26 Dec Huntington’s disease: New Drug Class May Benefit Patient and Offspring
Medical Research: What is the background for this study? What are the main findings?
Response: Increasing evidence has demonstrated that epigenetic factors can profoundly influence gene expression, and in turn, influence resistance or susceptibility to disease. Epigenetic drugs, such as histone deacetylase (HDAC) inhibitors, are finding their way into clinical practice, and are being proposed for therapeutic use in several neurological disorders. Our previous studies have shown that selective HDAC inhibitors can cause beneficial effects in mouse models of Huntington’s disease, improving symptoms, and reducing severity of the disease. Our current studies show that one such compound can alter DNA methylation, an epigenetic mark that can be inherited, leading to changes in gene expression that are seen in the parent mouse exposed directly to the drug, as well as in offspring from the drug-treated male mice. Concurrent with these changes, we observed that offspring from drug-treated males shown improved disease symptoms, showing a delay in disease onset and a reduction of motor and cognitive symptoms that included improved performance in tests of balance, speed and memory.
These finding have significant implications for human health as they enforce the concept that ancestral drug exposure may be a major molecular factor that can affect disease outcome in a subsequent generation. One exciting aspect of our study is that the parental drug treatment made the offspring better, not worse, like other compounds known to cause transgenerational effects.
Medical Research: What should clinicians and patients take away from your report?
Response: The take-home message is that certain drugs that benefit patients with a given disease, may also cause changes in gene expression that could benefit offspring who might inherit the disease.
Medical Research: What recommendations do you have for future research as a result of this study?
Response: Future studies would test whether the effects of HDAC inhibitors could be passed down through the female germline, and whether the beneficial effects could persist in generations of grandchildren or great-grandchildren. Further, we have interest in investigating whether drugs and therapeutic compounds used for other neurological disorders can also lead to transgenerational effects.
HDAC inhibition imparts beneficial transgenerational effects in Huntington’s disease mice via altered DNA and histone methylation
Haiqun Jia, Charles D. Morris, Roy M. Williams, Jeanne F. Loring, and Elizabeth A. Thomas
PNAS 2014 ; published ahead of print December 22, 2014, doi:10.1073/pnas.1415195112