Study Could Lead Way to Preventing Progressive Neurological Disorder

Irvine, Calif., April 8, 2002 -- A protein developed in the laboratory halts the progression of Huntington's disease in fruit flies, a study by UC Irvine and MIT has found.

The study is the first to identify a man-made protein that can stop the development of the disease, and it may help researchers find effective ways to use gene therapy to prevent--or halt--the disease. The study appears in the April issue of Nature Genetics.

Leslie Thompson, assistant professor of psychiatry in the College of Medicine, and Larry Marsh, professor of developmental biology in the School of Biological Sciences, along with Alex Kazantsev and David Housman at MIT, created a protein that binds tightly to another, mutated protein called Htt, which is produced by the genetic changes that cause Huntington's disease. Htt is known to lead to degeneration of nerve cells.

"This study shows us that synthetic proteins can effectively halt the development of this disease," Thompson said. "We believe that assuming gene therapy can be effective in this case, it may be useful to insert genes for this synthetic protein or others like it to help stave off Huntington's disease. It also proves that inhibiting protein interactions that lead to the formation of 'clumps' in neurons, a hallmark of Huntington's and other neurodegenerative diseases, may be an effective therapy."

Huntington's disease is a progressive disorder in which cells in the central nervous system degenerate. It affects about 30,000 people in the United States; another 150,000 are at risk for the disease. The disease is genetic, caused by a mutation or genetic change. This change results in altered structures of the mutant protein coded for by this gene, which results in nerve cell death. The mutation is dominant, so a child with one parent who carries the mutated gene has a 50-50 chance of getting the disease.

The researchers inserted into cells that had the HD genetic mutation a gene that was coded for an artificial protein. The inserted gene caused a reduction in the levels of the lethal Htt protein that leads to Huntington's disease and a reduction in "clump" formation prevalent in diseased nerve cells. Once produced, the proteins also halted the degeneration of nerve cells in the fruit flies' eyes. When the Htt suppressor gene was successfully inserted into flies expressing the mutant gene that causes Huntington's, it appeared to disrupt the molecular interactions that lead to the disease.

"The suppressor protein appeared to bind to the mutant Htt protein. This binding reduced the ability of Htt to cause nerve damage and appeared to disrupt the accumulation of the mutant protein," Marsh said. "This way, less of the pathological form of the protein was present."

Gene therapy would be one means for this protein to successfully combat the disease, because Htt would have to be blocked in all the nerve cells affected by the disease. Scientists have encountered, however, a number of obstacles to gene therapy, including problems with finding suitable delivery of the beneficial genes into cells, and other changes in the cell's biology that occur after the gene has been inserted. However, gene therapy is an area of intense research.

"This study helps focus on finding synthetic drugs or other chemicals that can disrupt the accumulation of Htt and may be readily administered using more traditional medical techniques, instead of gene therapy," Marsh added. "We have some reason to hope that such chemicals may halt the disease's progress."

Thompson, Marsh and their colleagues have spent the last several years investigating the genetic basis for, and possible treatments of, Huntington's disease. In October 2001, the team announced that HDAC inhibitors, which are experimental drugs now in clinical trials for cancer chemotherapy, appeared to arrest nerve damage in flies that developed the disease.

The researchers' work was supported by the Hereditary Disease Foundation, the Human Frontiers Science Program, the Leukemia and Lymphoma Society, the Sierra Foundation and the National Institutes of Health.

Thompson and Marsh's colleagues in the study included Aleksey Kazantsev, James Bear, Frank Gertler, David Housman and Elizabeth Preisinger of MIT, and Joan Steffan, Natalia Slepko, Heli Walker and Ya-Zhen Zhu of UCI.

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