Huntington's Disease Study Offers New Hope

By Robert Cooke
STAFF WRITER
From Newsday, November 20, 2001

FIRST HINTS that something can be done to defeat the inherited brain disorder called Huntington's disease are coming from experiments in fruit flies, scientists report.

By tinkering with the genes in flies, researchers have created creatures that show some symptoms of the devastating human disease. As a result, they've also found a potentially useful treatment - at least in fruit flies. The next step is to take the treatment into mammals, mutant mice, to see how it works.

"We're extremely excited about these dramatic findings," said Dr. Nancy Wexler, president of the Hereditary Disease Foundation, which supported the research. She said the new work "could have immediate therapeutic relevance," because it uses drugs that are already available.

Huntington's disease is an inherited disease currently afflicting about 25,000 people in the United States, with 75,000 more people destined to get the disease because they have the deadly mutation. Those who are susceptible usually live normal lives until about age 40, and then go into inexorable decline as the brain deteriorates. Death often comes before age 50.

Symptoms include gradual loss of muscular control, psychological disturbances, loss of mental capacity, and eventually death. So far, there has never been a useful treatment, and certainly no cure. But genetic testing can identify people who have inherited the mutant gene, so with a 50 percent chance of passing on the disease, they can at least decide whether to have children.

The new research work was done at the University of California, Irvine, where Dr. Leslie Thompson and her colleagues succeeded in slowing or stopping nerve damage, and in preventing the flies' deaths, even though the insects had the fatal mutation. Use of the drugs seems to restore a sort of balance between systems that turn genes on and off within nerve cells.

Research had already shown that the disease arises because a mutation causes production of an abnormal protein, huntingtin. Now it seems that this odd protein gets into the cell's nucleus, where it interferes with the normal system for reading genes. Without the ability to use its genes and continue normal metabolism, the cell soon gives up and dies.

The new findings, published recently in the journal Nature, suggest that the defective protein, huntingtin, may act like a glue-ball set among the cell's genes. As huntingtin accumulates inside the nucleus, it sops up various enzymes needed for gene-reading. And as these enzymes disappear, gene-reading grinds to a halt.

That in itself is an exciting idea, the scientists said. The gradual accumulation of enzymes on protein, and the gradual die-off of nerve cells, might explain why it usually takes 35 years or more before disease symptoms appear. Perhaps it takes that long for enough huntingtin to accumulate and do its lethal damage.

In the past two decades, biological research has succeeded in showing exactly what goes wrong to make the protein, huntingtin, so abnormal. Within the gene that makes the protein there's a stretch of repeating signals, called triplet repeats. The protein functions properly if the triplet repeat section of gene is not too long. For example, if the number of repeats is below 38, then life is normal. But if there are 40 or more repeats, then Huntington's disease ensues.

In fact, research has shown that the longer the repeat section is - even into the hundreds of repeats - then the sooner in life the disease strikes. Some people even see symptoms before age 20.

These repeats involve three specific sets of genetic chemicals in the gene, telling the cell to insert the amino acid glutamine into the protein. When these triplets are strung together, they read CAG-CAG-CAG-CAG, building up what is called a polyglutamine molecule. The fatal error occurs when the polyglutamine molecule gets too big - because there are too many CAG repeats in the gene - and the result is Huntington's disease.

What has been missing from this scenario, however, is what the extra-long protein does that leads to the disease. Now, that seems to be coming into focus.

According to Thompson and her colleagues, the misformed huntingtin molecule, the sticky protein, grabs on to several key enzymes called histone deacetylase, which help regulate gene expression. Once the enzymes are out of action, proper use of the genes is disrupted, or unbalanced, leading to sickness and death.

Having found that, Thompson and her colleagues began asking how the balance might be restored. They knew that several drugs, called histone deacetylase inhibitors, are already in use for cancer treatments. So they tried these same drugs in the mutant fruit flies, hoping to restore the balance and keep the nerve cells alive.

Indeed, their tests in the mutant fruit flies showed that the inhibiting drugs were able to halt the nerve cell damage, saving the cells from death, and allowing the mutant flies to live longer.

Thompson's co-worker at Irvine, Lawrence Marsh, noted that "if this study proves effective in other animals, such as mice, we will still need to know when to administer such a drug, how to administer it, and what the long-term side effects may be."