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Researchers Find Experimental Drug Inhibits or Prevents Diabetic Eye Disease
Scientists at the Wilmer Eye Institute, Johns Hopkins Medicine, have made a significant breakthrough in the fight against vision loss caused by diabetes. Their research indicates that an experimental drug has the potential to slow down or even prevent vision deterioration in individuals with diabetes. The study, which utilized mouse models, human retinal organoids, and eye cell lines, offers promising insights into combating common eye complications associated with diabetes.
According to the National Institutes of Health, nearly 8 million Americans suffer from eye conditions that lead to vision loss as a result of diabetes. Shockingly, this number is projected to nearly double by 2040. To address this growing concern, the research team focused on two prevalent diabetic eye conditions: proliferative diabetic retinopathy and diabetic macular edema, both of which impact the retina—the light-sensitive tissue at the back of the eye responsible for transmitting visual signals to the brain.
Proliferative diabetic retinopathy involves the excessive growth of new blood vessels on the surface of the retina. This abnormal growth can lead to bleeding, retinal detachments, and severe vision impairment. On the other hand, diabetic macular edema is characterized by fluid leakage from blood vessels in the eye, resulting in swelling of the central retina and damage to the cells responsible for central vision.
The study, recently published in the Journal of Clinical Investigation on May 25, unveils compelling findings regarding a compound known as 32-134D. Previously recognized for its ability to impede liver tumor growth in mice, this compound demonstrated its potential to prevent diabetic retinal vascular disease by reducing the levels of a protein called hypoxia-inducible factor (HIF). Moreover, the doses of 32-134D administered in the study appeared to be safer than an alternative treatment currently being investigated for diabetic eye disease, which also targets HIF.
Currently, the standard treatment for proliferative diabetic retinopathy and diabetic macular edema involves eye injections of anti-vascular endothelial growth factor (anti-VEGF) therapies. While these therapies can effectively halt the growth and leakage of blood vessels in the retina for some diabetic patients, they are not universally successful and may lead to side effects with prolonged usage, such as increased internal eye pressure or damage to eye tissues.
The findings from this groundbreaking study offer hope for diabetic patients at risk of vision loss. Further research and clinical trials will be necessary to validate the efficacy and safety of the experimental drug in humans. Nonetheless, these findings mark a significant milestone in the quest to combat diabetic eye conditions and preserve the vision of millions of individuals affected by diabetes.
Akrit Sodhi, M.D., Ph.D., an author of the new study, says that in general, the idea of inhibiting HIF, a fundamental protein in the body, has raised concerns about toxicity to many tissues and organs. But when his team screened a library of HIF inhibitor drugs and conducted extensive testing, “We came to find that the drug examined in this study, 32-134D, was remarkably well tolerated in the eyes and effectively reduced HIF levels in diseased eyes,” says Sodhi, 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.
HIF, a type of protein known as a transcription factor, has the ability to switch certain genes, including vascular endothelial growth factor (VEGF), on or off throughout the body. In the eye, elevated levels of HIF cause genes like VEGF to increase blood vessel production and leakiness in the retina, contributing to vision loss.
To test 32-134D, researchers dosed multiple types of human retinal cell lines associated with the expression of proteins that promote blood vessel production and leakiness. When they measured genes regulated by HIF in cells treated with 32-134D, they found that their expression had returned to near-normal levels, which is enough to halt new blood vessel creation and maintain blood vessels’ structural integrity.
Researchers also tested 32-134D in two different adult mouse models of diabetic eye disease. In both models, injections were administered into the eye. Five days post-injection, the researchers observed diminished levels of HIF, and also saw that the drug effectively inhibited the creation of new blood vessels or blocked vessel leakage, therefore slowing progression of the animals’ eye disease. Sodhi and his team said they also were surprised to find that 32-134D lasted in the retina at active levels for about 12 days following a single injection without causing retinal cell death or tissue wasting.
“This paper highlights how inhibiting HIF with 32-134D is not just a potentially effective therapeutic approach, but a safe one, too,” says Sodhi. “People facing diabetic eye disease and vision loss include our family members, friends, co-workers — this is a disease that impacts a large group of people. Having safer therapies is critical for this growing population of patients”. Sodhi says that further studies in animal models are needed before moving to clinical trials.
