Improvement Of Corneal Staining By A Sirt1 Activator In A Mouse Model Of Dry Eye

Abstract

Purpose: : To determine the effect of the SIRT1 activator SRT1460 on corneal epithelial staining in the desiccating stress model of dry eye.

Methods: : All studies were conducted after review by the GSK Institutional Animal Care and Use Committee and in accordance with the GSK Policy on the Care, Welfare and Treatment of Laboratory Animals. Female C57BL/6 mice were placed in a controlled environment chamber (CEC) for a total of 9 or 18 days to induce ocular surface dryness. Following 2 or 4 days in CEC topical treatment was initiated and continued for 7 or 14 days. SRT1460, dexamethasone or vehicle were administered twice daily to both eyes in a 3 µL volume. Corneal fluorescein staining (CFS) was assessed using the NEI grading scale. Ocular tissue exposure in cornea and conjunctiva tissues were determined following two single topical instillations (30 μL drop) of a 9 mg/mL formulation in Dutch-belted rabbits (doses were 24 hr apart, N=4 eyes per time point).

Results: : Within 48 hours of exposure to CEC corneal fluorescein staining increased as described previously (Barabino et al, IOVS 2005). Compared to the start of treatment on day 2, CFS on day 9 was reduced by topical treatment with dexamethasone and vehicle by 24 and 32%, respectively, whereas CFS was further increased in the untreated group by 48%. SRT1460 reduced CFS by 26 and 49% in the low and high-dose groups, respectively. The reduction for the high-dose group was significant compared to the low-dose group, vehicle, dexamethasone and no treatment. Following topical administration of SRT1460 in Dutch-belted rabbits, cornea levels were 13.6 ± 5.99 μg/gram tissue one hour post last dose and 5.91 ± 6.08 μg/gram tissue seventy-two hours post last dose. Bulbar conjunctiva levels at one and 72 hours post last dose were 7.50 ± 5.20 μg/gram tissue and 0.263 ± 0.315 μg/gram tissue, respectively.

Conclusions: : Topical treatment with the SIRT1 activator SRT1460 resulted in a significant improvement in corneal barrier function in a mouse model of dry eye. SIRT1 activators potentially represent a novel class for the treatment of dry eye disease.

Keywords: cornea: tears/tear film/dry eye • cornea: epithelium