genetic turn on

Researchers examine the potential fo treating genetic disorders by interfering with gene silencing.

By Lori Oliwenstein

Dispelling the belief that the only way to treat inherited diseases, aging and cancer is by fixing or replacing damaged genes, researchers from the USC/Norris Comprehensive Cancer Center heralded an entirely new approach. They are focused on the field of epigenetics—the study of changes in gene silencing that occur without changes in the genes themselves.


Many genes in our bodies are permanently turned off as part of normal development. But sometimes that process goes awry, turning off-—or silencing—genes that should otherwise remain active. The new field of epigenetic therapy, put forth by USC researchers in a review paper in the journal Nature, aims to switch these genes back on.
In their article, Peter Jones, Ph.D., director of USC/Norris, and his colleagues laid out their new perspective on the treatment of genetic disorders by discussing the potential ways to interfere with epigenetic gene silencing, and the ways in which that potential is already being exploited.

“The fact that many human diseases, including cancer, have an epigenetic etiology has encouraged the development of a new therapeutic option that might be termed ‘epigenetic therapy,’” Jones and his colleagues write in their article. They add that a number of chemical compounds have been found that have an effect on some form of epigenetic gene change, and note that “several of these agents are currently being tested in clinical trials,” including trials conducted at USC/Norris.

The Nature review came just days after the U.S. Food and Drug Administration approved the epigenetic inhibitor azacitidine (Vidaza,™ Pharmion Corporation) for the treatment of a pre-leukemic bone-marrow disorder known as myelodysplastic syndrome, or MDS.

MDS is characterized by the production of abnormal, immature blood cells, affects 10,000 to 30,000 people each year, is most prevalent in people over age 60, and can be fatal. Until now, there was no approved treatment for MDS.

Although the drug had initially been envisioned as a chemotherapy agent, Jones showed that it had great utility in the laboratory because it could turn on genes that had been previously locked by methylation—a type of epigenetic change in which a methyl group becomes physically attached to the region of a gene that regulates its production of protein, shutting it down.

But Jones, one of the world’s pre-eminent epigenetics experts, says that azacitidine’s approval is bigger than its role in MDS.

He notes, “This is the first approved drug in epigenetic therapy. That gives it tremendous potential importance not just in this disease, but in a host of others as well.”

Indeed, numerous diseases—most notably several that can lead to intellectual disabilities—appear to have epigenetic roots. Among them are Fragile X syndrome, Angelman syndrome, Prader-Willi syndrome and Rett syndrome. Jones also sees the application of epigenetic therapy to combat disorders caused by aging by turning on genes shut down by the aging process.

The search for the right drugs to undo epigenetic damage is as wide-ranging as their possible targets. Jones is involved in research of azadeoxycytidine—a more specific version of azacitidine that only affects DNA and thus potentially carries fewer side effects.

Jones and colleagues note in their review: “Elucidating the whole bandwidth of epigenetic mechanisms is an exciting challenge and will eventually lead to a clearer understanding of the development of human disease and lead therapeutic concepts into new directions.”