Prevention of corneal graft rejection by eye drop instillation of UNIL088, a hydrosoluble prodrug of cyclosporin A

Abstract

Abstract: : Purpose:To evaluate the efficacy of topically applied UNIL–088, a hydrosoluble prodrug enzymatically converted into cyclosporin A (CsA) within minutes after contact with tears, on a rat model of corneal graft rejection, and to compare its effect to systemic administration of CsA. Materials and methods:UNIL–088 (Debiopharm, Switzerland) was dissolved at 0.2% in phosphate buffer pH7. Fifty–two Lewis rats received technically successful corneal allografts from Brown Norway donors. Five instillations per day were administered to Group I (PBS alone, controls, n=18) and Group II (UNIL–088 0.2% drops in PBS, n=18). Group III (systemic CsA, n=16) received 10mg/Kg/day IM of commercial CsA. Treatments were for 2 weeks. A rejection evaluation was based on graft opacity, edema and neovascularization. Blood levels of CsA were measured 2 and 13 days after surgery. Results: On day 13, systemic CsA and UNIL088 instillations were equally active to prevent graft rejection (graft rejection: 88% for group I, 56% and 50% for group II and III resp., p= 0.026 group I vs. II, p= 0.013 group I vs. III, Χ² test). These differences were detected in all parameters tested. On day 13, CsA blood levels were above 1,000 ng/ml in group III, but below 40 ng/ml in group II . Conclusions: Local administration of 0.2% UNIL–088 inhibited corneal graft rejection as efficiently as systemic CsA. This inhibition is carried out after conversion of the prodrug to active CsA and its local release. Blood CsA levels after UNIL–088 administration were below the detection limits. UNIL088 reproduces the local efficacy of systemic CsA, while preventing its systemic adverse effects.

Keywords: cyclosporine • immunomodulation/immunoregulation • cornea: clinical science