Discovery of a key enzyme mechanism in geographic atrophy, a late stage in “dry type” age-related macular degeneration (AMD), is raising hope of two possible new therapies for a major cause of untreatable blindness in the industrialized world.

Ophthalmologist Dr Jayakrishna Ambati, of the University of Kentucky in the US, and colleagues, found that an accumulation of a toxic type of RNA, called Alu RNA, causes retinal cells to die in patients with geographic atrophy, and that in healthy patients an enzyme called “Dicer” breaks down the Alu RNA particles.

They write about their findings in a paper published in the 6 February online issue of Nature.

The paper also describes for the first time, how a large section of the human genome that was once thought to contain only “junk DNA” can actually have a role in causing disease.

As well as making this discovery, Ambati’s lab have started developing two promising new therapies to prevent geographic atrophy in AMD.

Geographic atrophy, for which there is currently no effective treatment, kills retinal pigmented epithelium cells and occurs in the later stages of the “dry type” of macular degeneration. About 10 million older Americans have AMD, and around 1 million are blinded by the disease.

Ambati, who is professor and vice chair of the Department of Ophthalmology and Visual Sciences and the Dr. E Vernon and Eloise C Smith Endowed Chair in Macular Degeneration Research at the University of Kentucky College of Medicine, told the press they found a dramatic reduction of the Dicer enzyme in the retina of patients with geographic atrophy.

“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,” he explained.

Alu elements are like recurring phrases in the text of the human genome. They consist of around 300 base pairs (the alphabet code of the genome) and make up a surprisingly large portion of the genome, about 11 per cent by weight.

Until now, their function was unknown, which is how they came to be described as “junk DNA” or part of the “dark” genome.

The discovery that Alu elements can be toxic and controlled by Dicer should be of great interest to scientists, said Ambati.

He and his team have developed two potential therapies based on the discovery and demonstrated how they work using lab models.

The first therapy over-expresses Dicer to increase levels of the enzyme in the retina.

The second blocks Alu RNA with an “antisense” oligonucleotide drug that binds and degrades it.

The University of Kentucky has applied for patents for both therapies and Ambati and his team hope to start clinical trials by the end of the year.

Scientists have welcomed the news with enthusiasm.

Dr Paul Sieving, director of the National Eye Institute in the US said:

“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.”

Dr Napoleone Ferrara, a researcher at Genentech and a member of the National Academy of Sciences and Lasker-DeBakey awardee, agrees:

“Ambati’s latest research provides important mechanistic insights in geographic atrophy, and identification of this novel pathway may result in new therapeutic targets for a major cause of blindness,” he said.

Dr Stephen J Ryan, president of the Doheny Eye Institute and member of the Institute of Medicine, said the study has “widespread implications” for future research:

“The authors have opened an important line of research with real possibilities for future therapeutic intervention for patients with geographic atrophy,” he said.

“DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration.”
Hiroki Kaneko, Sami Dridi, Valeria Tarallo, Bradley D. Gelfand, Benjamin J. Fowler, Won Gil Cho, Mark E. Kleinman, Steven L. Ponicsan, William W. Hauswirth, Vince A. Chiodo, Katalin Karikó, Jae Wook Yoo, Dong-ki Lee, Majda Hadziahmetovic, Ying Song, Smita Misra, Gautam Chaudhuri, Frank W. Buaas, Robert E. Braun, David R. Hinton, Qing Zhang, Hans E. Grossniklaus, Jan M. Provis, Michele C. Madigan, Ann H. Milam, Nikki L. Justice, Romulo J. C. Albuquerque, Alexander D. Blandford, Sasha Bogdanovich, Yoshio Hirano, Jassir Witta, Elaine Fuchs, Dan R. Littman, Balamurali K. Ambati, Charles M. Rudin, Mark M. W. Chong, Patrick Provost, Jennifer F. Kugel, James A. Goodrich, Joshua L. Dunaief, Judit Z. Baffi, and Jayakrishna Ambati.
Nature Published online 6 February 2011
DOI:10.1038/nature09830

Additional source: University of Kentucky (6 Feb 2011 press release).

Written by: Catharine Paddock, PhD