A New Biomarker is Identified for HD

 

Researchers in two Massachusetts laboratories have isolated a potential new biomarker in the blood of mouse models of HD and in human patients, the dynamic regulator of chromatin plasticity H2A histone family, member Y (H2AFY).  Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary protein components of chromatin are histones that organize the DNA.  Chromatin architecture is known to be dysfunctional in HD patients and the elevated levels of H2AFY may be related.  Although more research will be needed before the biomarker can be accepted for clinical studies, the results presented in this study are very promising.

 

The search for biomarkers is very important to promoting the development and availability of treatments.   Because HD is a slowly progressive disease, Phase III clinical trials of potentially disease modifying drugs take years, adding to the cost of trials and delaying the time needed before successful drugs can become available to patients.  A valid biomarker could shorten the time necessary for trials and also help to identify which drugs should be taken from Phase II to Phase III (final) trials.

 

The HD pipeline of potential treatments continues to grow; with limited resources (money and patients willing to volunteer for trials) it becomes important to prioritize which drugs are tried first.   Given the short time periods associated with Phase I and Phase II trials, clinical differences are not usually detectable so prioritizing is difficult.   When researchers examine a number of potential possible differences after a Phase II trial looking for signals whether to proceed, false positives become likely, as was the case with Dimebon.  A significant improvement in the Mini Mental States Exam following a Phase II trial was encouraging but Dimebon was later found ineffective in a Phase III trial.  In addition, once treatments become available, biomarkers will also be helpful in determining when to start administering treatments.

 

The new study is exciting since there the biomarker was confirmed in mice and patients and was found to respond to a treatment.  Further, as the researchers point out, a blood test is less invasive and less expensive than other possible tests of disease progression such as examining the cerebrospinal fluid or imaging.

 

In a systematic transcriptome-wide analysis of the blood of HD patients compared to controls, the researchers found that H2AFY was found to be overexpressed 1.6 fold.  A second study of HD patients was done to make sure that the original finding wasn’t a false positive; overexpression was 1.5 fold.  A longitudinal study found 1.4 at the baseline, 1.4 a year later, and 1.7 a year after that.  In addition, elevated levels were found in both the R6/2 mice and the knock-in mice.

 

The researchers then looked at the effect of sodium phenylbutyrate (SPD) on levels of H2AFY in mouse models and HD patients.  SPD is a histone deacetylase inhibitor.  Histone deacetylase (HDAC) inhibitors are of interest as potential treatments because of the possibility that they could restore the dysregulation of gene transcription that occurs in Huntington’s disease.  SPB has already been shown to be neuroprotective in the R6/2 mice. They found that SPB reduces  the elevated H2AFY levels in the R6.2 mice, showing that this biomarker responds to treatment.  They also examined frozen blood samples from the Phase II trial of SPB which took place several years ago and found that the biomarker also responded to treatment in human patients.

 SPB did not advance to Phase III trials because at the time of the study there were no indications of effectiveness and because basic researchers were attempting to determine which HDACs should be inhibited with the idea of developing a drug with a narrower target.

 

The new research is a collaboration between the laboratory of Clemens Scherzer, MD, in the Center for Neurologic Diseases at Brigham and Women's Hospital (BWH) and the laboratory of Steven Hersch, MD, Ph.D, at the Massachusetts General Institute for Neurodegenerative Disease at Massachusetts General Hospital (MGH).


"We know how to diagnose HD. What we don't have, however, is a simple test to tell us whether the disease is active and progressing or responding to new medications. Such a test would be critical for making clinical trials more efficient. We are excited about the potential of our discovery" said Scherzer, who is also an assistant professor of Neurology at Harvard Medical School. "The next challenge will be to develop this prototype biomarker into a test that is useful in drug trials."

                                                                                         Dr. Scherzer

"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 and that this biomarker gene, H2AFY, could help to facilitate research into the effectiveness of potential treatments for this disease," said Hersch, who is also a professor of Neurology at Harvard Medical School. "Even in very large studies lasting years, it is very difficult to use clinical measures to find evidence that a treatment might slow down Huntington's disease. Biomarkers like H2AFY can help considerably."

 

The Crest-E (creatine) trial will allow H2AFY to be followed longitudinally in a larger population of HD patients.  Future research will also look at whether H2AFY is a biomarker which responds to any disease modifying treatment or just transcriptional treatments. 

 

Reference:


Yi Hua, Vanita Chopra, Raman Chopra, Joseph J. Locascio, Zhixiang Liao, Hongliu Ding, Bin Zhenga, Wayne R. Matson, Robert J. Ferrante, H. Diana Rosas, Steven M. Hersch, and Clemens R. Scherzer. “Transcriptional modulator H2A histone family, member Y (H2AFY) marks Huntington disease activity in man and mouse.” Proceedings of the National Academy of Sciences 2011 Oct 3. [Epub ahead of print].

 

- Marsha L. Miller, Ph.D., October 12, 2011