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FUTURE FILE: Highlighting innovative early-stage and preclinical concepts in retina

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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.

Combating Diabetes-Related Vision Loss

■ Johns Hopkins University researchers have discovered a cell signaling pathway in mice that triggers vision loss in patients with diabetic retinopathy and retinal vein occlusion — diseases characterized by the closure of blood vessels in the retina, leading to blindness. In experiments that suppressed VEGF in the eye, researchers re-established normal blood flow in the retina, offering a potential means of stalling or even reversing diabetes-related blindness.

In the study, recently published in the Journal of Clinical Investigation Insight, researchers found that increased VEGF levels in the retina attract white blood into the retina, where they adhere to the walls of blood vessels, disrupting blood flow. Reducing VEGF or blocking it with an antibody caused the white blood cells to dissipate, opening the closed vessels and restoring blood flow to the area.

“This work is particularly important because it helps explain why diabetic retinopathy and retinal vein occlusion continue to worsen across a patient’s lifetime if left untreated,” said Peter Campochiaro, MD, director of the Retinal Cell and Molecular Laboratory and professor of ophthalmology at the Johns Hopkins Wilmer Eye Institute, in a news release.

The inspiration for the study came from observations made in clinical trials for ranibizumab (Lucentis, Genentech), a drug designed to block VEGF in patients with diabetic retinopathy and retinal vein occlusion. They saw that after VEGF was suppressed, the patients’ conditions not only improved, but the treatment also improved blood flow to parts of the retina that were previously blocked.

To investigate, Dr. Campochiaro chose 6 genetically modified mice to overexpress VEGF when given doxycycline. After 3 days of VEGF overexpression, Campochiaro’s team observed the telltale clumps of white blood cells collecting in the blood vessels of the retina. The researchers then stopped overexpressing VEGF in these mice, and 17 days later, they found that the white blood cell clumps had broken up and blood flow returned to areas of the retina that had been cut off.

The researchers found that when white blood cells interacted with VEGF, they were triggered to migrate into the blood vessels of the retina. The high levels of VEGF also activated a transcription factor, called NF-kB, which is responsible for the expression of many different kinds of proteins in the body. Most importantly, it controls a cell adhesion molecule called VCAM-1, which acts as an adhesive between many types of immune cells and blood vessels.

The group then repeated their previous experiment, but administered an antibody targeted to inhibit VCAM-1 while also increasing VEGF expression. When compared to the retinal vessels of mice not treated with the inhibitor, the VCAM-1 inhibitor-treated mice showed significantly less white blood cell clumps and better blood flow in the retinal blood vessels. This means that VEGF drives the early stages of diabetic retinopathy and retinal vein occlusion, as well as the late stages when vision is decreased, according to Dr. Campochiaro.

A Pain Medication That Protects Vision

■ Scientists have shown that pentazocine, a medicine prescribed for severe pain, can help preserve vision in a model of severe, blinding retinal degeneration. They have evidence the drug may activate Nrf2, one of the most powerful antioxidants in our cells by first activating sigma 1, a receptor that is already a target in neurodegenerative disease.

“We are very, very pleased that we can now explore the mechanisms,” says Sylvia Smith, PhD, chair of the Department of Cellular Biology and Anatomy at the Medical College of Georgia (MCG) at Augusta University and co-director of the James and Jean Culver Vision Discovery Institute at AU.

Dr. Smith is principal investigator on a new $1.14 million grant from the National Eye Institute that is helping further explore the connections and identify new treatment targets for sight-robbing conditions like retinitis pigmentosa, macular degeneration, and glaucoma.

Sigma 1 receptor is a well-established nonopioid pain receptor, but Dr. Smith’s team has shown it’s also essential to a healthy retina. They’ve also shown that pentazocine activates the sigma 1 receptor and reported in 2016 in Proceedings of the National Academy of Sciences that the drug helped preserve vision in their model of severe retinal degeneration. Now, they want to know if the magic is in the sigma 1 receptor modulating the Nrf2-Keap1 pathway.

The MCG team has evidence that pentazocine interacts with the Nrf2-Keap1 pathway, but they don’t know how it alters proteins and their function in that pathway. In their animal model, they found that low doses of the drug every other day modulate levels of Nrf2 in the retina and they suspect that change is central to how it protects vision.

They also are exploring the impact of pentazocine treatment over time to see if the early protection of cone cells continues to hold. They are looking at a few other compounds that bind to the sigma 1 receptor to see if they yield similar, beneficial vision effects. RP