Damaging DNA builds up in eyes to lead to blinding age-related macular degeneration

Damaging DNA builds up in the eyes of patients with geographic atrophy, an incurable and poorly understood form of age-related macular degeneration that causes blindness, new research from the University of Medicine School of Medicine finds. Virginia. Based on this finding, the researchers believe it may be possible to treat the disease with common anti-HIV drugs or an even safer alternative.

Harmful DNA, known as Alu cDNA, was previously discovered to be made in the cytoplasm by Jayakrishna Ambati, MD, UVA, and colleagues. The new findings are believed to be the first time that an accumulation of toxic Alu cDNA has been confirmed in patients regardless of disease.

The new findings offer insight into the progression of geographic atrophy over time.

While we know that geographic atrophy spreads over time, we don’t know how or why. Our finding in human eyes that toxic Alu cDNA levels are highest at the leading edge of the geographic atrophy lesion provides strong evidence that it is responsible for this expansion over time that leads to vision loss. “

Jyakrishna Ambati, Department of Ophthalmology and Center for Advanced Vision Science, University of Virginia Health System

About age-related macular degeneration

Geographic atrophy is an advanced form of age-related macular degeneration, a potentially blinding disease that affects 200 million people worldwide. The disease eventually destroys vital cells in the retina, the light-sensitive part of the eye.

Ambati, a leading expert in macular degeneration, and his colleagues found that this destruction is caused by the buildup of Alu DNA, which the researchers found floating in the cytoplasm of cells. That Alu DNA was made in the cytoplasm came as a surprise, as it is generally believed that DNA is contained in the cell nucleus.

As Alu DNA builds up in the eye, it triggers harmful inflammation through a part of the immune system called the inflammasome. Researchers have identified how this happens, uncovering a previously unknown structural facet of Alu that triggers the immune mechanism that leads to the death of vital retinal cells.

This is where anti-HIV drugs called nucleoside reverse transcriptase inhibitors, or NRTIs, might come in. New work by researchers in lab mice suggests that these drugs, or safer derivatives known as of Kamuvudines, may block harmful inflammation and protect against the death of retinal cells.

“Over the past two decades, dozens of clinical trials for geographic atrophy that have targeted other pathways have failed,” Ambati said. “These findings from the eyes of patients give a strong impetus to a new direction.”

Ambati says its latest findings provide further support for conducting clinical trials testing the drugs in patients with macular degeneration. An earlier study of four different health insurance databases – covering more than 100 million patients over two decades – found that people taking NRTIs were almost 40% less likely to develop dry macular degeneration.

“Our findings from human eyes show that these toxic molecules, which activate the inflammasome, are most abundant precisely in the area of ​​greatest disease activity,” Ambati said. “We are optimistic that a clinical trial of Kamuvudines will soon be launched in geographic atrophy so that we can potentially offer a treatment for this devastating disease.”