Hope for the ‘Worried Man Blues’
Study yields potential biomarker for Huntington’s disease activity and drug response
NEW YORK—Folk singer Woody Guthrie is known for his balladsof hardscrabble lives, migrant workers and the urban poor. But perhaps his mostlasting legacy is putting a name and face on Huntington's disease (HD), ahereditary neurodegenerative disorder marked by jerky movements, changes inmood, judgment, memory, increasing physical disability, dementia and death.After battling the disease for 15 years, Guthrie died in 1967 at the age of 55,from the ravages of the same "silent killer" that claimed his paternalgrandfather, mother and two daughters.
Although there is no known cure or effective treatment forHD, a team of researchers from Brigham Women's & Children's Hospitalrecently found a genetic key to possibly unlock the door to effective treatmentof individuals with the deadly disease which lurks in affected families. Whatresearchers discovered was that a gene coding for a histone protein involved inchromatin plasticity was found at elevated levels in blood samples from those withHuntington's disease, according to a study published Oct. 4 in the Proceedingsof the National Academy of Sciences (PNAS).
"Although [Huntington's disease] symptoms reflectpreferential neuronal death in specific brain regions, the Huntington [protein]is expressed in almost all tissues and may cause clinically silent changes ingene expression and biochemistry in blood cells," the authors wrote. "Ourstudy hints at a potentially powerful new link between the specialized histoneH2AFY and the dysfunctional chromatin architecture of Huntington's disease. Theprecise mechanistic role of H2AFY in the disease process can now be thoroughlyinvestigated."
Lead researcher Clemens Scherzer says the gene H2AFY wasmore highly expressed in blood samples from Huntington's disease patients inthe discovery stage of the study, and during follow-up experiments involvedhundreds more individuals. Levels of the gene seemed to wane in response toHDAC inhibitor treatment in mouse models of the disease and in samples from aPhase II clinical trial.
Furthermore, patients treated with a drug that slows theeffects of the disease had reduced levels of H2AFY activity compared withpeople given a placebo, Scherzer says. This suggests that H2AFY could work as atool for monitoring the progression of the disease and act as an indicator ofwhether prospective treatments are effective.
To come up with the results, the research team firstanalyzed expression data from every gene in the blood cells of more than 100people. Eight people had HD, and more than 80 had other neurologicalconditions. Compared with the other participants, the HD patients had elevatedlevels of H2AFY expression—levels that were as much as two times highercompared with those of healthy people.
To further study the gene as a candidate biomarker, Scherzerteamed up with Steven Hersch and colleagues at Massachusetts General Hospital(MGH), who were conducting a clinical trial of a compound called sodiumphenylbutyrate as a potential therapeutic drug for HD.
The collaborators measured H2AFY activity in blood cells oftrial participants before and after they began taking sodium phenylbutyrate. Aspatients continued to take the compound, the researchers found decreasing H2AFYactivity—a sign that the drug-like compound might be slowing the nerve-celldamage inflicted by the disease.
If such findings hold up in larger groups of patients and infunctional studies, H2AFY may eventually become a useful tool for gauging theeffectiveness of new and existing HD treatments, Scherzer says.
As a child, Guthrie was told he could not "catch"Huntington's chorea, as it was called then, from his mother, Nora, whoalternately flew into violent rages and suffered long spells of depression.However, HD is an inherited autosomal dominant genetic disease, which meansthat each child of a parent who is carrying a defective gene for the diseasehas a 50 percent risk of inheriting the gene, Scherzer says.
"Huntington's disease is diagnosed if you have the clinicalsymptoms of Huntington's plus the abnormal gene test," Scherzer tells ddn. "So diagnosing the disease is not the issue, buttracking disease progression, disease activity and response to treatment is.That's why we need biomarkers. However, several compounds have shown promisingeffects in animal models. Rapidly advancing basic research is creating anexpanding pipeline of candidate disease-modifying therapeutics that areentering clinical trials. These lead compounds, together with biomarkers formore efficient drug trials, hold great promise for the future."
MGH researchers actually found the HD gene mutation in 1993,which led to the development in 1996 of transgenic mice. These mice have aportion of the HD gene and develop symptoms and the other neurologicalhallmarks of the disease, according to researchers. Ongoing genetic studies inthe MGH Center for Human Genetic Research directed by Dr. James Gusella includefinding genetic modifiers that influence the age of onset of HD and theprogression of the disease.
Follow-up experiments confirmed the enhanced H2AFYexpression in the Huntington disease group but not the controls, as didexperiments in mouse models of the disease, according to the research.
In addition, the team's findings suggest that H2AFYoverexpression, while stable in affected individuals over time, was markedlydecreased in mouse models of HD given a histone deacetylase (HDAC) inhibitortreatment that curbed neurodegeneration.
There are already effective tests for diagnosing thedisease, which stems from an expansion of repeats in the N terminal region ofthe HD protein, according to the research. But it is difficult to know when thedisease will become active—and a lack of reliable measures for determiningwhether treatments are working has made it especially challenging to come upwith effective therapies.
"If prospectively and mechanistically confirmed, H2AFYmay become a biomarker of disease activity and therapeutic response useful forprioritizing lead compounds for Phase III clinical trials and for bridging the'valley of death' between preclinical drug discovery and clinical drugtrials," the study authors concluded.
In an accompanying commentary in PNAS, Michelle Ehrlich and Sam Gandy of the Mount SinaiSchool of Medicine and James J. Peters VA Medical Center discussed the team'sfindings, calling the new H2AFY data "tantalizing."
"Only deeper inquiry will reveal the robustness of thebiomarker function, and only direct studies in cell and mouse model systemswill elucidate the role of H2AFY in [Huntington disease] pathogenesis,"Ehrlich and Gandy wrote.