Clusterin reverses epitheliopathy, reduces inflammation, and restores goblet cells and corneal nerves in a mouse model of autoimmune dry eye

Abstract Chronic ocular surface disease (OSD) is characterized by corneal epitheliopathy, reduced barrier function and loss of nerves, accompanied by persistent inflammation. Current treatments offer limited relief and there is no approved therapy that promotes neurosensory regeneration in OSD. Here, we tested the therapeutic efficacy of clusterin (CLU), a molecular chaperone and MMP9 inhibitor found in tears, in Thbs1-deficient mice, a preclinical model of autoimmune dry eye associated with Sjögren’s disease (SjD). These mice were treated topically at the ocular surface, bilaterally, for 3 weeks with recombinant human CLU (rhCLU) or human plasma-derived CLU (pCLU) eyedrops and compared to standard-of-care 0.1% dexamethasone eyedrops. Treatment with CLU significantly improved corneal barrier integrity, increased corneal nerve density, enhanced the proportion of corneal nerves with immunoreactivity for CGRP and promoted conjunctival goblet cell regeneration. Furthermore, CLU reduced immunoreactivity for ADAM17 in the corneal epithelium and reduced Tnfa expression in the conjunctiva, supporting its anti-inflammatory effect. Notably, all these effects were comparable to, or even exceeded, those resulting from treatment with dexamethasone. Based on its efficacy, we introduce CLU as a multifunctional and promising biotherapeutic for a widespread range of ocular inflammatory conditions involving corneal epitheliopathy and nerve loss, including dry eye associated with SjD. Competing Interest Statement M.E.F. is a co-founder of Proteris Biotech and an employee of the company, serving as Chief Scientific Officer. S.M. and M.R.W. hold equity in Proteris Biotech and serve on the Medical and Scientific Advisory Board. M.E.F. is named as a co-inventor on U.S. patent number 9241974 entitled "Clusterin Pharmaceuticals and Treatment Methods Using the Same" granted to the University of Southern California and optioned for exclusive license to Proteris Biotech. S.M. and M.E.F. are named as co-inventors on a preliminary U.S. patent application co- submitted by Boston University and Proteris Biotech, claiming some of the new findings of this study (63/734,859). All other authors declare that they do not have any competing interest.