Fenofibrate microemulsion for treating nitrogen mustard induced corneal injury

PROJECT SUMMARY We aim to develop a novel fenofibrate-loaded microemulsion (Feno-ME) eyedrop as a new, non-steroid treatment for nitrogen mustard (NM)-induced corneal injury. NM is in the list of the Chemicals of Concern (CoC) in NIH CounterACT. Ocular exposure to NM causes a range of complications including corneal ulceration, corneal neovascularization (NV), corneal opacity, chronic inflammation, and eventually blindness. Effective interventions to treat vesicants-induced ocular injury have not been developed yet, which highlights the need to establish effective treatment options. Our previous studies reported that PPARα agonist fenofibrate confers anti- inflammatory, anti-angiogenic effects and promotes corneal wound healing. We demonstrate that PPARα levels are decreased in the cornea with NM-induced wound and fenofibrate alleviates corneal neovascularization and opacity in rats with NM-induced corneal injury. These observations suggest that PPARα has an important therapeutic function in the cornea and is a promising drug target for NM-induced corneal injury. Here we have developed a novel fenofibrate microemulsion (Feno-ME) with high drug loading and excellent stability. We hypothesize that Feno-ME eyedrops are effective on corneal ulceration, corneal NV, corneal opacity, and suppressing inflammatory and angiogenic biomarkers in the cornea exposed to NM. In Aim 1 (UG3), we plan to validate PPARα signaling as a drug target for NM-induced corneal injury and optimize the Feno-ME eyedrop formulations. In Aim 2 (UG3), we will investigate Feno-ME eyedrops for the treatment of NM-induced corneal injury in rabbit model and identify a lead Feno-ME and optimize the regimen of administration. To facilitate the translation to human use, Aim 3 (UH3) targets the development and characterization of an NM-induced corneal wound model in minipigs, and verify the efficacy the lead Feno-ME identified in UG3 in a minipig model. Lastly, in Aim 4 (UH3), we intend to determine the pharmacokinetic profile and toxicity of the lead Feno-ME eye drop in minipigs. These studies will identify a new drug target for the treatment of NM-induced corneal injury and promote repurposing fenofibrate for the treatment of mustard-induced corneal injury.