of the dunk and no-dunk groups, respectively, were culture-positive after, but not before hot tub exposure. The quantity of organisms before and after hot tub exposure was not significantly different between the two arms (P = 0.12). However, the dunk group only showed a small increase in the quantity of organisms after as compared to before hot tub use (P = 0.03). None of the samples from subjects or hot tubs were culture-positive for Acanthamoeba. Conclusions: Head submersion in a public hot tubs during a 15-minute soak does not appear to change conjunctival flora, as determined by culture plate yield, this does not eliminate the association between hot tub use and devastating and painful corneal blindness. Therefore, our recommendation is to remove contact lenses prior to hot tub use, avoid head submersion in a hot tub, and urgently seek ophthalmological help if any eye pain and/or decrease in vision is experienced after hot tub use.