Diabetic retinopathy, is a complication of both type 1 and type 2 diabetes. It can lead to permanent vision damage, if not treated. Two research projects seek to learn more about diabetic retinopathy. One project at the Medical College of Georgia at Augusta University is looking into a possible treatment pathway. Another project, at Johns Hopkins Wilmer Eye Institute is studying how an experimental drug can treat diabetic retinopathy.
Protein as a Treatment Target
Researchers in the lab of vascular and endothelial biologist Shruti Sharma, PhD at the Medical College of Georgia Center for Biotechnology and Genomic Medicine, are studying a how a protein known as Interleukin-6 (IL-6), might be use as a treatment pathway for diabetic retinopathy. This protein is involved in both immunity and inflammation. There have been other therapies that targeted IL-6, but whenever researchers tried to block it, it didn’t work.
Sharma and her team feel that the reason blocking IL-6 doesn’t work has to do with how it initiates physiological changes in the body. One mechanism involves IL-6 interacting with its receptor on the cell surface, known as cis-signaling. Another mechanism uses a soluble form of the IL-6 receptor, known as trans-signaling. The harmful inflammatory effects of IL-6 take place via trans-signaling, while the helpful beneficial effects are made possible through cis-signaling.
That meant blocking all IL-6 was removing both good and bad. So, there had to be something else that could be done. Researchers found that that blocking the pro-inflammatory IL-6 trans-signaling with a drug called sgp130Fc, helped balance levels of two proteins in the retina, the VEGFA, which damages the blood-retina barrier and increases oxidative stress, and VEGFB, which is protective. They feel that when these proteins aren’t in balance is what leads to diabetic retinopathy.
Researchers want to find a way to restore the balance between the VEGFA and VEGFB proteins and they think it could come from Müller glial cells. These cells play an important role in maintaining homeostasis and the exchange of nutrients in the retina. In order to do this, they will study different animal models and they are:
One that uses trans-signaling
One that uses cis-signaling
One that uses both
From these models, researchers will gather baseline measurements of the photoreceptor response. These measurements will tell them how well the eye detects light, which is a sign of retinal health.
“We believe that when we selectively inhibit trans-signaling using this drug, while allowing cis-signaling to continue, we will be able to stop the damage,” Sharma said.
An Experimental Drug
Work done in the lab of Akrit Sodhi, MD, PhD, associate professor of ophthalmology and the Branna and Irving Sisenwein Professor of Ophthalmology at the Johns Hopkins University School of Medicine and the Wilmer Eye Institute found that hypoglycemia or low blood sugar may lead to the breakdown of the blood-retinal barrier and subsequently diabetic retinopathy.
Scientists studied diabetic mice to learn the origins of this disease, specifically in persons with episodes of hypoglycemia. This study demonstrates how a specific protein known as hypoxia-inducible factor (HIF) collects in certain cells in the retina during times of low blood sugar. This protein can lead to a chain reaction of overproduction of other proteins that lead to the overgrowth and leakage of blood vessels in the retina. What scientists in this study found is that HIF plays a role in how the blood-retinal barrier breaks down during hypoglycemia.
To test this, researchers induced periods of low blood sugar in mice with and without diabetes. The experiments demonstrated that mice with diabetes had higher levels of HIF during hypoglycemia. This lead to the breakdown of the blood-retinal barrier and caused leakage in the retinal blood vessels, which contributes to damage to the retina and vision loss. Whereas mice without diabetes didn’t experience higher levels of HIF.
The scientists went further in their work by testing an experimental drug 32-134D, which inhibits the HIF protein. Some diabetic mice received an injection of this drug before an induced episode of low blood sugar and these mice had lower HIF levels. This prevented the expression of proteins that lead to the breakdown of the blood-retinal barrier and blood vessel leakage.
“These studies help explain why patients with diabetes who are initially started on tight glucose control, the cornerstone of diabetic management, or those who have high glycemic variability (transient episodes of very low—followed by very high—serum glucose levels), experience worsening of their diabetic eye disease,” said Sodhi. “Our findings underscore why therapies targeting HIF will be an effective approach to prevent or treat diabetic retinopathy.”
Whether it is targeting a protein or using an experimental drug, the work of researchers at the Medical College of Georgia and Johns Hopkins show how the treatment of diabetic retinopathy is evolving from just preserving vision to treating the underlying condition. Thanks to the work of these and other researchers, persons with diabetic retinopathy won’t have to worry when vision damage will occur, since there will be treatments that improve outcomes for this disease.
Sources:
https://jagwire.augusta.edu/mcg-scientists-secure-1-5-million-grant-to-treat-diabetic-retinopathy/