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Expression Study Yields Potential Marker for Huntington Disease Activity, Drug Response

NEW YORK (GenomeWeb News) – A gene coding for a histone protein involved in chromatin plasticity is found at elevated levels in blood samples from those with Huntington disease, according to a study in the early, online edition of the Proceedings of the National Academy of Sciences last night.

An American research team assessed gene expression patterns in blood samples from 119 individuals with or without Huntington disease, reasoning that they might find detectable expression shifts — even outside of the tissues that undergo characteristic neurodegeneration during Huntington disease.

"Although [Huntington disease] symptoms reflect preferential neuronal death in specific brain regions, huntingtin [protein] is expressed in almost all tissues and may cause detectable but clinically silent changes in gene expression and biochemistry in blood cells," the authors explained.

Their search led them to H2AFY, a gene that was more highly expressed in blood samples from Huntington disease patients in the discovery stage of the study and during follow-up experiments involving hundreds more individuals. Levels of the gene seemed to wane in response to HDAC inhibitor treatment in mouse models of the disease and in samples from a phase II clinical trial, they reported, suggesting that H2AFY could be a promising candidate biomarker for Huntington disease.

"Our findings, taken along with previous research, suggest that Huntington's disease progression and patient responses to some treatments could be measured by a blood test," co-corresponding author Steven Hersch, a researcher at the MassGeneral Institute for Neurodegenerative Disease, said in a statement, "and that this biomarker gene, H2AFY, could help to facilitate research into the effectiveness of potential treatments for this disease."

For the first stage of the study, the team used the Affymetrix Human GeneChip U133A arrays to measure gene expression in blood samples from eight individuals with Huntington disease and 111 unaffected controls, including 83 individuals with other neurodegenerative conditions.

Among the 99 genes showing significantly different expression in the samples from individuals with Huntington disease compared to controls, the team found H2AFY, a gene whose expression was about 1.6 times higher in the Huntington patients.

The researchers verified the expression differences with real-time quantitative PCR analyses of samples from the eight Huntington disease patients and eight of the controls and from dozens more individuals with other neurological or neurodegenerative movement conditions.

The follow-up experiments in these and other individuals confirmed the enhanced H2AFY expression in the Huntington disease group but not the controls, as did experiments in mouse models of the disease.

In addition, the team's findings suggest that H2AFY over-expression, while stable in affected individuals over time, was markedly decreased in mouse models of Huntington disease given a histone deacetylase (HDAC) inhibitor treatment that curbed neurodegeneration.

The researchers saw similar patterns when they assessed blood samples from individuals participating in a phase II clinical study called the Phenylbutyrate Development for Huntington's Disease trial. There, they found, H2AFY levels declined in the blood of patients treated with the HDAC inhibitor sodium phenylbutyrate over several weeks.

If such findings hold up in larger groups of patients and in functional studies, they noted, H2AFY may eventually become a useful tool for gauging the effectiveness of new and existing Huntington disease treatments.

There are already effective tests for diagnosing the disease, which stems from an expansion of repeats in the N terminal region of the huntingtin protein, they explained. But it is difficult to know when the Huntington disease will become active. And a lack of reliable measures for determining whether treatments are working has made it especially challenging to come up with effective therapies.

"If prospectively and mechanistically confirmed, H2AFY may become a biomarker of disease activity and therapeutic response useful for prioritizing lead compounds for phase III clinical trials and for bridging the 'valley of death' between pre-clinical drug discovery and clinical drug trials," the study authors concluded.

In an accompanying commentary in PNAS, Michelle Ehrlich and Sam Gandy of the Mount Sinai School of Medicine and James J. Peters VA Medical Center discussed the team's findings, calling the new H2AFY data "tantalizing."

"[O]nly deeper inquiry will reveal the robustness of the biomarker function, and only direct studies in cell and mouse model systems will elucidate the role of H2AFY in [Huntington disease] pathogenesis," Ehrlich and Gandy wrote.

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