Abstract
Purpose :
We explored pharmacodynamic biomarkers of sirolimus in tear collected from Meibomian gland dysfunction (MGD) patients.
Methods :
Sirolimus suspension or vehicle was topically administrated to the eyes of 29 MGD Japanese patients twice a day for 10 weeks (15 patients for sirolimus; 14 patients for vehicle). Tear samples were collected using Schirmer’s strips before and after treatment, and then proteins and lipids in tears were analyzed using quantitative proteomics and lipidomics. Changes in proteins and lipids were first evaluated by pre-post comparison in each treatment group and they were arranged in descending order of change through differential expression analysis, enriched gene ontology, or pathway analysis. Top-ranked proteins and lipids were then evaluated for differences between treatment groups using the estimation plot.
Results :
More than 3,000 proteins and 55 lipids were quantified in tears from MGD patients. Protein-protein interaction (PPI) network analysis showed that mTOR signaling pathway (ATP6V1D, RRAGC, and DEPTOR) is one of the affected pathways related to MGD and sirolimus treatment. Among them, ATP6V1D showed the greatest decrease by pre-post comparison in the sirolimus-treated group (p = 0.0024), and a significant difference in the post-treatment was confirmed by comparison to the vehicle-treated group (p = 0.0006), while no significant difference at the pre-treatment was observed. As for lipids, 12-HETE and 13-HpODE in sirolimus showed a significant increase in tear concentration after treatment compared to pre-treatment with sirolimus (p = 0.0006 and p = 0.0156, respectively).
Conclusions :
The inhibition of mTOR signaling pathway in MGD patients was confirmed after administration of the sirolimus ophthalmic suspension and ATP6V1D was suggested to be a pharmacodynamic biomarker for sirolimus.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.