Pharmaceuticals currently used to treat cancer and other diseases may be successful for treating Huntington's disease, a UC Irvine research team has found.
If further research proves that this approach is effective in humans, the study--conducted on Drosophila fruit flies--may lead to the first treatment for the disease. Huntington's disease is an incurable genetic brain disorder that affects 30,000 people in the United States; another 150,000 people are at risk for the disease. The study appears in the Oct. 18 issue of the journal Nature.
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 discovered that chemicals called HDAC inhibitors might counteract the course of Huntington's and possibly other progressive neurological disorders. The scientists found that HDAC inhibitors curbed the neuronal degeneration caused by the genetic mutations that lead to Huntington's disease.
The study indicates that HDAC inhibitors, currently in clinical trials or approved 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. More rarely, symptoms can appear in childhood. It causes uncontrolled movements, loss of intellectual capacity and severe emotional disturbances. It eventually results in death. The disease has been described in medical literature under a host of different names since the Middle Ages.
Most notably, the American folk singer and composer Woody Guthrie died in 1967 after suffering from the disease for 13 years.
"While there is presently no cure for Huntington's disease, we believe we have traced one way that the mutation changes chemical pathways to cause the disease," Thompson said. "By reversing the 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 Htt, or "Huntingtin," that results from genetic changes causing Huntington's disease inhibits the actions of several other proteins whose normal function is essential for brain cells. The mutated form of Huntingtin stifles the activity of key enzymes called acetyltransferases. Reducing the levels of these acetyltransferases and related proteins results in the nerve damage seen in the diseased brain.
Cells in the body normally maintain a balance between the opposing forces of acetyltransferase 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 HDAC activities to compensate. The HDAC inhibitors were able to prevent neuron 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 significantly reduce the effects of that mutation," Marsh said. "This 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.
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.