A Novel Topical Formulation of FTY720 Protects Photoreceptors in Animal Model of Light Induced Retinal Degeneration

Abstract

Purpose : FTY720 (Fingolimod) is an FDA approved drug for Multiple Sclerosis. It is a structural analog of the bioactive sphingolipid sphingosine, but also inhibit the enzyme Ceramide Synthase (CS) thereby inhibiting ceramide biosynthesis. Increase in ceramide levels had been associated with photoreceptor apoptosis and reducing ceramide levels by FTY720 have been shown to prevent their degeneration in multiple animal models. This study was aimed to develop a novel topical formulation of FTY720 and test its efficacy in preventing photoreceptor degeneration in animal models.

Methods : Sprague-Dawley rats (8-10 weeks) raised in dim (~50 lux) cyclic light (12 hours ON/OFF) from birth receive eye drops of a novel nano-particle based formulation with or without 0.3% FTY720 (w/w) twice a day. After three days, they were subjected to light induced retinal degeneration (LIRD) by exposure to white fluorescent light (~3000 lux) for 12 hours, and the treatment were continued for another seven days. Same age littermates either treated with placebo formulation or without LIRD served as control. At the conclusion of the treatment, retinal functions were measured by Electroretinography (ERG) and the retinas were used for histochemical and lipidomic analysis.

Results : We were able to identify formulation #1003-92, as a stable proprietary formulation that does not cause any ocular inflammation, irritation to the eye or visible distress, in the treated animals. FTY720 can be detected in picomole levels in the retina of the treated animals after ten days of treatment. Histochemical analysis showed preservation of photoreceptors in FTY720 treated animals compared to the placebo treated animals after LIRD. Eye drops with FTY720 protects the retinal functions after LIRD as observed by scotopic and photopic ERG.

Conclusions : Our study identified a novel proprietary ocular eye-drop formulation that can deliver the drug of interest to the retina without causing any distress to the eye. Our results also confirmed that reducing ceramide level by FTY720 prevents photoreceptor apoptosis and preserve retinal function. Our data established FTY720 as a potentially promising drug candidate for ocular diseases that causes photoreceptor apoptosis. It also emphasizes the fact that reducing ceramide levels could be a potential therapeutic approach for preventing photoreceptor degeneration in multiple human retinal diseases.

This is a 2021 ARVO Annual Meeting abstract.