Scientists Find Gene’s Trigger in Gehrig’s Disease
UCLA and La Jolla Cancer Foundation scientists believe they have solved the mystery of how a defective gene causes the inherited form of Lou Gehrig’s disease, a discovery that is expected to lead swiftly to trials of new experimental therapies for the devastating disorder.
The researchers traced the problem to overactivity of the copper-containing enzyme produced by the defective gene. This overactivity, in turn, leads to the death of nerve cells in the brain and spinal cord that control muscle movement, Dr. Dale E. Bredesen of the cancer foundation and his colleagues report today in the journal Science.
Certain medications--some already approved by the Food and Drug Administration for other uses--appear capable of halting this degenerative process by binding to the copper in the enzyme, the scientists said.
Researchers are testing the drugs in mice bearing the defective gene and are gearing up to test them in humans if the mouse studies are successful.
The disorder, known clinically as amyotrophic lateral sclerosis, or ALS, strikes 30,000 people each year in the United States and there are few effective treatments.
“This is another important step in helping us to understand the pathogenesis of this terrible disease,” said Robert Abendroth, chairman of the Research Committee of the ALS Assn. in Woodland Hills. “Dr. Bredesen’s answer is particularly significant because of its long-range therapeutic implications.”
“The most important thing we need to gain is an understanding of the relationship of the [mutant] gene to the disease itself,” said Donald S. Wood, director of science technology for the Muscular Dystrophy Assn. Bredesen’s discovery “doesn’t yet answer that question definitively . . . but it does give us a sense that we are on the right track. If solid evidence comes up to support his conclusions, then we’ll see some real excitement.”
ALS strikes about one in every 100,000 people worldwide. The ALS-triggered nerve cell death produces muscle weakness and paralysis. Most ALS victims die within two years after the disorder’s onset, but some live much longer.
ALS occurs in two forms. Hereditary or familial ALS, in which a defective gene is passed down through a family, accounts for about 10% of cases. The sporadic form, which does not run in families and whose cause is unknown, accounts for the remaining 90%.
About three years ago, researchers discovered that the familial form of the disease is caused by a mutation in the gene that is the blueprint for a protein called superoxide dismutase, or SOD1. The same gene that causes the familial form is now known to be responsible for at least a quarter of the sporadic cases.
SOD1 is an enzyme that clears certain types of toxic wastes, called superoxides, from the body. Researchers immediately assumed that the mutant gene could no longer do this, and that the accumulation of superoxides caused the death of neurons characteristic of ALS.
Two years of intensive research in several laboratories showed that this is not the case. Instead, it has become clear that the mutant gene has picked up a deadly new function.
Bredesen and chemist Joan S. Valentine of UCLA knew that SOD1 had a secondary, less desirable activity--adding oxygen to molecules in the cell, causing the molecules to break down. In healthy people, this so-called peroxidase function is outweighed by the benefits of the destruction of superoxides.
When the team studied this secondary effect in cells containing the mutant enzyme, Bredesen said, “lo and behold, [the peroxidase activity] was increased dramatically.”
They then tried blocking the activity. Since SOD1 only works in the presence of atoms of copper, the researchers tied up copper atoms with so-called chelating agents. These drugs, which are used to treat accidental copper poisoning from industrial or household chemicals, reduced the death of cells containing the mutant gene by 30% to 70%. Moreover, they had no effect on cells containing normal SOD1.
At least two laboratories are testing the chelators in mice that have mutant SOD1 and develop ALS, Bredesen said. “If these tests are successful, we’ll see clinical trials in humans fairly soon.”
But he cautioned that the chelating agents can be toxic in high doses, and warned against doctors prescribing them before tests are completed. “I would be very, very cautious about suggesting to anybody that they go out and buy these things.”
Although the new research so far applies only to the familial form of ALS, experts are optimistic that it will eventually provide insight into the sporadic form as well. “Pathologically, the sporadic and familial forms are identical,” Bredesen.
The one drug approved for treating ALS, riluzole, equally helps people with both types of the disease, he noted.
“In all likelihood, there is a common biochemical pathway” between the two forms, even if they have a slightly different cause. A new treatment that works for one form, scientists reason, may work for the other.
“People are fairly optimistic,” Wood added, “that if we continue to pursue the research here, we’re going to get answers to a lot more than just the familial cases of ALS.”
