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Ambati study published in PNAS
Date:4/6/2009

LEXINGTON, Ky. (April 6, 2009) The side effects of an experimental "gene-silencing" treatment that is currently being investigated for a variety of diseases are even more wide-ranging than previously discovered, according to a study by a University of Kentucky researcher.

Following up on groundbreaking research published last year in the journal Nature, Dr. Jayakrishna Ambati, a UK ophthalmologist , and his colleagues found that the new drug modality, siRNA (21-nucleotide small-interfering RNA), is toxic not only to blood endothelial cells, which line blood vessels, but also to the cells lining the lymphatic channels.

These findings reinforce the note of caution sounded by Ambati's previous Nature study, which has been cited nearly 50 times and highlighted in special reviews in premier journals such as Cell and in Nature, which termed it "stunning." But these side effects could themselves find useful application, for example, in cornea transplantation, where growth of new blood and lymph vessels is believed to be a major cause of graft failure.

The new findings are published in this week's online issue of Proceedings of the National Academy of Sciences, the official journal of the U.S. National Academy of Sciences.

In the earlier study, the Ambati laboratory discovered previously unrecognized immune side effects of siRNA, which is currently in FDA trials for numerous diseases including age-related macular degeneration and life-threatening viral infections.

Specifically, they showed that in two different established animal models of new blood vessel growth, siRNA killed these cells by activating an immune receptor called toll-like receptor 3 (TLR3). This was a critical finding, as immune and blood vessel toxicities were not believed to occur with this pharmacologic technique. As a result, siRNA is now recognized as a new class of anti-vascular drugs that could potentially be used to treat some of the 10 percent of the world
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Contact: Ann Blackford
ann.blackford@uky.edu
859-559-1964
University of Kentucky
Source:Eurekalert

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