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

rned they could shut down the production of specific proteins by introducing double-stranded RNA into the cell that is identical to the RNA they wanted to turn off. These strands of RNA, known as short interfering RNA (siRNA), slice apart the original RNA, which the cell then destroys.

But nine years ago, when researcher Neil Aronin, who is also at UMass Medical School, proposed using the technique to attack Huntington's, Zamore couldn't see a way.

"I explained to him that you can't," Zamore said. The problem was that the disease gene and its healthy allele are almost identical, and Zamore told Aronin that he wouldn't be able to distinguish between the two forms of Huntingtin. "Then, as he was leaving my office, it occurred to me that you could," he recalled. The key was something called a single nucleotide polymorphism or SNP.

A SNP is any place on the genetic code that varies by a single unit. The genetic code is written with four letters, A, C, T, and G, which stand for the four nucleotides, adenosine, cytidine, thymidine, and guanosine. The pattern of these nucleotides dictates which protein is encoded by a given gene. DNA in the nucleus is transcribed as messenger RNA, which leaves the nucleus and begins making proteins based on the order of these four bases. A person's two copies of any gene may vary at these locations "simply because the two parents have different ancestries," Zamore said.

Zamore, Aronin, and their collaborators decided to look for such variation in the Huntingtin gene. It was a bit of a long shot. Even if the lab found relevant SNPs, it was likely few people would share the same polymorphisms, making drug development and testing nearly -- if not completely -- impossible.

Then they got lucky. The search for SNPs in the genetic material of 109 Huntington patients uncovered a single SNP carried by 48 percent of people with Huntington's. "This SNP is actually associated with the disease
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Contact: Jennifer Michalowski
michalow@hhmi.org
301-215-8576
Howard Hughes Medical Institute
Source:Eurekalert

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