SCIENCE / MEDICINE : ‘We have not put all of our eggs in one basket’ : The Hunt for the Huntington’s Disease Gene
While the children of Huntington’s disease victims live with the fear that they will suffer the same terrible fate as their parents, scientists are struggling to find a way to treat the incurable disease.
Although some of the trembling and depression caused by Huntington’s disease can be alleviated with drugs, there is no way to halt the deterioration that killed folk singer Woody Guthrie.
But researchers believe that they will eventually find the gene that causes the disease, unlocking much of the mystery surrounding it. A new class of drugs is raising some hopes.
“Within the past eight years we’ve gone from knowing virtually nothing about (this disease) to at least localizing where the gene sits on the chromosome and knowing a tremendous (amount) more about the chemistry in the brain,” said Dr. Anne Young, a professor of neurology at the University of Michigan in Ann Arbor.
Cell Death
The disease is caused by the death of cells in a part of the brain known as the striatum, which controls muscles and thought. The striatum consists of sections that sit on each side of the brain called the caudate and putamen.
Researchers have long known that the disease, named after Dr. George Huntington because of his detailed 1872 description, is triggered by a genetic defect that is inherited.
In 1983, an international team of scientists found the approximate location of the culprit gene on chromosome 4, creating excitement that the gene itself might be found. Scientists believe that finding the gene will enable them to determine its function, figure out what kills brain cells and devise treatments accordingly.
Researchers at Massachusetts General Hospital in Boston and elsewhere have been working steadily since then to find the gene by examining more samples of genetic material from people in families with a history of the disease.
They have found more variations--or markers--that are inherited with the gene. These have made possible a test to determine whether someone has inherited the gene and have brought researchers closer to finding the gene itself. Last month, UC Irvine researchers reported finding a marker that lies so close to the disease gene that the two are almost always inherited together.
Even after the gene has been located, however, determining its function and developing genetically oriented treatments will take years. Because of that, some researchers are pursuing other approaches to treatment.
“We have not put all of our eggs in one basket,” said Dr. Richard Myers, a geneticist at the Boston University School of Medicine and Massachusetts General Hospital.
Dr. Flynt Beal and his colleagues at Massachusetts General reported in 1986 that cells killed in Huntington’s disease may die by over-excitation of activation points, known as n-methyl d-aspartic acid (NMDA) receptors.
Researchers speculate that the disease may be caused by excess amounts of substances that activate brain cells through NMDA receptors. Because there is too much of one or more of these normally harmless substances, cells are literally stimulated to death, this theory holds. Such substances include the neurotransmitter glutamate and a related substance known as quinolinic acid.
Other possibilities are that Huntington’s disease victims may have lower-than-normal levels of other substances that block these excitatory substances or that they may have oversensitive NMDA receptors.
Drug to Block Receptors
Regardless, researchers believe that they may be able to halt the cell death if they can find a drug that blocks the NMDA receptors.
“It doesn’t matter what the bottom line cause is. If the bottom-line end-state is an excessive activation, if you can block it, you can treat it,” Beal said.
Several drugs could be effective, including one known as MK-801, which has appeared promising in animal studies, and another substance known as dextrorphan.
“I’m sure there will be a number of other compounds coming along shortly,” said Beal, an associate professor of neurology at Harvard Medical School.
Huntington’s disease researchers plan to meet in Ann Arbor this month to discuss which drugs offer the most potential and how best to test them.
But Beal and other researchers cautioned that these drugs could produce intolerable side effects, such as hallucinations, and much more research is needed before they may become available.
“The last thing in the world I want to be guilty of is raising false expectations,” said Dr. Dennis Choi, an assistant professor of neurology at Stanford University School of Medicine.
Young has also been studying the effect of heroin-addiction treatment with methadone in 14 Huntington’s patients. Methadone also blocks NMDA receptors, Young said. The study is about half completed, and it is too early to evaluate its effectiveness, she said.
The only other drug that has progressed as far as clinical trials patients is baclofen, which blocks glutamate. Dr. Ira Shoulson of the University of Rochester has tested baclofen on 60 Huntington’s disease patients, but the results have not been released.
Meanwhile, Dr. George Allen grafted pieces of tissue from the adrenal gland of a 41-year-old Huntington’s disease patient from Tennessee into the affected part of his brain for the first time at Vanderbilt University in Nashville on March 1.
A spokesman said it is too early the evaluate the operation, which has shown promise for Parkinson’s disease.
BRAIN AREA AFFECTED BY HUNTINGTON’S DISEASE Huntington’s Disease is caused by the death of cells in a part of the brain that controls muscles and thought. The cell death occurs in sections that sit on each side of the brain, the caudate nucleus and putamen. Brain is shown in cross-section, as viewed from the rear.
