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New therapeutic strategy could target toxic protein in most patients with Huntington's disease
Date:4/9/2009

Howard Hughes Medical Institute researchers have designed tiny RNA molecules that shut off the gene that causes Huntington's disease without damaging that gene's healthy counterpart, which maintains the health and vitality of neurons. Laboratory studies suggest that a single small interfering RNA could reduce production of the damaging Huntingtin protein in nearly half of people with the disease. Another 25 percent of patients might benefit from one of a set of four additional small interfering RNAs.

Phillip D. Zamore, an HHMI investigator at the University of Massachusetts Medical School in Worcester, and his colleagues reported their findings in an article published April 9, 2009, in the journal Current Biology.

There is no treatment for Huntington's disease, which is caused by a mutant form of the Huntingtin gene. Huntingtin is required for healthy nerve cells, but the mutant gene makes a toxic protein that contains excess amounts of the amino acid glutamine.

The key to whether the Huntingtin gene is normal or defective lies in a kind of genetic stutter: a repetitive sequence of the DNA triplet CAG, which codes for the amino acid glutamine. Stretches of CAG "repeats" appear in every human being's Huntingtin gene, but the length varies. Whereas the normal gene has a sequence of between six and 34 CAG repeats, the abnormal gene contains many more. In fact, any stretch of DNA containing more than 40 of these repeats ensures that its bearer will develop Huntington'sthe greater the number of repeats, the earlier the disease strikes and the greater its ferocity. The abnormal Huntingtin protein causes movement disorders, cognitive failure, and ultimately, death. Children who have a parent with Huntington's disease have a 50 percent chance of inheriting the disease themselves.

Zamore studies how RNA interference can be used to silence genes selectively. In the 1990s, he and other scientists lea
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Contact: Jennifer Michalowski
michalow@hhmi.org
301-215-8576
Howard Hughes Medical Institute
Source:Eurekalert

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