New Approaches for Diabetic Keratopathy in the Eye?

A new discovery of differences between the eyes of people with and without diabetes could point to new approaches for treating diabetic keratopathy, as well as other diabetes-related wound healing problems.

Vision loss due to diabetes arises primarily from retinopathy, but up to 70% of people with diabetes also experience corneal problems, including keratopathy and neuropathy. Diabetic keratopathy involves impairments in epithelial wound healing, barrier function, and tear production, along with epithelial erosions and keratitis. As a result, the cornea may heal more slowly and less completely following an injury or procedures such as cataract surgery or laser therapy for diabetic retinopathy.

The abnormal wound healing is due to impaired limbal epithelial stem cells, and the new research, published online July 18 in Diabetologia, involved isolation of those cells from 30 donor eyes of humans with and 23 without diabetes. Significant differences were found in DNA methylation between the cells of those two groups. Specifically, the WNT5A gene was hypermethylated at the promotor region in the diabetic cells and its protein markedly repressed.

However, treatment with various approaches, including exogenous WNT5A methylation inhibitors and a nanoconjugate that inhibits WNT5A suppression, improved corneal epithelial wound healing as well as expression of the limbic epithelial stem cells.

“Overall, Wnt-5a is a new corneal epithelial wound healing stimulator that can be targeted to improve wound healing and stem cells in the diabetic cornea,” write Ruchi Shah, PhD, of the Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, and colleagues.

The finding represents more cellular changes than researchers had previously been aware of, said study senior author Alexander Ljubimov, PhD, DSc, director of the Eye Program at the Institute, in a statement.

“The discovery does not affect gene sequence but entails specific DNA modifications altering gene expression — what are known as epigenetic alterations,” he said.

In the experiments, treatment of the impaired diabetic limbal epithelial cells with the exogenous Wnt-5a accelerated wound healing by 1.4 fold (P < .05) compared with untreated cells and reduced healing time in diabetic organ-cultured corneas by 37% (P < .05).

Treatment with the DNA methylation inhibitor zebularine also increased levels of Wnt-5a in the diabetic limbic epithelial cells by 37% (P < .01), dose-dependently stimulated wound healing by 60% at 24 hours (P < .01), and improved wound healing by 30% in diabetic organ-cultured corneas.

The finding of Wnt-5a as a new diabetic corneal marker regulating wound healing and stem cell function may have implications for other diabetes complications involving impaired wound healing, including diabetic foot ulcers, as they share similar neurovascular, sensory, and immunological compromise with diabetic eye disease, Shah and colleagues say.

“Novel therapies to reverse both types of epigenetic silencing could benefit corneal function and may also prove to be beneficial in other wound healing-related diabetic complications,” they write.

The investigators are now working on combination therapies that target both mRNA and DNA methylation in hopes of obtaining even better wound healing.

“Our goal is to develop topical, sustained-release drugs for corneal wound healing,” said Ljubimov. “Drugs that are [Food and Drug Administration] approved and could be easily applied may be one of the most promising approaches for effective future therapies.”

This work was funded by the US National Institutes of Health and the Cedars-Sinai Board of Governors Regenerative Medicine Institute. The authors have reported no further disclosures.

Diabetologia. Published online July 18, 2023. Full text

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR’s Shots blog, and Diabetes Forecast magazine. She is on Twitter: @MiriamETucker.

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