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Too Much? Too Little? The Goldilocks Story of Iron in the Eye

The body needs just the right amount of iron, otherwise all manner of havoc happens. Too little iron and the body malfunctions because it carries oxygen to all the cells. Roughly two-thirds of the mineral resides in hemoglobin, the oxygen-transporting protein in red blood cells. And if the body doesn’t make enough healthy red blood cells, which leads to anemia, it can't get enough oxygen.

However, this is a story of excess. Too much iron is also toxic, especially in the brain and eyes.

“We absorb iron from our diet every day, especially from red meat, but human don’t excrete it, except during menstruation,” said Joshua Dunaief, MD, PhD, the Adele Niessen Professor of Ophthalmology, who studies the role of iron overload and oxidative stress in a blinding disease called age-related macular degeneration (AMD). “Like any food we eat, it’s all about balance.”

“But iron levels increase in the body with age, and excess iron is a major source of oxidative stress,” he added.

In the past, Dunaief’s lab has shown that retinas from people with AMD, the leading cause of blindness in the elderly, have higher iron levels than people in the same age group without the disease.

In a recent FASEB Journal article from his lab, featured on the cover, they showed that mice with a mutation in the iron transporter protein called ferroportin have increased iron levels in the retina, which causes degeneration. The retina is a layer of light-sensitive cells at the back of the eye that trigger impulses to the optic nerve and on to visual centers, where images are formed.

Normally, ferroportin carries excess iron out of cells – and, it’s the only molecule that can do that. Using a mouse model of AMD, developed in the Dunaief lab, in which iron accumulates specifically in the retina, they verified that ferroportin is located in the retina and showed exactly where and how it’s regulated. Answering these questions is important to understand why it accumulates. “What is wrong with the iron disposal system in these patients?” he asked.

They found that retinas from people with AMD obtained from post-mortem donated eyes have higher iron levels than people without the disease, but how that iron accumulation affects an individual depends on their specific environmental and genetic features.

On the other hand, the team also found that higher iron levels do not lead to an up- regulation of ferroportin in the cells affected by AMD, so they can’t get rid of the excess iron. “Ferroportin in retina is not regulated the same way as in the rest of the body,” Dunaief explained.

What’s next in trying to achieve a “just right” amount of iron the eye?

“We’re trying to figure out how to get rid of excess iron in the retina,” he said. “We know of two ways so far. First, increasing the amount of ferroportin in the retina with a drug. We would need to search a library of candidate compounds since there are no drug candidates as of yet.”

And, second, Dunaief and colleagues at Penn’s Center for Advanced Retinal and Ophthalmic Therapeutics are in the midst of developing gene therapies to add ferroportin to the retina. “This could be quite doable,” he said.

The use of chelators to remove the iron is another option to bring about a happy ending to the Goldilocks tale of iron in the eye. The Dunaief lab has shown that they can protect the mouse retina from degeneration. Future work will focus on accomplishing this while minimizing side effects.

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