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Delaying Huntington’s
Scientists Hope They Can Postpone the Onset of Huntington’s Disease

By Edward R. Winstead

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Beside Lake Maracaibo, Venezuela
Scientists who ten years ago tracked down the gene mutation that causes Huntington’s disease are now searching for genes that could lead to drugs that delay the onset of the disease in patients, perhaps by decades.

The next best thing to curing a fatal disease like Huntington’s may be postponing its onset. The inherited disorder is caused by a single gene and leads to the progressive loss of brain cells over time. There are currently no effective treatments for stopping its progression.

“Failing a complete and utter cure that stops the disease in its tracks, we’d like to slow it down,” says David E. Housman, a molecular geneticist at the Massachusetts Institute of Technology in Cambridge who works on Huntington’s.

The key to postponing the disease may lie with genes that help modify the precise timing of the disease. The age of onset can vary from one person to the next by as much as 30 years.

In the past few months, a series of studies has suggested that “modifier” genes can influence a person’s age of disease onset, and several gene candidates have been identified.

“If you could come up with a drug that mimics the action of one of these genes, then you’d have a proven way to delay the disease,” says Marcy E. MacDonald, a Huntington’s researcher at Massachusetts General Hospital in Charlestown.

The latest study to suggest the existence of modifier genes has just been published by the U.S.-Venezuela Collaborative Research Project, an international team of doctors and researchers who have been helping and studying a large Huntington’s community near Lake Maracaibo in Venezuela since the early 1980s.

Man from Lake Maracaibo and Nancy Wexler.
The team reports that both genes and environment influenced the ages of onset among hundreds of individuals in Venezuela, all of whom are part of the world’s largest extended family affected by Huntington’s.

According to the study, 40 percent of the variability in the age of onset was due to a gene or genes. The rest was due to environmental factors. Now the researchers have begun to search for the modifier genes as the first step in developing ways to delay the disease.

“This is exciting because Huntington’s has always been thought of as the least malleable and the most intractable of all the genetic diseases,” says Nancy S. Wexler of Columbia University in New York. Wexler founded the U.S.-Venezuela Collaborative Research Project.

The U.S.-Venezuela project includes some 18,000 people who are descendents or relatives of a woman who lived in a stilt village on Lake Maracaibo in the early 1800s. She had the disease, and her chromosome carrying the mutation has been passed through ten generations.

Over the last 20 years, the U.S.-Venezuela project has gathered detailed information, including DNA and health histories, for many of these people. The data show that two people born at the same time who have the exact same mutation may develop the disease more than 30 years apart.

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“The real strength of our study is the Venezuelan kindred,” says Wexler. “We have an enormous amount of data, and this wealth of information has allowed us to do the analysis.”

No single human gene is likely to have a dramatic effect on the age of onset, a recent study found. Rather, a number of genes spread across the genome may each contribute in a small way to the overall timing of onset.

Huntington’s typically appears between ages 30 and 40, but it has been diagnosed in children as young as 2 and adults as old as 69. The timing is determined largely but not entirely by the number of repeated DNA sequences in the mutated Huntington’s gene. Longer repeats are associated with an earlier onset of the disease.

“People thought the repeat length was the final word when it comes to age of onset, but we have shown that’s not the case,” says Wexler. “Now we need to find the modifier genes.”

The U.S.-Venezuela Collaborative Research Project. Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington’s disease age of onset. Proc Natl Acad Sci USA 101, 3498-3503 (March 9, 2004).

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