Gene Therapy May Switch off Huntington's

From the Fall/Winter 2003 issue of Hopes & Dreams, newsletter of the Illinois Chapter, Huntington's Disease Society of America.

(from the New Scientist Print Edition ~

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 way,” 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 defense 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.

Huntington’s is caused by mutations in the huntington 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 in 2002, her team showed that it is possible to reduce the amount of a similar protein by up to 90%, by adding DNA that codes for an siRNA to rodent cells engineered to produce the protein.

Disease-causing genes
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 that you can make an siRNA that recognizes and silences only the mutant gene. (Continued on Page 9)

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% of defective genes.

Adding an siRNA that matches this telltale sequence reduced expression of the defective protein by over 80%, while production of the normal protein was hardly affected, Davidson told a gene therapy conference in Banff, Canada.

The hunt is now on for similar mutations in the huntingtin gene itself. One promising candidate has been discovered in about 40% of disease-causing genes.

The same approach could probably be used for many other genetic diseases. 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.


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Created: Feb. 8, 2004
Last updated: Nov. 13, 2010