Experimental Drug Found Effective in Preventing Diabetic Eye Disease
Researchers at the Wilmer Eye Institute, Johns Hopkins Medicine, have recently unveiled compelling evidence suggesting that an experimental drug shows promise in preventing or slowing down vision loss among individuals with diabetes. The groundbreaking results emanate from a comprehensive study that utilized both mouse models and advanced human retinal organoids and eye cell lines.
The prevalence of eye conditions leading to vision loss is a common complication observed in people with diabetes. Currently, it affects an estimated 8 million Americans, with projections indicating a staggering increase of nearly double this number by the year 2040, as reported by the National Institutes of Health. These concerning statistics underscore the urgency for effective preventive interventions.
In their research, the team directed their attention to two prevalent diabetic eye conditions: proliferative diabetic retinopathy and diabetic macular edema. These conditions primarily impact the retina, which serves as the light-sensing tissue located at the posterior of the eye, responsible for transmitting visual signals to the brain.
Proliferative diabetic retinopathy manifests as an excessive growth of new blood vessels on the surface of the retina. This abnormal growth can result in bleeding, retinal detachments, and significant vision impairment. On the other hand, diabetic macular edema involves the leakage of fluid from blood vessels within the eye. This leakage leads to swelling in the central retina, causing damage to the retinal cells responsible for central vision.
The findings of the study, which were published on May 25 in the Journal of Clinical Investigation, reveal compelling results. The researchers discovered that a compound called 32-134D, known for its ability to impede the growth of liver tumors in mice, exhibited a preventive effect on diabetic retinal vascular disease. This effect was achieved by reducing the levels of a protein called HIF, or hypoxia-inducible factor. Notably, the doses of 32-134D administered during the study appeared to be safer compared to an alternative treatment currently being investigated for its potential in treating diabetic eye disease, which also targets HIF.
The existing treatment approach for both proliferative diabetic retinopathy and diabetic macular edema involves the administration of eye injections containing anti-vascular endothelial growth factor (anti-VEGF) therapies. These therapies are designed to halt the growth and leakage of blood vessels in the retina of diabetic patients. However, it is important to note that these treatments do not yield effective results for a significant number of patients. Furthermore, prolonged use of anti-VEGF therapies can lead to side effects, including elevated internal eye pressure or damage to eye tissues.
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.
Hypoxia-inducible factor (HIF), a specific type of protein referred to as a transcription factor, possesses the remarkable ability to activate or deactivate certain genes, including vascular endothelial growth factor (VEGF), in various regions of the body. Within the eye, elevated levels of HIF stimulate the upregulation of genes like VEGF, which promotes the production and leakiness of blood vessels in the retina. This process significantly contributes to vision loss in affected individuals.
To evaluate the effectiveness of 32-134D, the researchers conducted experiments involving multiple types of human retinal cell lines that are associated with the expression of proteins responsible for facilitating blood vessel production and leakiness. Following the administration of 32-134D, the researchers observed a noteworthy outcome: the expression levels of genes regulated by HIF returned to a state resembling normal levels. This outcome proved pivotal as it effectively halted the creation of new blood vessels while maintaining the structural integrity of existing ones.
In addition, the researchers conducted tests on two distinct adult mouse models of diabetic eye disease to further assess the potential of 32-134D. The drug was administered via eye injections in both models. Remarkably, five days after the injections, the researchers noted a significant reduction in HIF levels. Moreover, they observed that the drug effectively impeded the formation of new blood vessels and prevented vessel leakage, thereby considerably decelerating the progression of the eye disease in the animals.
An unexpected finding emerged during the study. The research team was surprised to discover that a single injection of 32-134D remained active in the retina for approximately 12 days without causing any detrimental effects such as retinal cell death or tissue wastage. This extended period of sustained drug activity adds to the potential therapeutic value of 32-134D in treating diabetic eye disease.
"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."
Reference
Jing Zhang et al, Targeting hypoxia-inducible factors with 32-134D safely and effectively treats diabetic eye disease in mice, Journal of Clinical Investigation (2023). DOI: 10.1172/JCI163290
