Controlled release of an HDAC inhibitor for reduction of inflammation in dry eye disease

Abstract

Dry eye disease (DED), also known as keratoconjunctivitis sicca, is an ocular surface disease characterized by T-cell-mediated inflammation. Current therapeutics, such as immunosuppressive agents, act to suppress the clinical signs and inflammation. However, long-term usage of these treatments can cause severe side effects. In this study, we present an alternative therapeutic approach that utilizes a histone deacetylase inhibitor (HDACi) to regulate transcription of a variety of immunomodulatory genes. Specifically, HDACi have emerged as a potential anti-inflammatory agent, which can modulate the functions of a subset of suppressive T lymphocytes known as regulatory T cells (Tregs), enhancing FoxP3 acetylation and subsequently guarding the transcription factor from proteasomal degradation. Here, a specific HDACi known as SAHA (suberoylanilide hydroxamic acid) was formulated to controllably release in the lacrimal gland. Intralacrimal gland injection of PLGA-based SAHA microspheres prevented clinical signs of DED in mice with Concanavalin A-induced DED, reduced expression of pro-inflammatory cytokines, and increased expression of FoxP3 in the lacrimal glands. Murine T cell culture experiments also revealed that SAHA decreased effector T cell proliferation and enhanced suppressive function of Tregs in co-cultures of Tregs and effector T cells.

Statement of significance: In this study, we demonstrate a therapeutic approach that utilizes a histone deactylase inhibitor (HDACi) to regulate transcription of a variety of immunomodulatory genes. HDACi have emerged as a potential anti-inflammatory agent, which can modulate the functions of a subset of suppressive T lymphocytes known as regulatory T cells (Tregs). Here, HDACi microspheres composed of a biocompatible and biodegradable polymer (poly(lactic-co-glycolic acid) (PLGA)), were able to locally release the HDACi and prevent clinical signs of DED. This work is timely given the recent shift in treatments of DED towards immunological based therapies to reduce ocular inflammation. However, notably, many of these treatments require large amounts of drug, and non-specifically suppress the immune system, leading to several systemic side effects. Instead of merely suppressing or blocking inflammation, the formulation described herein intends to balance the microenvironment promoting immunological homeostasis. This particular drug delivery system may also have broad implications in the field of inflammatory mediated ocular disorders such as uveitis, Sjögren's syndrome, allergic conjunctivitis.

Keywords: Dry eye disease; HDACi; Microspheres; PLGA; SAHA.