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Scientists Identify Potential New Treatment for Huntington's Disease

For release: Wednesday, February 27, 2002

A drug called cystamine alleviates tremors and prolongs life in mice with the gene mutation for Huntington's disease (HD), a new study shows. The drug appears to work by increasing the activity of proteins that protect nerve cells, or neurons, from degeneration. The study suggests that a similar treatment may one day be useful in humans with HD and related disorders.

Previous studies have identified several other drugs with potential for treating HD. However, cystamine appears to work differently than those drugs, and it may add to the benefits of other therapies if it is used in combination with them, says senior author Lawrence Steinman, M.D., of Stanford University in California. The study was supported by the National Institute of Neurological Disorders and Stroke (NINDS) and the Hereditary Disease Foundation. It appears in the February 2002 issue of Nature Medicine.

In HD, a defective gene produces an abnormal form of a protein named huntingtin. This abnormal protein triggers a process that kills neurons in a brain region called the corpus striatum and leads to the symptoms of the disorder. The abnormal protein aggregates, or clumps together, inside many kinds of neurons. Some researchers believe these clumps contribute to the problems seen in HD, although it is not yet clear if this is the case. Previous studies have found that cystamine inactivates an enzyme called transglutaminase which helps create the clumps of huntingtin protein.

In the study, lead scientist Marcela Karpuj, Ph.D., and colleagues injected cystamine into mice with an abnormal huntingtin gene. The mice that received the drug had fewer tremors and other abnormal movements and less weight loss than the untreated mice. They also lived about 20 percent longer. However, cystamine did not reduce the number of huntingtin clumps found in the brain.

Using gene chips, which can analyze the activity of many different genes at once, the researchers identified two genes that had increased activity in the mice treated with cystamine, as well as in brain tissue collected during autopsies of HD patients. A third, related gene had increased activity in HD patients but not in mice. Previous studies have shown that the proteins produced by these genes protect brain cells from damage. The presence of these proteins in brains of HD patients who were not treated with cystamine may result from a natural attempt at recovery that ultimately failed, the researchers say.

Cystamine may be able to stop huntingtin clumps from forming, even though it does not destroy clumps that are already there, says Dr. Steinman. If so, treatment earlier in the disease process may be able to prevent the clumps entirely. In addition, the protective proteins that increase with cystamine treatment may be able to disarm errant huntingtin proteins before they cause damage. For example, a recent study showed that the abnormal huntingtin protein interferes with another protein called CBP that is crucial for cell survival.

While these findings may lead to a new way of treating HD, they also may be relevant to other disorders, such as the spinocerebellar ataxias and spinobulbar muscular atrophy (SBMA), which have the same type of gene defect and the same kind of protein clumps as HD. The protective proteins identified in this study have also been found in several of these related diseases.

Cystamine is closely related to another drug called cysteamine that is approved to treat a kidney disease called cystinosis in humans. Researchers at Massachussetts General Hospital in Boston are now planning a clinical study of cysteamine for Huntington's disease. In addition, several other substances, including the antibiotic minocycline and the dietary supplement creatine, are currently being tested in clinical trials for Huntington's disease.

Reference: Karpuj MV, Becher MW, Springer JE, Chabas D, Youssef S, Pedotti R, Mitchell D, Steinman L. "Prolonged survival and decreased abnormal movements in transgenic model of Huntington's disease, with administration of the transglutaminase inhibitor cystamine." Nature Medicine, February 2002, Vol. 8, No. 2, pp. 143-149.

- By Natalie Frazin


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Last Modified January 28, 2016