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The earliest efforts have focused on cancer; foundational work in the field two decades ago showed that DNA methylation can be misregulated during tumor formation, silencing tumor suppressor genes as well as other genes. Treating precancerous cells with a compound called azacytidine reverses DNA methylation, reactivating the genes and differentiating the cells back into muscle cells. The drug, later approved by the U.S. Food and Drug Administration for bone marrow diseases, is now one of four approved epigenetic drugs, all aimed at cancer.

Long-term, the hope is that the epigenome can be manipulated to treat a wide variety of other diseases, too, from autism to depression to immune disorders. Big pharmaceutical firms, including GlaxoSmithKline and Novartis, are also exploring epigenetics, bolstered by the success of these four drugs. “The fact that these drugs have been demonstrated to be effective suggests strongly that we’re just beginning to scratch the surface” of what epigenetic medicines can do, says Peter Jones, director of the University of Southern California Norris Comprehensive Cancer Center.

To develop epigenetic drugs, Constellation scientists are in part targeting different human histone methylases–enzymes that attach methyl groups onto the proteins that DNA is wrapped around. Because there are so many different types of these enzymes, the expectation is that they can be used to target specific health problems, while minimizing side effects for patients, says Robert J. Gould, president and chief executive officer of Epizyme, another Cambridge-based epigenetic startup.

Constellation will also target the class of enzymes that reverse the process, as well as those involved in another type of chemical modification called acetylation.

Constellation president and CEO Mark A. Goldsmith says he sees the biggest potential in combination therapies, pairing epigenetic treatments with drugs that target other synergistic pathways. “This is a very powerful way to take advantage” of epigenetics, he says.

“Medicine and drug development has been dominated for 50 to 60 years by the [the idea that genetic mutations cause disease]. What we’re now appreciating is that it’s not all about mutations,” says George Q. Daley, a professor of hematology and oncology at Children’s Hospital Boston and a member of Epizyme’s scientific advisory board. “Especially in cancer, it may be that [genetic] mutations may be essential for initiating or establishing aberrant patterns, but a lot of what happens on top of that is epigenetic.”

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Tagged: Biomedicine, Business, cancer, drug development, methylation

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