Future File is a Retinal Physician feature designed to highlight new and innovative early-stage and preclinical concepts that could one day help to advance the everyday practice of retina specialists.
Potential therapy for bacterial endophthalmitis
■ Wayne State University researchers recently received a $1.9 million grant from the National Eye Institute of the National Institutes of Health to study a novel, potentially dual-action therapeutic for bacterial endophthalmitis.
The study, led by Ashok Kumar, PhD, of the Kresge Eye Institute at Wayne State in Detroit, Michigan, will investigate the mechanism to harness the therapeutic value of a lipid mediator, Resolvin D1 (RvD1), to potentially prevent and treat endophthalmitis.
“Although the ideal treatment for bacterial endophthalmitis should aim for both bacterial eradication and inflammation resolution, monotherapy with intravitreal antibiotic injections remains the current standard of treatment,” said Dr. Kumar. “The antibiotics, while destroying the bacteria, may release various bacterial cell wall components, which can enhance inflammatory responses. Hence, the identification of novel targets for the development of new anti-inflammatory therapeutics are urgently needed; agents which may be used to treat endophthalmitis alone or in combination with antibiotics and are nonimmunosuppressive.
“While addressing this clinical problem, we discovered that administration of RvD1 — a type of specialized proresolving mediator — in a mouse model of bacterial endophthalmitis drastically reduced inflammation, prevented tissue damage and maintained retinal function in otherwise blinded mice. In this study, we are investigating the protective mechanisms of RvD1 treatment.”
Blocking an adenosine receptor combats DR
■ Scientists have identified a new target for reducing dysfunctional blood vessel development in the eye in DR.
“If we block the adenosine receptor A2a, the blood vessels will not leak and not as many new blood vessels will grow,” says Yuqing Huo, MD, PhD, chief of the vascular inflammation program at the Vascular Biology Center at the Medical College of Georgia at Augusta University.
An inhibitor of adenosine receptor A2a already is in clinical trials for Parkinson disease. Adenosine is a natural structural component of basic body essentials like DNA and RNA as well as the ubiquitous cell fuel ATP. It can help blood vessels expand, battle bad heart rhythms, and even provide pain relief. Its family of receptors includes adenosine receptor A2a, which is important for the retina and found on the endothelial cells that line blood vessels, says Dr. Huo, co-corresponding author of the study in the journal Nature Communications.
In diabetes, endothelial cells that line the blood vessels of the retina begin to shrink or even disappear. Expression of adenosine receptor A2a increases, apparently to enable endothelial cells to take up more glucose that can be converted to energy to help restore good oxygen and blood flow. In this case, that means repairing existing blood vessels and growing new ones in angiogenesis. But in a scenario where the cells don’t use energy efficiently or build blood vessels well, it’s called “pathological angiogenesis.” Old and new blood vessels alike readily bleed or contract, leading to hemorrhage and/or retinal detachment and blindness, the scientists write.
“They grow too much, too fast,” Huo says. It’s not yet clear whether it’s the high glucose levels of diabetes and/or the resulting inflammation or other factors that increase expression of adenosine receptor A2a.
Protein that leads to DR identified
■ Researchers at University of Utah Health in Salt Lake City have identified a protein called ARF6 that, when inhibited, reduces DR. Findings reported in a recent issue of The Journal of Clinical Investigation offer a pathway to develop new treatments for this eye disorder.
“What is exciting about this study is that we and our collaborators identified a compound called NAV-2729 that inhibits ARF6, which is crucial for the development of DR,” explained co-first author Wendy Zhu, PhD, research assistant professor in internal medicine at University of Utah Health. NAV-2729 was discovered by researchers at a company called A6, a subsidiary of Navigen, Inc., a drug discovery and development company.
Studies were conducted in rodents treated to simulate DR. By injecting NAV-2729 into the eyes of these animals, vessel leakage, as well as the overgrowth of blood vessels, were significantly reduced. The long-term efficacy of treatment remains unknown.
“ARF6 acts like a traffic cop at a busy intersection within a cell,” explained Dean Li, PhD, vice president and head of translational medicine at Merck & Co. and senior author on the paper. “ARF6 orchestrates multiple inflammatory signals that contribute to inflammation common in many diseases, including diabetic eye disease.”
ARF6 amplifies and maintains the signal protein VEGF receptor, which stimulates a series of cascading responses, leading to a diseased state in the eye. In the study, injections of NAV-2729 into the eyes of diabetic mice were more effective in reducing blood vessel leakage than the anti-VEGF injections. RP