An ideal neurodegenerative disease prevention trial would include a well-demonstrated genetic risk factor, a validated biomarker panel to track therapeutic progress in affected individuals, and safe therapies that target promising molecular entities.
The work by Dr. Hu and his associates may have identified a blood-based biomarker for HD that could aid in future prevention trials. In their impressive work, the researchers demonstrate that H2AFY mRNA levels are significantly elevated and associated with disease status in HD patients, that H2AFY mRNA is significantly increased in HD even before the presence of clinically recognizable symptoms, and that the macroH2A1 protein encoded by the H2AFY gene is elevated in the brains of patients and mouse models of the disease.
Perhaps most importantly, the investigators demonstrated that blood levels of H2AFY mRNA are reduced in a randomized, double-blind, phase II clinical trial of HD patients who were treated with an emerging histone deacetylase inhibitor, SPB, that was previously shown to suppress huntingtin-induced neurodegeneration in a mouse model.
The authors discuss the limitations of their work extensively with an appropriate emphasis on independent replication in a larger sample set. Assuming that the H2AFY mRNA biomarker is independently validated, HD now tentatively meets several of the above-outlined hurdles for the initiation of well-informed neurodegenerative disease–prevention trials.
Perhaps the major question left unanswered is the efficacy of available therapeutics in combating the early stages of HD. However, if the H2AFY biomarker is eventually shown to indicate the underlying pathobiology of HD, then it is very encouraging that the histone deacetylase inhibitor appeared to shift the biomarker in the direction of the placebo group.
Neurodegenerative disease–prevention trials are clearly going to test many aspects of the standard clinical trials system, including the inclination of pharmaceutical companies to explore such trial designs and the Food and Drug Administration's willingness to acknowledge the role of such trials in the vetting of novel neurodegenerative disease–treatment approaches.
The coupling of biomarker and genetic approaches with therapeutic agents administered during the disease process when they have the greatest chance to be efficacious can be nothing but motivating for the field. The new work by Dr. Hu and his colleagues could poise HD at the front of the pack for these disease-prevention trials, and should be nothing but encouraging to individuals and families at risk for the disease.
MATTHEW J. HUENTELMAN, PH.D., is head of the neurobehavioral research unit and associate professor in the neurogenomics division of the Translational Genomics Research Institute in Phoenix. He disclosed no conflict of interest.
