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Published on: April 1, 2019
Tear Biomarkers of Topical Sirolimus in Meibomian Gland Dysfunction: A Randomized Trial
Lei Zhou1,2, Hiroyuki Shimizu3, Yuki Togashi3
1School of Optometry, Department of Applied Biology and Chemical Technology, Research Centre for SHARP Vision (RCSV), The Hong Kong Polytechnic University, Hong Kong, People's Republic of China.
Purpose:
Pharmacodynamic biomarkers of sirolimus were investigated using omics analysis of tear fluids from Japanese patients with meibomian gland dysfunction (MGD).
Methods:
In a Phase 2a trial, sirolimus or vehicle eyedrops were administered twice daily for 12 weeks. Tear samples from 29 patients (15 sirolimus, 14 vehicle) were collected pre- and post-treatment. LC-MS/MS-based proteomics and lipidomics were performed. Within-group changes were analyzed, followed by differential expression and pathway analysis. Key candidates were evaluated using estimation plots (Registration ID: UMIN000049186).
Results:
Over 3000 proteins and 55 lipids were quantified. mTOR signaling components (ATP6V1D, RRAGC, DEPTOR) were significantly modulated. ATP6V1D showed a significant decrease in the sirolimus group (p = 0.0024), but not in the vehicle group (p = 0.528). Lipids 12-HETE and 13-HpODE significantly increased post-treatment in the sirolimus group.
Conclusion:
Results suggested that sirolimus inhibited the mTOR pathway. ATP6V1D, 12-HETE, and 13-HpODE were suggested to be pharmacodynamic biomarkers for sirolimus. These findings may facilitate pharmacodynamic monitoring of mTOR-targeted therapies for ocular surface disorders.
