Protein seen in dry eye disease injuries could have therapeutic potential

Even in those moments where there isn’t a dry eye in the room, chances are someone’s having trouble making tears. Roughly 15 million people in the United States alone have dry eye disease, a condition where the eyes don’t produce enough tears or the tears they do make evaporate too quickly.

Dry eye disease isn’t just uncomfortable—it also puts patients at greater risk of corneal injury. Now, scientists may have identified a new approach to protecting them. In a study published Jan. 2 in PNAS, researchers from Washington University School of Medicine in St. Louis described how they discovered that the protein encoded by a gene called SPARC is involved in healing the eyes of mice with dry eye disease and other types of corneal injury. Increasing levels of the protein accelerated wound healing.

“There’s a huge knowledge gap in terms of understanding [dry eye disease], and also a huge unmet need in terms of therapy for this condition,” Rajendra Apte, M.D., Ph.D, senior author of the study, told Fierce Biotech Research.

Dry eye disease causes the patient’s cornea to dry out from lack of a tear film, leading to a burning, gritty sensation and blurry vision. It’s associated with normal aging as well as autoimmune conditions like Sjögren's syndrome. There are five FDA-approved prescription drugs for the disease, all of which either combat inflammation or increase tear production. Lubricating over-the-counter eye drops may be used too.  

These therapies work well for only a minority of patients, Apte said, likely because the causes of dry eye are so diverse.

“Depending on what’s causing the majority of the deficit in the tear film, you can imagine that your therapies may help with just one part of it,” he explained. Targeting a common pathway could help move toward treatments with broader applicability, he added.

The researchers’ findings came about by studying the gene expression patterns behind the differentiation of limbal stem cells, a type of stem cell that replenishes and maintains the cornea’s epithelium. They also wanted to understand how aging, diabetes, injury and dry eye disease changed gene expression.

“Because these stem cells are critically important in repopulating the epithelium, we wanted to see what characteristics we could find in terms of the gene expression signatures that could educate us about what happens in dry eye disease,” Apte said.

To do that, the scientists first used single-cell RNA sequencing to map gene expression in cell populations from mice as they evolved from stem cells to mature epithelial cells, comparing the expression patterns between homeostasis and aging, diabetes and corneal injury in dry eye disease.

While neither diabetes nor aging seemed to change the cells’ gene expression profiles, the scientists found many different genes that were unique to injuries in mice with dry eye disease. One of them was SPARC, which upregulated expression of the SPARC protein.

Wondering what role SPARC was playing, the researchers studied human corneal cells. Examining injured cells more closely showed that gaps in the epithelium were closed more quickly when SPARC was stimulated.

It isn’t clear if SPARC’s activity is unique to dry eye disease or if it might be upregulated in all forms of corneal injury—that’s a direction for future research.

“It’s very possible that this gene and this protein may be playing a broader role in injury healing in general,” Apte said. “We just don’t know yet.”

Apte’s lab also found several other genes that were upregulated in corneal injuries in dry eye disease. They plan to explore the function of these genes to see if they too have therapeutic effects. 

“This is towards getting answers about which are the best genes or proteins that are involved in the therapeutic response,” he said. The lab plans to look at them both in isolation as well as in combination with SPARC.

Editor's Note: This article has been updated to clarify the researchers' methods and change the name of the protein from "SPARC 1" to "SPARC".