THURSDAY, MAY 20, 1999
Hope in Brain-Disorder Fight / Tests yield Huntington's clues By Robert Cooke. STAFF WRITER
New experiments in mice are yielding the first good evidence that symptoms can be delayed and lives prolonged in the dreadful brain disorder called Huntington's disease, scientists in Boston said yesterday. Based on work with genetically engineered animals, scientists found that blocking the activity of an enzyme called caspase-1 slows the onset of symptoms, and allows the animals to live about 25 percent longer. The enzyme is involved in killing brain cells. The results also hint that similar neurological disorders - Alzheimer's disease and Parkinson's disease - may benefit from the same enzyme-blocking approach, the researchers said. "In a disease that has no treatments whatsoever, we've identified the pathway" that leads to the death of brain cells, said neurosurgeon Robert Friedlander, at the Harvard School of Medicine. "And if we block the pathway, we can slow down disease progression." Although so far the results apply only to mice, they are important because "this is the first time anything has worked to improve the symptoms of Huntington's disease," said Dr. Nancy Wexler, president of the Hereditary Disease Foundation, and a faculty member at Columbia University. One experiment involved crossbreeding two genetically engineered strains of mice. This eliminated the enzyme, caspase-1, in mice that were designed to get a disorder mimicking Huntington's disease. Without caspase-1, the symptoms took longer to begin and the animals survived longer. Similar results were obtained by pumping a chemical compound into engineered animals' brains, also blocking activity of the caspase-1 enzyme, easing disease symptoms. So the two complementary experiments indicate such research is on the right track. Equally important, the same enzyme - or family of enzymes - seems to be involved in other neurological disorders where the death of brain cells is the central problem. These include Alzheimer's disease, Parkinson's disease, ALS (amyotrophic lateral sclerosis), strokes, and even head injuries. All of them are caused, or worsened, by the death of cells in the brain. The new research indicates, Wexler said, "that they all have similar mechanisms, that they are killing brain cells in similar ways." It may mean, in fact, that regardless of the insult involved, responses such as inflammation may be similar in all these forms of brain injury, and that the cells are dying because of the same mechanism, called apoptosis. The term apoptosis refers to a built-in suicide system that sick cells seem to use if they're damaged beyond repair. Apoptosis - programed cell death - is probably a safety mechanism that is important, for example, in killing cancer cells so they can't grow to form a tumor. The new results were reported by Friedlander and his colleagues yesterday in the journal Nature. The next step, he added, is to seek safe drugs that eventually might be used by people to block abnormal cell death in the brain. "Now we need to find a candidate drug that would be tolerable," he said. Huntington's disease afflicts about 30,000 people in the United States, and is the disorder that killed folk singer Woody Guthrie. Anyone who inherits the damaged gene gets the disease. Symptoms usually begin after age 35, and include jerky, uncoordinated muscle movements, dementia, facial grimacing, difficulty in swallowing and speaking, and eventually death. There are no treatments, but carriers of the faulty gene can now be identified via genetic testing. Although the engineered mice don't exactly mimic Huntington's disease as seen in humans, the new findings are "extremely important," said biologist Ethan Signer, executive director of the Cure H-D Initiative, an arm of the Hereditary Disease Foundation. "It's the first time such a large amelioration of symptoms has been achieved by providing a small-molecule compound" as a potential treatment. According to Wexler, "What's really spectacular about this finding is that it does two things: First, it gives us an entirely new direction for developing therapies. Second, it's a new explanation for what's going wrong" to kill brain cells. "This immediately gives us new avenues to try" in the search for treatments, Wexler added. "It's something that opens our eyes in a very biologically important way." Wexler explained that the experiment "uses a mouse that has the human gene, our own gene, and it also uses a mouse that doesn't have the caspase gene. And when you cross the two you have protection." The Hereditary Disease Foundation provided some of the funding that supported Friedlander's research at Harvard. Wexler has a vital interest in the foundation, and in Huntington's disease, because it's known to be in her own family. The gene that causes Huntington's disease makes a protein called huntingtin, which plays an unknown role in the brain's physiology.
Copyright 1999, Newsday Inc.
Hope in Brain-Disorder Fight / Tests yield Huntington's clues., pp A06.