"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 people with Huntington's.
Working on a similar disease using human cells, Davidson and her colleague Henry Paulson have now shown you can make an siRNA that recognises and silences only the mutant gene. They could not target the disease-causing mutation itself because, as in Huntington's, the mutation merely makes a long stretch of repeats even longer, without actually altering any particular short sequence. But they did find another difference, a change in a single DNA letter that appears in 70 per cent of defective genes.
Adding an siRNA that matches this telltale sequence reduced expression of the defective protein by over 80 per cent, while production of the normal protein was hardly affected, Davidson told a gene therapy conference in Banff, Canada, last week. The hunt is now on for similar mutations in the huntingtin gene itself. One promising candidate has been discovered in about 40 per cent of disease-causing genes.
The same approach could probably be used for many other genetic disorders. Even if both copies of a gene are faulty, a healthy copy of the gene could be added alongside an siRNA that turns off both defective copies.
Bob Holmes, BANFF
New Scientist issue: 15th March 2003
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