Although most of the focus of diabetic eye disease is on the retina, up to 70 percent of diabetics suffer from problems with the cornea, the transparent, protective outer surface of the eye.
In advanced diabetes, corneal stem cells become inactive, and the cornea heals more slowly and less completely after an injury or after procedures such as cataract surgery and laser treatment for diabetic retinopathy.
The study, published in the peer-reviewed journal Diabetologia, also identified for the first time two related pathological changes in the cornea, three therapeutic pathways that reverse these changes and partially restore wound-healing function in the cornea. A discovery that could eventually inform new treatments for diabetes.
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“Current treatments only address symptoms, so there is an urgent need to understand the molecular mechanisms underlying diabetes-related wound healing problems,” said first author Ruchi Shah, a scientist at Cedars-Sinai Medical Center in Los Angeles, USA.
“An understanding of this novel epigenetically regulated wound-healing mechanism may lead to therapeutic treatments that may help patients avoid long-term ocular health problems,” he added.
The new research also identifies for the first time an important role of Wnt-5a, a secreted signaling protein the investigators found responsible for corneal wound healing and the function of stem cells — cells capable of differentiating into many cell types.
“We have found that diabetes induces more cellular changes than we previously knew,” said Alexander Ljubimov, director of the eye program at Cedars.
“This finding does not affect gene sequence, but rather involves specific DNA modifications that alter gene expression, known as epigenetic changes,” he added. Epigenetic changes are not firmly embedded in the genome from birth, but are introduced later
For the study, the team compared cells from corneas from six diabetic patients with corneas from five healthy donors.
They found that in the diabetic cornea, the protein product of the WNT5A gene was suppressed. Additionally, in diabetic samples, they found an increase in a microRNA that inhibits WNT5A.
The team of scientists then induced lesions on corneal cells in culture and corneal organ culture, and tested three interventions designed to normalize Wnt-5a protein expression. They added the Wnt-5a protein directly; They introduced a DNA methylation inhibitor, which was originally approved for cancer treatment; And they targeted microRNA levels with an innovative gene therapy approach using a nanoscale compound.
In diabetic samples all three therapeutic approaches stimulated stem cell marker production and improved tissue regeneration, which accelerated wound healing.
“Our goal is to develop topical, sustained-release drugs for corneal wound healing,” Ljubimov said. “Drugs that are FDA (Food and Drug Administration) approved and that can be easily implemented may be one of the most promising approaches to effective future therapies.”