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Switching off Huntington's

USING gene therapy to switch off genes instead of adding new ones could slow down or prevent the fatal brain disorder Huntington's disease. The method, which exploits a mechanism called RNA interference, might also help treat a wide range of other inherited diseases.

"When I first heard of this work, it just took my breath away," says Nancy Wexler of Columbia University Medical School, who is president of the Hereditary Disease Foundation in New York. Though the gene-silencing technique has yet to be tried in people, she says it is the most promising potential treatment so far for Huntington's.

It involves a natural defence mechanism against viruses, in which short pieces of double-stranded RNA (short interfering RNAs, or siRNAs) trigger the degradation of any other RNA in the cell with a matching sequence. If an siRNA is chosen to match the RNA copied from a particular gene, it will stop production of the protein the gene codes for (see Graphic).

Huntington's is caused by mutations in the huntingtin gene. The resulting defective protein forms large clumps that gradually kill off part of the brain. Studies in mice have shown that reducing production of the defective protein can slow down the disease, and Beverly Davidson at the University of Iowa thinks the same could be true in people.

"If you reduce levels of the toxic protein even modestly, we believe you'll have a significant impact," she says. Late last year, her team showed that it is possible to reduce the amount of a similar protein by up to 90 per cent, by adding DNA that codes for an siRNA to rodent cells engineered to produce the protein.

The team was the first to use gene therapy to deliver such a payload, and they have now done the same with the huntingtin protein itself. Completely silencing the gene in people with the disease is not an option because brain cells may not survive without the protein. But we have two copies of most genes, and usually only one is defective in peop
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Contact: Claire Bowles
claire.bowles@rbi.co.uk
44-207-331-2751
New Scientist
12-Mar-2003


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