New antibody therapy can reverse diabetic retinopathy and other eye conditions

Insulin-saving insulin, developed at the University of Toronto 100 years ago, was the first biological therapy, a protein to treat disease. A century later, a new biological therapy also developed by U of T researchers has the potential to reverse a common complication of diabetes.

A team led by Stéphane Angers, associate professor and dean of the Leslie Dan School of Pharmacy, and Sachdev Sidhu, professor of molecular genetics at the Donnelly Center for Cellular and Biomolecular Research, have developed a synthetic antibody as a promising treatment for in diabetic retinopathy, which causes blindness and affects about 30 percent of patients with diabetes.

The researchers tested the antibody in both cell cultures and mice, and the newspaper EMBO Molecular Medicine has published the results today.

“This study has shown that these antibodies they are very attractive therapeutics for restoring the blood retina barrier defects, “said Rony Chidiac, a postdoctoral fellow in the Angers laboratory and lead author of the study.” It gives new hope for the treatment of eye diseases such as diabetic retinopathy and macular degeneration. “

Angers and his team are experts in the Wnt cell signaling pathway, which is crucial for the formation and maintenance of the blood-retina barrier, a physiological barrier that prevents molecules from entering the retina.

When there is an interruption in the signaling pathway, which can occur due to genetic mutations in rare eye conditions such as Norrie disease, or when tissue oxygen is low, as in diabetic retinopathy, blood vessels they can leak and cause damage to the eye.

In previous research, Angers had collaborated with Sidhu at the Donnelly Center to develop a catalog of synthetic antibodies that could activate Wnt signaling.

His new publication describes how one of the antibodies, which specifically activated the Frizzled4-LRP5 receptor complex, successfully stimulated Wnt signaling at the blood-retina barrier and effectively restored barrier function.

The antibody binds to two receptors on the surface of key cells (Frizzled4 and LRP5) that bind them together, and this induced proximity activates the Wnt pathway that holds blood vessels.

The team first tested the antibody in cell cultures and found it to be a very accurate way to activate the signaling pathway and restore barrier function. They then tested the antibody on different mouse models in collaboration with Harald Junge at the University of Minnesota and AntlerA Therapeutics, a start-up company founded by Angers and Sidhu. One model represented an eye genetic condition and one represented diabetic retinopathy.

Notably, the antibody restored barrier function and corrected the formation of retinal blood vessels in these mice. In addition, it normalized the pathological formation of nuts blood vessels, one of the consequences of a leaking blood-retina barrier that causes additional eye damage.

With promising preclinical antibody results, AntlerA Therapeutics will now lead commercialization and translation into clinical trials.

Although the results of the current study focus on eye conditions, the similarities between the blood-brain barrier and the blood-brain barrier make their applications much broader than eye conditions.

“Retinal vasculature was the first indication and we have new funds to explore the role of this pathway in other contexts,” Angers said. “For example, we are testing whether this antibody could have implications for the blood-brain barrier and whether it could repair the barrier in the context of a stroke.”

“We have found a way to activate Wnt signaling very accurately to have a viable therapeutic opportunity and treat these diseases,” Chidiac added. “We anticipate that this could have a huge impact on several applications in regenerative medicine.”