HD research news - medical research into treatment & prevention

A new lead in the quest for treatment

by Robert Cooke - Staff Writer

Surprising new evidence that the disastrous brain disorder called Huntington’s disease may be treatable, and even reversible, is being seen in genetically engineered mice, scientists report.

By inserting a special gene that can be turned on and off as needed, researchers at Columbia University have shown they can cause the disease symptoms in animals, then stop the brain damage and finally see the damage get repaired.

The possibility of repair was wholly unexpected and ranks as a major surprise in brain science. It is not yet clear that the same can be done in people, but it offers the first clues that inheriting Huntington’s disease may not remain an inevitable death sentence.

Extremely Exciting

"This is extremely exciting," said biologist Ethan Signer, executive director of the Cure HD Initiative.

In their report in the journal Cell, neurobiologists Rene Hen, Ai Yamamoto and Jose Lucas described how they created mice with a Huntington’s-like disorder, how they turned the mutant gene off after disease symptoms appeared and how the brain damage was gradually repaired.

"We find that abolishing expression of the mutant protein not only halts progression of the disease but can reverse aggregate formation and progressive motor decline," the researchers wrote.

What they saw, and what was so unexpected, was that accumulated globs of abnormal protein gradually disappeared from the damaged brain regions, once production of the abnormal protein was shut off. This suggests that continuous production of the damaging protein is needed to cause the disease.

Earlier tests had indicated that the clumps, called inclusions, are very difficult to dissolve. But the new experiments indicate that living brain cells do have a way of getting rid of the inclusions.

250,000 Americans at risk

Huntington’s disease is a threat to about 250,000 Americans who either have it now or are at risk of having inherited a copy of the faulty gene. Anyone who inherits even one copy of the damaged gene gets the disease. The risk of inheriting the mutant gene from a parent who carries it is 50 percent.

As yet nothing can be done about the disease in humans, but genetic tests have been devised that can show who carries the mutant gene and who will get the disease. That information is of little use to those with the gene, although it can help with family planning to avoid passing the gene on to another generation.

The symptoms of Huntington’s disease include gradual loss of muscular control, shown by spasmodic, jerky movements, personality changes, loss of mental capacity and early death. Symptoms are usually not seen until after age 35, however.

Signer, a Professor of Biology Emeritus at the Massachusetts Institute of Technology, said the new findings are especially encouraging "because it means if and when we succeed in identifying a drug therapy, the prospect is not only that we might halt progression of the disease but even be able to reverse it." Neurobiologist Peter Davies, at the Albert Einstein College of Medicine in the Bronx, said of Hen’s report:

Raises hope

"That’s fantastic. It raises enormous hope for the patients and for their families, that we may be able to do something about Huntington’s disease. It’s a beautiful piece of work, very elegant." Although the genetically engineered mice do not perfectly mimic Huntington’s disease as seen in humans, they do exhibit the abnormal behaviour, and parts of the brain called the striatum and the cortex do get burdened with inclusions, as in the human disorder. So as experimental models, the animals are extremely useful.

The protein inclusions, which were discovered only three years ago, are made of a substance called polyglutamine, which is made by the mutant gene. The gene mutation itself is unusual, in that it is an expansion of a normal, healthy gene. In its healthy form, the HD gene makes a protein called huntingtin, which performs some unknown but necessary function in normal cells.

Part of the huntingtin protein consists of so-called CAG repeats, chunks of the same amino acid lined up in a row. The healthy version contains six to 34 such repeats, while the protein causing Huntington’s disease contains more than 40 CAG repeats. Research has shown that the larger the protein is, extending even into the hundreds of repeats, the more severe the disease, and the earlier the symptoms begin.

Almost everyone has fewer than 34 CAG repeats and faces no danger. But those who inherit more than 40 repeats encounter the onset of the disease, first known as Huntington’s chorea.

As it has now turned out, the excess CAG repeats, put in place by the faulty gene, somehow ruin huntingtin’s function. This seems to occur because the aberrant protein accumulates in certain parts of the brain such as the striatum and the cortex, disrupting function.

Numerous experiments

Numerous experiments have been done in which mice were engineered to have excessively long sets of CAG repeats. In general, they have all exhibited the behavioural and tissue changes seen in Huntington’s disease. But Hen’s team went a step further, creating a "conditional mutant" version of the huntingtin gene that was activated by feeding the animals an antibiotic, tetracycline. Mice that got the drug in their diet also got the disease.

What Hen and his colleagues did was give tetracycline long enough to ensure the mice got the brain-damaging disorder. Then they shut the gene off by withdrawing tetracycline and watched to see what happened. To their surprise, once the abnormal protein was no longer being made, the damaging "inclusions" disappeared, and the abnormal behavior was less pronounced.

• With thanks to the Hereditary Disease Foundation for this article.