Clusterin Targeting Epitheliopathy for Dry Eye

PROJECT SUMMARY/ABSTRACT Dry eye is a common affliction with a significant impact on vision and quality of life. The focus in drug development has been to target inflammation, thought to be the core driver of disease. However, the two drugs that dominate the market promote only modest improvements in dry eye symptoms, and are inconsistent in reversing epitheliopathy. Other approaches are clearly warranted and needed. The applicant team has is taking a novel and innovative approach by targeting epitheliopathy using the natural tear protein clusterin (CLU). CLU does not work through a specific receptor or epitope like most other biologics. Instead it binds selectively to the damaged regions of the OcS to seal, solubilizing denatured proteins, inhibiting proteolysis and apoptosis, while also suppressing inflammation and autoimmunity. Simply stated, CLU protects, seals, heals. The team has generated a substantial amount of proof-of concept data on efficacy, mechanism-of- action, tolerability/safety and pharmacokinetics, obtained using two different in vivo dry eye protocols. They have also characterized the biochemical properties of CLU and have developed a manufacturing process for recombinant human CLU. These studies are reported in four perspectives/review articles and twenty-one research papers, all published in respected, peer-reviewed journals. Further, they now present new preliminary data demonstrating that CLU reverses epitheliopathy, reduces inflammation, and restores goblet cell density and corneal nerves in a genetic model of Sjögrens Syndrome. In this Phase I application, the team requests funding to complete early development of CLU. Specific Aims (SAs) will be conducted in company incubator space in Boston. In Aim 1, a non-GMP stability analysis will be conducted on the drug substance and drug product. In Aim 2, non-GLP ocular tolerability screening and pharmacokinetic testing will be performed after topical dosing. In Aim 3, the team will hold a pre-investigational new drug meeting with the FDA. Results of SA1/SA2 studies will enable the team to provide the FDA with quantitative information about shelf-life of their drug substance and drug product, tolerability/safety data in rabbits, and new information on bodily distribution. Milestones to advance to Phase II are: 1) demonstrate that CLU is a viable drug candidate of sufficient stability and 2) demonstrate that the drug product, at the proposed clinical concentration, is non-toxic to eyes in vivo.