Gene expression levels may reveal stage of Huntington's disease

Main Category: Huntingtons Disease
Article Date: 18 Aug 2005 - 13:00 PDT

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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.

The study's co-lead authors are Fran Borovecki, MD, PhD, Luca Lovrecic, MD, and Jessica Zhou, BS, of MIND and MGH Neurology. Other co-authors are H. Jeong, MS, Florian Then, MD, Herminia Rosas, MD, Steven Hersch, MD, PhD, and Berengere Bouzou, PhD, of MIND; Penelope Hogarth, MD, Oregon Health & Science University; and Roderick Jensen, PhD, University of Massachusetts, Boston. The study was supported by grants from the National Institutes of Health, the High Q Foundation, the Huntington's Disease Society of America and the U.S. Public Health Service.

Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $450 million and major research centers in AIDS, cardiovascular research, cancer, cutaneous biology, medical imaging, neurodegenerative disorders, transplantation biology and photomedicine. In 1994, MGH and Brigham and Women's Hospital joined to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups, and nonacute and home health services.

Sue McGreevey
smcgreevey@partners.org
617-724-2764
Massachusetts General Hospital
http://www.mgh.harvard.edu

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