Blocking a common genetic variation in Huntington's patients might diminish the disease's effects.

Gathering the sequences of Huntington's genes lets researchers zoom in on an ideal drug target.

Although the gene mutation that causes Huntington's disease—a neurodegenerative disorder that causes jerky, random movements—was discovered in 1993, a genetic cure has been elusive. Huntington's patients have one abnormal version of the Huntingtin gene and one healthy version that allows for limited motor function. Researchers have been unable to find a drug target that exists only on the diseased copy of the gene. Now, HHMI investigator Phillip Zamore has spotted a key difference.

Huntingtin contains a region with a repetitive sequence of DNA—it reads “C-A-G” between 6 and 28 times in the normal gene. The abnormal gene contains this repetition many more times—over a hundred in some cases. More repeats means more severe disease and an earlier age of onset.

Zamore, at the University of Massachusetts Medical School, studies small molecules called small interfering RNA (siRNA) that can bind to a given mRNA sequence and prevent it from functioning. It was hard to imagine how an siRNA could bind just the abnormal Huntingtin if the only difference from the healthy copy was a greater number of repeats.

“The problem is that even the normal gene has too many C-A-G repeats for an siRNA to tell the difference between it and the disease version,” says Zamore. But it occurred to him that if he looked more closely at the disease version, there might be small, but common, variations—called polymorphisms—that don't affect the way a gene works but could be exploited to block it.

Zamore and his collaborators sequenced the genes of more than a hundred patients. They uncovered a polymorphism that, in 48 percent of the patients, appeared only in the disease-causing version of Huntingtin. It was far rarer in healthy copies of the gene—either in patients or in control subjects. The results appear in the May 12, 2009, issue of Current Biology.

Zamore is working to develop an siRNA that targets the polymorphism; it would block only the diseased Huntingtin gene, allowing the normal version to keep doing its job.

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