Biomarkers in the blood

HD Lighthouse Contributing Editor's Comment: This is very good news! Currently HD research uses the United Huntington's Disease Rating Scale to measure disease progression. The scale is subjective, contains at least one subscale (the psychological, behavioral one) which does not correlate to progression, and is not sensitive enough to measure changes in shorter periods of time. As a result, the HD community's first Phase III clinical trial (CARE-HD) took 30 months and the second planned one (2CARE) is planned for 60 months. Even more problematic, there is no way to measure the prevention of HD onset using the UHDRS so it's not currently possible to include gene positive, nonsymptomatic people in research.

The search is on for biomarkers that would measure the progression of the disease and improvement through treatments. Researchers at Massachusetts General Hospital have found a set of twelve genes whose expression is affected by the disease and which can be measured in blood samples. Expression levels begin to increase as presymptomatic individuals near onset and increase with the progression of the disease. Following four weeks of treatment with the histone deacetylase inhibitor sodium phenylbutyrate, expression levels decreased. This looks very promising and I hope researchers conducting the next Phase III clinical trial will monitor this set of biomarkers so they can be validated.
--Marsha L, Miller, Ph.D.
Posted to the HDL: 17 Aug 2005

Dimitri Krainc, MD, PhD, Massachusetts General Hospital

The Press Release:

Gene expression levels may reveal stage of Huntington's disease

Markers 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.

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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.

The Abstract:

Huntington's disease (HD) is an autosomal dominant disorder caused by an expansion of glutamine repeats in ubiquitously distributed huntingtin protein. Recent studies have shown that mutant huntingtin interferes with the function of widely expressed transcription factors, suggesting that gene expression may be altered in a variety of tissues in HD, including peripheral blood. Affymetrix and Amersham Biosciences oligonucleotide microarrays were used to analyze global gene expression in blood samples of HD patients and matched controls. We identified 322 mRNAs that showed significantly altered expression in HD blood samples, compared with controls (P < 0.0005), on two different microarray platforms. A subset of up-regulated mRNAs selected from this group was able to distinguish controls, presymptomatic individuals carrying the HD mutation, and symptomatic HD patients. In addition, early presymptomatic subjects showed gene expression profiles similar to those of controls, whereas late presymptomatic subjects showed altered expression that resembled that of symptomatic HD patients. These elevated mRNAs were significantly reduced in HD patients involved in a dose-finding study of the histone deacetylase inhibitor sodium phenylbutyrate. Furthermore, expression of the marker genes was significantly up-regulated in postmortem HD caudate, suggesting that alterations in blood mRNAs may reflect disease mechanisms observed in HD brain. In conclusion, we identified changes in blood mRNAs that clearly distinguish HD patients from controls. These alterations in mRNA expression correlate with disease progression and response to experimental treatment. Such markers may provide clues to the state of HD and may be of predictive value in clinical trials.

Source: Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):11023-8.

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