In mouse and human cell models, the drug 32-134D reduced protein levels that contribute to diabetic macular edema and diabetic retinopathy — ScienceDaily

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The team focused on models of two common diabetic eye conditions: proliferative diabetic retinopathy and diabetic macular edema, which affect the retina, the light-sensitive tissue at the back of the eye that also transmits vision signals to the brain. In proliferative diabetic retinopathy, new blood vessels grow too large on the surface of the retina, causing retinal bleeding or detachment and profound vision loss. In diabetic macular edema, the blood vessels in the eye leak fluid, causing swelling of the central retina and damaging the retinal cells responsible for central vision.

The results of the study, published May 25 in the Clinical Research Journal, show that a compound called 32-134D, previously shown to slow liver tumor growth in mice, prevented diabetic retinal vascular disease by lowering levels of a protein called HIF, or hypoxia-inducible factor. Doses of 32-134D also appeared to be safer than another treatment that also targets IFH and is under investigation to treat diabetic eye disease.

Current treatment for both proliferative diabetic retinopathy and diabetic macular edema includes ocular injections with anti-vascular endothelial growth factor (anti-VEGF) therapies. Anti-VEGF therapies can stop the growth and leakage of retinal blood vessels in patients with diabetes. However, these treatments are not effective for many patients and can cause side effects with prolonged use, such as increased internal eye pressure or damage to eye tissue.

Akrit Sodhi, MD, Ph.D., an author on the new study, says that overall, the idea of ​​inhibiting HIF, a critical protein in the body, has raised concerns about toxicity to many tissues and organs. But when his team evaluated a library of HIF-inhibiting drugs and did extensive testing, “we found that the drug examined in this study, 32-134D, was remarkably well-tolerated in the eyes and effectively lowered HIF levels in the eyes.” sick”. says Sodhi, an 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 turn certain genes, including vascular endothelial growth factor (VEGF), on or off throughout the body. In the eye, elevated HIF levels cause genes such as VEGF to increase blood vessel production and leakage in the retina, contributing to vision loss.

To test 32-134D, the researchers dosed multiple types of human retinal cell lines associated with the expression of proteins that promote blood vessel production and leakage. When they measured the HIF-regulated genes in cells treated with 32-134D, they found that their expression had returned to near-normal levels, which is enough to stop the creation of new blood vessels and maintain the structural integrity of the blood vessels.

The researchers also tested 32-134D in two different adult mouse models of diabetic eye disease. In both models, the injections were administered into the eye. Five days after injection, the researchers observed reduced levels of HIF and also found that the drug effectively inhibited the creation of new blood vessels or blocked vessel leakage, slowing the progression of the animals’ eye disease. Sodhi and her team said they were also surprised to find that 32-134D remained in the retina at active levels for about 12 days after a single injection without causing retinal cell death or tissue wear.

“This paper highlights how HIF inhibition with 32-134D is not only a potentially effective but also a safe therapeutic approach,” says Sodhi. “People facing diabetic eye disease and vision loss include our family members, friends, co-workers – this is a disease that affects a large group of people. Safer therapies are critical for this growing population of patients”.

Sodhi says that further studies in animal models are needed before moving on to clinical trials.

Additional authors involved in this study are Jing Zhang, Deepti Sharma, Aumreetam Dinabandhu, Jaron Sanchez, Brooks Puchner Applewhite, Kathleen Jee, Monika Deshpande, Ming-Wen Hu, Chuanyu Guo, Jiang Qian, Shaima Salman, Yousang Hwand, and Gregg Semenza of Johns Hopkins University School of Medicine; Miguel Flores-Bellver and Maria Valeria Canto-Soler of the University of Colorado School of Medicine; Nicole Anders and Michelle Rudek of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center; and Silvia Montaner from the University of Maryland.

Funding for this work was supported by NIH grants (R01EY029750, R01EY032104, EY001765, P30 CA006973, 1S10RR026824, UL1 TR003098); the TEDCO Maryland Innovation Initiative, the Special Award for Research Scholars to Prevent Blindness, Inc.; the Sybil B. Harrington Stein Award for Innovation; an unrestricted grant to the Wilmer Eye Institute, Johns Hopkins University School of Medicine, and the University of Colorado; the Armstrong Family Foundation; the CellSight Development Fund; the Doni Solich Family Chair in Ocular Stem Cell Research; and the Branna Irving Sisenwein Chair in Ophthalmology.