New eye drop formulation shows promise for dry eye disease

Researchers at Baylor College of Medicine and Okayama University in Japan have developed and tested in mice a promising new eye drop formulation for treating dry eye disease. The team reports in Investigative Ophthalmology & Visual Science that the treatment significantly reduced typical dry eye characteristics, such as inflammation, damage to the eye surface and loss of goblet cells, which produce factors that help stabilize tears and lubricate the eye. The findings support conducting human studies to assess the safety and efficacy of this treatment that could potentially benefit millions of people with dry eye disease.

Dry eye disease is a common condition that causes irritation, redness and blurred vision,. Dry eye disease occurs more commonly as we age and in women. It develops when the eyes do not produce enough tears or when tears evaporate too quickly, often due to environmental conditions like dryness or wind. In more severe cases, dry eye can damage the surface of the eye, the cornea, and affect daily activities such as reading or driving. People with the condition tend to have it for the rest of their lives."

Dr. Stephen C. Pflugfelder, corresponding author, professor and James and Margaret Elkins Chair in Ophthalmology at Baylor

Current therapies include steroid medications that suppress the immune response that leads to inflammation in the eyes. "Unfortunately, long-term use of steroids is not recommended because it can lead to glaucoma – damage to the optic nerve that can result in blindness – or cataracts," Pflugfelder said. "There is a need for improved treatments."

Previous studies had shown that the immune system plays an important role in the health of the eye. Among immune cells, resident macrophages act as protectors. These cells live in tissues long-term and help maintain normal function by clearing debris, reducing inflammation and supporting tissue repair.

This balance is disrupted in dry eye disease. Stress leads to the recruitment of other immune cells from the blood, circulating monocytes, that promote inflammation. At the same time, the helpful resident macrophages become less effective, making less of the protective molecules they normally produce. Altogether, these changes contribute to damage to the cornea and loss of specialized goblet cells.

"We hypothesized that boosting the function of the protective macrophages could reduce inflammation and improve eye health," Pflugfelder said. "We began a collaboration with Dr. Hiroki Kakuta, research professor at Okayama University, who is an expert in generating alternatives to steroids for the treatment of immune-mediated diseases. We were interested in testing his compounds called rexinoids in our mouse model of human dry eye."

The Kakuta lab had developed a rexinoid called NEt-3IB, that enhances the protective role of resident macrophages. However, NEt-3IB in its original form does not mix well in water, a requirement for eye drops. The Kakuta team modified the compound so it would dissolve well in water while maintaining its ability to stimulate the macrophage's protective role.

"In the current study, we were excited to find that applying NEt-3IB eye drops shifted the resident macrophages toward a protective role by suppressing their production of inflammatory compounds and stimulating their production of healing compounds that promote debris-clearing and immune balance," Pflugfelder said. "The treatment also maintained the integrity of the corneal barrier and the number and size of goblet cells during exposure to desiccating stress."

Importantly, while steroid eye treatments can raise pressure inside the eye, which can lead to glaucoma with extended use, in this study, NEt-3IB caused much smaller increases in eye pressure than the steroid dexamethasone, suggesting it could be safer for long-term use. More research is needed to assess the consequences of prolonged use of NEt-3IB.

Current treatments for dry eye often focus on reducing inflammation, but they don't necessarily restore the eye's natural protective mechanisms. This study suggests that redirecting immune cells to both reduce inflammation and enhance protective functions could offer an improved treatment option for dry eye disease.

First author Jehan Alam, Yangluowa Qu, Jianming Shao, Ebru Yaman and Karen Zheng, all at Baylor College of Medicine, also contributed to this work.

This study was supported by Lions Foundation for Sight, National Institutes of Health (NIH) (grants EY11915, U01 EY034692, CA125123, S10OD018033, S10OD023469, 1S10OD02346901, 2P30ES030285), NIH Core Grant (EY002520), CPRIT Core Facility Support Award (CPRIT-RP180672), P30 Digestive Disease Center support grant (NIDDK-DK56338), P30 Cancer Center support grant (NCI-CA125123), an unrestricted grant from Research to Prevent Blindness, the Hamill Foundation and the Sid W. Richardson Foundation.