Abstract
Purpose :
Sjögren’s syndrome (SS) is associated with lymphocytic infiltration of lacrimal glands (LG), resulting in dry eye. Systemic Rapamycin (Rapa) treatment significantly reduces LG inflammation and improves dry eye symptoms in male Nonobese Diabetic (NOD) mice, a model of SS-associated dacryoadenitis. However, systemic toxicity of Rapa such as hyperglycemia and hyperlipidemia may limit its applications. Here, we demonstrate that local delivery of Rapa using 5FA, a nanoparticle comprised of a thermo-responsive protein polymer (Elastin-Like Polypeptide, ELP) and FKBP, the cognate receptor for Rapa, delivers sufficient Rapa to achieve a comparable therapeutic effect as when Rapa is systemically administered, without causing systemic toxicity.
Methods :
All studies were conducted in male NOD mice, aged 13 weeks old. For each LG, 0.22 mg/kg of Rapa carried by 5FA in total was injected once across 3 sites at 2 μl per site (Intralacrimal 5FA-Rapa). Intralacrimal injection of PBS once in the same format served as an injection control, while subcutaneous ELP-Rapa at 1 mg/kg every other day for two weeks (systemic Rapa) was used as a positive control for response to Rapa therapy. Blood glucose, tear secretion, and lymphocytic infiltration of the LG were measured after 2 weeks.
Results :
A significant increase in basal tear production was observed with intralacrimal 5FA-Rapa when compared to intralacrimal PBS (+0.7 mm vs -1.0, p<0.05), while no difference was seen between systemic Rapa and intralacrimal PBS. A significant increase in stimulated tear volume was seen for intralacrimal 5FA-Rapa when compared with systemic Rapa (5.2 vs 3.2 μl, p<0.05). Tear CTSS activity was significantly reduced by intralacrimal 5FA-Rapa relative to systemic Rapa (p<0.05). A significant reduction in lymphocytic infiltration was seen between intralacrimal PBS vs 5FA-Rapa (24% vs 15%, p<0.01) and intralacrimal PBS vs systemic Rapa (24% vs 7%, p<0.001). Significantly higher blood glucose levels (144 vs 75 mg/dl, p<0.001) and cholesterol levels (139 vs 69mg/dl, p<0.001) were seen with systemic Rapa compared with intralacrimal PBS, whereas no significant differences were seen for intralacrimal 5FA-Rapa and PBS.
Conclusions :
Compare with systemic delivery of Rapa, intralacrimal delivery of Rapa may inhibit local inflammation and improve tear production without causing systemic side effects.
This is a 2020 ARVO Annual Meeting abstract.