Gene expression levels may reveal stage
of Huntington's disease
Markers could help track response
to new therapies, protective strategies
BOSTON - August 16, 2005 - 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
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.
Media Contact: Sue
McGreevey, MGH Public Affairs
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