Researchers show how existing therapies may be used to treat the debilitating effects of Huntington's disease (08.29.2002)
Sitting on the shoulders of Huntington’s disease sufferers may be the angels of two UCI researchers and fruit flies.
For it is through fruit flies that collaborating researchers Professor J. Lawrence Marsh (right) of the School of Biological Sciences and Assistant Professor Leslie M. Thompson of the School of Medicine, have shown that the debilitating effects of incurable Huntington’s disease may be treated with already known anti-cancer drugs.
“Other researchers have confirmed our research in cell culture and yeast systems to show that the consequences of Huntington’s disease may be prevented by these drugs, known as HDAC inhibitors. This is causing an incredible amount of excitement in the field. People think it's the best hope we have in our hands at this moment.”
Huntington’s disease is an incurable genetic brain disorder that affects 30,000 Americans and threatens to harm another 150,000. The disorder attacks progressively, typically striking people in their prime of life. It causes uncontrolled movements, loss of intellectual capacity and severe emotional disturbances. Ultimately, it causes death.
The latest UCI research came as an outgrowth of seminars designed to promote cross-fertilization of ideas between biology and medical researchers who share an interest in genetics. Marsh, who experimented for 25 years with fruit fly genetics to explain basic biological principles, linked up originally with the late John Wasmuth and members of his human genetics lab who had an interest in Huntington’s disease. Thompson was a member of the Wasmuth lab at that time and had been involved in the identification of the Huntington’s disease gene in 1993.
When Wasmuth died, Thompson and Marsh decided to direct their research toward nerve degeneration in Huntington’s disease and together obtained funding from the Hereditary Disease Foundation to pursue these studies. In healthy cells, there is a careful balance between forces that promote genetic activity and forces that reduce it. But in victims of Huntington’s disease, the balance is upset. Marsh says it is much like an algebra problem. If you subtract three from one side of the equal sign, you must take away three from the other side to make the equation equal again. In Huntington’s disease victims, part of the forces that promote genetic activity are subtracted. The side that reduces gene activity, namely HDAC enzymes, dominates. The net result: nerve damage.
Marsh and Thompson, with Joan Steffan, an associate professor in Thompson’s lab in the College of Medicine, reasoned that if they could reestablish the equation by subtracting some of the HDAC activity, they could halt the nerve damage.
Enter the fruit fly, Dropsophila. This fly provides a unique opportunity for research testing. It is more complex than cells grown in a test tube, but not as advanced as a mouse. Yet the fly has a nervous system, a brain and many of the same processes as humans. With a life cycle of just 10 days, Marsh says, scientists can turn around several tests in a much shorter period than with mice.
“They are fast and they are cheap,” Marsh says.
So Marsh and Thompson engineered fruit flies to carry a form of the disease. They then gave flies HDAC inhibitors, which in turn prevented nerve cell damage.
The entire cell process involves a broad range of proteins, Marsh says, and he and Thompson are conducting further research to determine if they can find the exact protein or proteins affected and a better-refined inhibitor to deal with it.
“We’re testing other HDAC inhibitors and other therapeutics in the flies,” Thompson says. “We’re trying to establish a real approach to therapeutics with these flies by testing compounds from different researchers all over the world.”
What raises researchers' hopes so high is that many HDAC inhibitors are well along in advanced testing for human use in cancer chemotherapy. One used by the UCI team has passed through Phase I trials. In this phase, researchers try to determine at what level a dosage is toxic. So far, Thompson says, those researchers have continued to increase dosages without hitting a toxic level.
The next step will be limited human tests to see if the drugs produce benefits for ill people and, if successful, then a larger trial. Thompson says she thinks the advanced testing already under way could shave years off the wait to use the drugs for Huntington’s disease.
But Marsh is more cautious. While most pharmaceuticals on average require seven years of testing, Marsh says that Huntington’s disease testing could take longer.
“The effects of Huntington’s disease occur slowly over such a long period of time,” he says, “I don’t know how you can bypass the time element in human trials.”
It could take years to observe whether the drugs slow or stop the progress of the disease in affected patients, he says.
Then again, drug researchers could decide “this drug isn’t doing any harm. This is the only thing we’ve got. It’s going to take a long time to sort out, but let’s see what happens,” Marsh says. “But to prove it scientifically is not a ‘here-today-done-tomorrow’ thing.”
However, that decision will be left to clinical researchers. For Marsh and Thompson, it is back to work with the lab team of Steffan, Laszlo Bodai, Judit Pallos and others to treat flies with drugs to see what works and why, and also to cross-fertilize ideas between researchers in different schools of science to find the most productive match and novel ideas.
“People are like chemicals,” Marsh says. “They can’t react unless you put them together.”
— Alan Janson