Top right and bottom right images show reduction of the Dicer enzyme, while the top left and bottom left images show the eye when Alu RNA is blocked   (Source: Ambati Laboratory/University of Kentucky)
Alu RNA plays a crucial role in the death of retinal cells in those with geographic atrophy, but two new therapies could prevent this toxic RNA from accumulating, thus preventing blindness in older Americans with this condition

Dr. Jayakrishna Ambati, vice chair and professor of the Department of Ophthalmology at the University of Kentucky, and a team of researchers, are working with a new molecular mechanism associated with geographic atrophy and are developing two therapies that could prevent this condition.

Geographic atrophy is considered to be the "dry" form of advanced age-related macular degeneration. This condition occurs due to atrophy to the retinal pigment epithelial layer below the retina, which then leads to the loss of photoreceptors in the central part of the eye. The end result is vision loss. There is no known cure for this condition, and it is currently affecting 10 million older Americans while causing blindness over 1 million. 

The molecular mechanism that Ambati and his team found was Alu RNA, which is a toxic type of RNA that plays a disease-causing role in a large section of the human genome that has been nicknamed "junk" DNA. These Alu-related elements make up 11 percent of the human genome, and were considered "junk" DNA because researchers did not understand their role.

When Alu RNA accumulates, it kills retinal cells in patients with geographic atrophy. A "Dicer" enzyme usually degrades these Alu RNA particles in a healthy eye. This enzyme is greatly reduced in those with geographic atrophy. 

"We discovered that in patients with geographic atrophy, there is a dramatic reduction of the Dicer enzyme in the retina," said Ambati. "When the levels of Dicer decline, the control system is short-circuited and too much Alu RNA accumulates. This leads to death of the retina."

At the same time that Ambati and his team made this discovery, they also developed two therapies that may prevent geographic atrophy. The first therapy increases Dicer levels in the retina by "over-expressing the enzyme," and the second therapy blocks Alu RNA with a drug that clings to the toxic structure and degrades it. Lab models have proved that both therapies could efficiently prevent geographic atrophy. 

"These findings provide important new clues on the biological basis of geographic atrophy and may provide avenues for intervention through preventing toxic accumulation of abnormal RNA products," said Dr. Paul Sieving, director of the National Eye Institute, which supports Ambati's laboratory. 

The University of Kentucky has filed for patents on both therapies, and clinical trials are expected to begin by the end of this year. 

This study was published in Nature.

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