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Gene expression levels may reveal stage of Huntington's disease
August 17, 2005Markers could help track response to new therapies, protective strategies
A survey of the genome of patients with Huntington's Disease (HD) has identified potential markers of the progression of this devastating neurological disorder. Researchers from the MassGeneral Institute for Neurodegenerative Disorders (MIND) found a set of genes that are expressed at higher levels in blood samples from people with HD than in samples from controls. The expression of these genes also rose as the disease progressed from asymptomatic to symptomatic stage. The study has been published in the August 2 issue of Proceedings of the National Academy of Sciences.
"These biomarkers may be valuable in monitoring patients' response to experimental treatments," says Dimiti Krainc, MD, PhD, of MIND and the MGH Department of Neurology. "Since these changes can be seen at the earliest stages of the disease, they may be particularly helpful in evaluating neuroprotective strategies that could be applied before symptoms develop."
HD is an inherited disorder caused by a mutation in the gene for a protein called huntingtin. Although its normal function has not yet been discovered, huntingtin is essential for growth and development. The HD-associated mutation involves excessive repetition of a specific gene segment, causing an abnormal version of the protein to accumulate in the brain and destroy brain cells in an area called the striatum. Symptoms of HD, which usually begin to appear in the middle years, include uncontrolled movement, erratic emotions and problems with thinking and memory. Symptoms worsen over the 10- to 30-year course of the disorder, until patients die from a variety of complications.
Although HD appears to affect only the central nervous system, mutant huntingtin and proteins it interacts with are found throughout the body, including blood cells. This suggests that the mutation may have effects that, while not producing symptoms, could show up on a blood test. Such a test could provide a more accessible way to monitor the underlying disease process in the brain. The MGH team analyzed blood samples from patients with HD, including asymptomatic carriers of the HD mutation, and compared their gene expression patterns to those of control participants.
The researchers found hundreds of genes for which expression levels were significantly altered in HD patients or carriers, compared with controls, and then identified a set of 12 genes for which the differences were most significant. In addition, expression levels in younger presymptomatic carriers of the HD mutation were closer to those of the controls and rose to disease-associated levels in carriers approaching the age at which symptoms usually appear. The investigators then analyzed blood samples from participants in a Phase 1 trial of a potential HD treatment and found that four weeks of treatment produced a significant reduction in expression of the 12-gene set in most participants.
"We need to analyze these findings in a larger phase III clinical study where changes in gene expression can be correlated with possible delay in disease onset or progression. Moreover, further research may identify other combinations of marker genes that reflect various stages of HD and predict clinical effects of new experimental treatments," says Krainc. He also notes that the identified 12-gene set is only one potentially useful biomarker, and others of the hundreds of genes with altered expression may also provide critical information in various clinical situations. Krainc is an assistant professor of Neurology at Harvard Medical School.
Massachusetts General Hospital
HD is an inherited disorder caused by a mutation in the gene for a protein called huntingtin. Although its normal function has not yet been discovered, huntingtin is essential for growth and development. The HD-associated mutation involves excessive repetition of a specific gene segment, causing an abnormal version of the protein to accumulate in the brain and destroy brain cells in an area called the striatum. Symptoms of HD, which usually begin to appear in the middle years, include uncontrolled movement, erratic emotions and problems with thinking and memory. Symptoms worsen over the 10- to 30-year course of the disorder, until patients die from a variety of complications.
Although HD appears to affect only the central nervous system, mutant huntingtin and proteins it interacts with are found throughout the body, including blood cells. This suggests that the mutation may have effects that, while not producing symptoms, could show up on a blood test. Such a test could provide a more accessible way to monitor the underlying disease process in the brain. The MGH team analyzed blood samples from patients with HD, including asymptomatic carriers of the HD mutation, and compared their gene expression patterns to those of control participants.
The researchers found hundreds of genes for which expression levels were significantly altered in HD patients or carriers, compared with controls, and then identified a set of 12 genes for which the differences were most significant. In addition, expression levels in younger presymptomatic carriers of the HD mutation were closer to those of the controls and rose to disease-associated levels in carriers approaching the age at which symptoms usually appear. The investigators then analyzed blood samples from participants in a Phase 1 trial of a potential HD treatment and found that four weeks of treatment produced a significant reduction in expression of the 12-gene set in most participants.
"We need to analyze these findings in a larger phase III clinical study where changes in gene expression can be correlated with possible delay in disease onset or progression. Moreover, further research may identify other combinations of marker genes that reflect various stages of HD and predict clinical effects of new experimental treatments," says Krainc. He also notes that the identified 12-gene set is only one potentially useful biomarker, and others of the hundreds of genes with altered expression may also provide critical information in various clinical situations. Krainc is an assistant professor of Neurology at Harvard Medical School.
Massachusetts General Hospital
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