Development and Effects of FTY720 Ophthalmic Solution on Corneal Allograft Survival

Abstract

Fingolimod (FTY720), a novel class of sphingosine 1-phosphate receptor modulators, has received special interest among ophthalmologists, particularly given that oral administration of FTY720 has proven to effectively treat corneal graft rejection in animal models. However, no studies have examined the performance of FTY720 as an ophthalmic solution in reducing corneal rejection in high-risk corneal rejection models, and the stability and ocular irritation profile of FTY720 ophthalmic solution are also unknown. Thus, we developed 0.1%, 0.2% and 0.5% FTY720 ophthalmic solutions and evaluated their chemical stabilities under various storage conditions with high- performance liquid chromatography. To investigate the ocular irritancy of the FTY720 ophthalmic solution, New Zealand albino rabbits were subjected to the Draize test. Furthermore, classic, well-established rat allogenic penetrating keratoplasty models were used to investigate the anti-rejection efficacy of the tested FTY720 ophthalmic solutions. We found that the non-irritating 0.5% FTY720 ophthalmic solution could prolong corneal allograft survival in rats with significant efficacy for about one month. Furthermore, no significant concentration changes occurred in any of the types of FTY720 ophthalmic solutions within three months. These results revealed crucial profiles of FTY720 ophthalmic solutions and warrant further investigation and optimization of FTY720 in the anti-rejection therapy after keratoplasty.

Rapamycin Nano-Micelle Ophthalmic Solution Reduces Corneal Allograft Rejection by Potentiating Myeloid-Derived Suppressor Cells' Function

“…Therefore, ani-rejection therapy after keratoplasty is of paramount importance for preserving the vision of patients, especially in high-risk cases. However, due to their low solubility, unfavorable stability, or side effects, traditional immunosuppressants are unsatisfactory for clinical application ( 33 ). Although emerging evidence had demonstrated that RAPA was a novel immunosuppressive agent for prevention of corneal-allograft rejection ( 15 – 19 ), its water insolubility and the existence of a blood/eye barrier has restricted its clinical application.…”

Hemin Promotes Corneal Allograft Survival Through the Suppression of Macrophage Recruitment and Activation

“…36,37 In the rat penetrating keratoplasty model, retaining the interrupted sutures and exposing suture nodes to induce corneal neovascularization may lead to a high probability of graft rejection. [38][39][40][41] Accordingly, this animal model possesses, to some extent, the characteristics of a high-risk transplant. Therefore, the sutures were not removed in some studies; in contrast, graft sutures were removed in other studies to mimic penetrating keratoplasty in patients.…”

Corneal pain and experimental model development

“…a Albino rabbit eye following application of the standardized Draize test, a common toxicity assay using clinical scoring post-topical irritant application to appropriately label chemicals based on their propensity to cause corneal damage (Wilhelmus, 2001). Image reproduced from (Liu et al, 2015) with permission. b Bright field image of an enucleated porcine eye and isolated cornea proper following chemical application.…”