DOI: 10.25549/usctheses-c40-336082
title: Evaluation of rapamycin for the treatment of autoimmune-mediated dry eye in a mouse model of Sjögren's syndrome

description: Dry eye associated with Sjögren's Syndrome (SS) is a multifaceted disease resulting from inflammation and dysfunction of the ocular surface including the tear-producing lacrimal gland (LG), which plays a very crucial role in maintaining the integrity of the ocular surface. Any damage to the lacrimal gland could lead to decreased secretion of proteins, nutrients, and most importantly, aqueous tear fluid on to the surface of the eye, which in turn leads to dryness. Currently, symptoms associated with dry eye are mostly managed by lubricating the eye using artificial tears or corticosteroids, the long term use of which is associated with severe side effects. Due to recent progress in understanding of the immunological mechanisms in SS, targeted, immune-based therapies are increasingly being tried in an attempt to not only manage the symptoms but also treat this multifaceted disease. However, there’s still a lack of an effective FDA approved anti-inflammatory therapeutic strategy to alleviate specific immunological factors in the pathogenesis of SS. There are two FDA-approved drugs for the treatment of dry eye, Restasis and Xiidra and although the former is commonly used in SS patients, most published clinical studies have been conducted in mixed SS and non-SS dry eye populations, making its actual efficacy in SS patients unclear and a lot of studies indicate that only limited success has been achieved in the treatment of SS-associated dry eye with Restasis. Since Xiidra was only recently approved in 2016, its effectiveness in treatment of SS-mediated dry eye has not been extensively studied. For SS-associated dry eye, treatment still remains symptomatic without pharmaceutical firms trying to target the underlying cause, i.e. ocular surface inflammation. Many targets are available including but not limited to different immune cells, cell-cell interactions, different cytokines and chemokines but the best avenue for research is modulation of the immune system without a specific target and the broad objective of my thesis was to develop toxicity-free and tolerant formulations of a poorly soluble immunosuppressant called Rapamycin and either directly (topical) or indirectly (systemic) test their in vivo efficacy in lowering inflammation both in the lacrimal gland and on the ocular surface and in doing so contribute to increased tear secretion and subsequently treat dry eye. By directly targeting the underlying cause, the goal was to maximize the therapeutic effect and avoid or lessen systemic toxicities associated with its use. Several therapeutic studies have demonstrated that Rapamycin can be developed as an eye drop/systemic formulation for the reduction of inflammation of the tear-secreting lacrimal gland, which could eventually help in reversing reduced tear secretion and subsequent dry eye in SS patients. To the best of my knowledge, this is the first attempt at developing novel formulations of Rapamycin and using them as intravenous injections or eye drops for the treatment of autoimmune dacryoadenitis (LG inflammation) in male non-obese diabetic (NOD) mice, a widely used model of SS. The formulations were well tolerated in these mice and significant changes were observed in pathological causes of autoimmune-mediated dry eye with both a 12-week Rapamycin eye drop treatment and a 1-week IV treatment. For the long-term treatment, the reduction in LG inflammation happened concurrently with increased tear secretion and improved corneal barrier integrity. And when Rapamycin was delivered in a novel nanoparticle-based carrier for IV administration, the toxic side effects of the drug that have limited its treatment potential were reduced. The success of these studies has increased the translational value of this project especially due to their consistent, reproducible, and robust nature and I strongly believe that Rapamycin has the potential to be clinically developed into a promising therapy for SS-associated dry eye.