Experimental drug found to slow vision loss and retina damage in diabetics

"We came to find that the drug examined in this study was remarkably well tolerated and effectively reduced HIF levels in diseased eyes"
Amal Jos Chacko
An illustration of an eye.jpg
An illustration of an eye.


A team of scientists at Wilmer Eye Institute, John Hopkins Medicine have published evidence of an experimental drug that can prevent or slow loss of vision in diabetic patients, according to a press release.

According to the National Institutes of Health, vision loss as a result of diabetes affects almost 8 million Americans currently and is expected to double by 2040.

The team used mouse as well as human retinal organoids in their study and focused on two common diabetic eye conditions: proliferative diabetic retinopathy and diabetic macular edema.

Although both these conditions affect the retina, the tissue that senses light and transmits vision signals to the brain, new blood vessels overgrow on the retina’s surface in proliferative diabetic retinopathy, leading to bleeding or retinal detachments and vision loss.

Patients with diabetic macular edema exhibit swollen central retinas and damaged retinal cells as a result of fluid leaking from blood vessels in the eye, causing a loss of central vision.

Experimental drug found to slow vision loss and retina damage in diabetics
Artistic rendition of diabetic eye disease highlighting vascular changes (i.e., retinal neovascularization) observed in patients with proliferative diabetic retinopathy.

A safer, better alternative

These diseases are currently treated with eye injections with anti-vascular endothelial growth factor (anti-VEGF) therapies.

Although these stop the growth of new abnormal blood vessels and thus limit leakage, they have not been effective for many patients and cause side effects including increased internal eye pressure and eye tissue damage, in the long run.

The team studied a compound, 32-134D— previously observed to slow tumor growth in mice— and detected lower levels of the protein hypoxia-inducible factor (HIF) in patients using the compound.

HIF gets activated in the walls of arteries and produces several proteins that promote the growth of new blood vessels. Lower levels of HIF prevent diabetic retinal vascular diseases. Furthermore, doses of 32-134D were found to be safer than other treatments that target HIF.

“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,” said Akrit Sodhi, M.D., Ph.D., associate professor of ophthalmology and the Branna and Irving Sisenwein Professor of Ophthalmology at the Wilmer Eye Institute, and co-author of the new study.

When tested in two different adult mouse models of diabetic eye disease, 32-134D was found to diminish levels of HIF and inhibit the creation of new blood vessels, thereby slowing the progression of the disease five days post-injection.

32-134D was also tested in multiple types of human retinal cell lines associated with the expression of proteins promoting blood vessel production and leakiness and was found to reduce HIF to their near-normal levels, halting the creation of new blood vessels.

“This paper highlights how inhibiting HIF with 32-134D is not just a potentially effective therapeutic approach, but a safe one, too. This is a disease that impacts a large group of people. Having safer therapies is critical for this growing population of patients,” Sodhi concluded.

Study Abstract

Many patients with diabetic eye disease respond inadequately to anti-VEGF therapies, implicating additional vasoactive mediators in its pathogenesis. We demonstrate that levels of angiogenic proteins regulated by hypoxia-inducible factor (HIF)-1 and -2 (HIFs) remain elevated in diabetic eyes despite treatment with anti-VEGF therapy. Conversely, by inhibiting HIFs we normalized the expression of multiple vasoactive mediators in mouse models of diabetic eye disease. Accumulation of HIFs and HIF-regulated vasoactive mediators in hyperglycemic animals was observed in the absence of tissue hypoxia, suggesting that targeting HIFs may be an effective early treatment for diabetic retinopathy. However, while the HIF-inhibitor acriflavine prevented retinal vascular hyperpermeability in diabetic mice for several months following a single intraocular injection, accumulation of acriflavine in the retina resulted in retinal toxicity over time, raising concerns for its use in patients. Conversely, 32-134D, a recently developed HIF inhibitor structurally unrelated to acriflavine, was not toxic to the retina, yet effectively inhibited HIF accumulation and normalized HIF-regulated gene expression in mice and in human retinal organoids. Intraocular administration of 32-134D prevented retinal neovascularization and vascular hyperpermeability in mice. These results provide the foundation for clinical studies assessing 32-134D for the treatment of patients with diabetic eye disease.

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