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Research represents major breakthrough in macular degeneration

April 26, 2012--University of Kentucky researchers, led by Dr. Jayakrishna Ambati, have made a major breakthrough in the "dry" form of age-related macular degeneration known as geographic atrophy (GA).

GA is an untreatable condition that causes blindness in millions of individuals due to death of retinal pigmented epithelial cells.

The paper, "DICER1 loss and Alu RNA Induce Age-Related Macular Degeneration via the NLRP3 Inflammasome and MyD88," was published in the April 26 online edition of the premier journal Cell.

Ambati, professor of physiology, and professor and vice chair of ophthalmology and visual sciences at UK, is a leader in the field of macular degeneration research. Previous research from the Ambati laboratory published in the journal Nature showed that in human eyes with geographic atrophy there is a deficiency of the enzyme DICER1, leading to accumulation of toxic Alu RNA molecules in the retinal pigmented epithelium.

The Cell paper shows that when these RNAs build up in the eye they trigger activation of an immune complex known as the NLRP3 inflammasome.

In turn, this leads to the production of a molecule known as IL-18, which causes death of retinal pigmented epithelial cells and vision loss by activating a critical protein known as MyD88.

Importantly, Ambati and colleagues found evidence that activity of the inflammasome, IL-18, and MyD88 were all increased in human eyes with GA.

They then showed that blocking any of these components could prevent retinal degeneration in multiple disease models. The researchers are excited that blocking these pathways could herald a new potential therapy for GA, for which there is no approved treatment.

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Ambati is working with iVeena Pharmaceuticals, Inc. of Salt Lake City to commercialize therapies for geographic atrophy. iVeena can be contacted at info@i-veena.com.

Authors on the paper include Ambati as well as Valeria Tarallo, Yoshio Hirano, Bradley D. Gelfand, Sami Dridi, Nagaraj Kerur, Younghee Kim, Won Gil Cho, Hiroki Kaneko, Benjamin J. Fowler, Sasha Bogdonaovich, Romulo J.C. Albuquerque, Judi Z. Baffi and Mark E. Kleinman, all of the UK Department of Opthalmology and Visual Science. Additional authors include: William W. Hauswirth and Vince A. Chiodo of the University of Florida; Jennifer F. Kugel, James A. Goodrich and Steven L. Ponicsan of the University of Colorado; Gautaum Chaudhuri of Meharry Medical College; Michael P. Murphy of the MRC Mitochondrial biology Unit; Joshua L. Dunaief of the University of Pennsylvania; Balamurali K. Ambati of the University of Utah and the Veterans Affairs Salt Lake City Healthcare System; Yuichiro Ogura of the Nagoya City University Graduate School of Medical Sciences, Japan; Jae Wook Yoo and Dong-ki Lee of Sungkyunkwan University, Korea; Patrick Provost of Université Laval, Quebec; David R. Hinton of the University of Southern California; and Gabriel Nunez of the University of Michigan Medical School.

Ambati is also the Dr. E. Vernon and Eloise C. Smith Endowed Chair in Macular Degeneration Research.

This research was supported by the National Eye Institute, the Doris Duke Charitable Foundation, the Burroughs Wellcome Fund, and Research to Prevent Blindness.