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Hereditary Disease Foundation Scientists Find Possible Treatment For Huntington's Disease

UC Irvine Researchers Show for the First Time How Existing Therapies May Arrest and Prevent Nerve Damage in Incurable Genetic Brain Disorder

Irvine, Calif. - Discoveries by a UC Irvine team - supported by the Hereditary Disease Foundation - may lead to the first treatment for Huntington's disease, a fatal, hereditary brain disorder. Reporting in the October 18th issue of the journal Nature, the team announced that they had successfully prevented cell death in a Drosophila fruit fly model they created carrying the HD gene. Most promising of all, the pharmaceuticals they used to protect the fly eye are currently in clinical trials for treating cancer in humans. Already approved by the Food and Drug Administration for research in a human population, these drugs could rapidly be used in clinical trials for Huntington's disease and other similar progressive, neurodegenerative disorders. Huntington's disease affects more than 100,000 people in the United States. Thirty-five thousand individuals are symptomatic and another 75,000 people carry the abnormal gene and will definitely manifest the disease in the future. Preventing the disorder before a person shows symptoms is probably the most effective treatment possible. The Irvine team achieved this result in their flies.

Leslie Thompson and Joan Steffan of the College of Medicine, Lawrence Marsh of the School of Biological Sciences, and colleagues studied the genetic and molecular interactions in the disease and found that chemicals called histone deacetylase (HDAC) inhibitors might counteract the course of Huntington's and possibly other progressive, neurological disorders. The scientists found that HDAC inhibitors curbed neuronal degeneration caused by the genetic mutations that lead to Huntington's disease.

This study indicates that HDAC inhibitors, currently in clinical trials for cancer chemotherapy, may be effective treatments for Huntington's disease.

Huntington's disease is caused by a genetic mutation. Since the mutated gene causes what scientists call a dominant disease, a child with one parent who carries the gene runs a 50 percent chance of getting Huntington's disease. The disorder is progressive, and typically strikes individuals in the prime of life, between 35-50 years of age. Twenty percent of people who have the disease manifest symptoms when they are younger than 20 or older than 60 years of age. If you inherit the abnormal gene - the disease will definitely appear. It causes uncontrolled movements, loss of intellectual capacity and severe emotional disturbances. It inevitably results in death, after a ten to twenty year course, without remission. It has been described in medical literature under a host of different names since the Middle Ages.

The famous American folk singer and composer Woody Guthrie died in 1967 after suffering from Huntington's disease for thirteen years.

"While there is presently no cure for Huntington's disease, we believe we have traced one way that the mutation alters chemical pathways to cause the disease," Thompson said. "By reversing key changes in these pathways, we have identified a potentially effective way to slow or prevent the disease. What's especially exciting is that existing drugs known as HDAC inhibitors have the potential to provide this treatment."

The researchers found that the mutant form of the protein called "huntingtin" - or htt - which results from genetic changes causing Huntington's disease, inhibits the actions of several other proteins whose normal function is essential for normal brain cells. The mutated form of huntingtin stifles the activity of key enzymes called acetyltransferases (ATs). The huntingtin protein reduces the levels of these acetyltransferases and related proteins, resulting in the nerve cell damage seen in the diseased brain.

Cells in our body normally maintain a balance between the opposing forces of AT enzymes that modify proteins to increase genetic activity and HDAC enzymes that reverse these modifications to reduce gene activity. Since the mutated huntingtin protein destroys this balance, the researchers sought to restore the balance by reducing the HDAC activities to compensate. The HDAC inhibitors were able to prevent neuronal damage in fruit flies that were engineered to carry a disease-producing form of human huntingtin.

"While presently we can't eliminate the genetic mutation that ultimately causes Huntington's disease, this study indicates that we may be able to reduce significantly the effects of that mutation," Marsh said. "Our study also points the finger at a complex of genes and tells us what we need to do next. Perhaps we can find even better and more precisely targeted strategies to help this disease. If this strategy proves effective in other animals such as mice, we will still need to know when to administer such a drug, how to administer it and what the long-term side effects may be."

Thompson and Marsh have collaborated for years on projects funded by the Hereditary Disease Foundation, working on unlocking the causes of and finding effective treatments for Huntington's disease and other progressive, neurological disorders.

"We are extremely excited by these dramatic findings that could have immediate therapeutic relevance," said Dr. Nancy Wexler, President of the Hereditary Disease Foundation.

Their colleagues in the study, in addition to Steffan, include Laszlo Bodai, Marnix Poelman, Barbara Apostol, Emily Schmidt, Ya-Zhen Zhu and Marilee Greenwald of UCI, Alexander McCampbell of the National Institute of Neurological Disorders and Stroke, Alexey Kazantsev and David Housman of the Massachusetts Institute of Technology, Riki Kurokawa of UC San Diego and George R. Jackson of UCLA. In addition to the primary support from the Hereditary Disease Foundation, support came from the Huntington's Disease Society of America, Human Frontier Science Program and the National Institutes of Health.

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