Drugs that Go Beyond the Genome
Startup Constellation Pharmaceuticals aims to develop drugs that target a broad array of diseases by manipulating one of the fundamental mechanisms by which cells control the expression of genes: epigenetics. By designing compounds to alter the activity of the enzymes that coil and unwrap the genome, Constellation hopes to turn off errant genes and turn on ones key to fighting disease.
“Epigenetics is the mechanism that allows genes to be expressed in the right spatial and temporal manner, so it’s just as important as genetics,” says Yang Shi, a Harvard Medical School pathology professor, who founded Constellation along with David Allis of Rockefeller University and Danny Reinberg, of New York University. “Our first line of attack will be on enzymes that either write or erase modifications.”
Constellation announced last week that it has completed its second round of financing, raising $22 million, for a total of $54 million; confirming its own promise and the potential for epigenetic drugs. The new investment comes from Third Rock Ventures, which helped launch the Cambridge, MA, company two years ago, and the venture capital arm of pharmaceutical giant GlaxoSmithKline, among others.
Epigenetics refers to changes in cell traits or characteristics that are inherited without changes in DNA sequence. Epigenetic regulation is most commonly controlled by a number of chemical modifications that alter the way DNA is packed, which in turn makes those genes easier to turn on or off. This natural pattern of activation, which is influenced by fetal environment, stress, diet, exercise and toxic exposure, among other things, is unique to each person. This regulation can go awry in the development of disease. Identical twins can have different patterns of epigenetic modifications, helping to explain why one twin can develop cancer despite similar environmental exposures.
Developing drugs to reverse these mistakes cell has become a hot target over the last few years as scientists learn more about the key role these mechanisms play in variety of diseases, including neurological and metabolic diseases, such as Alzheimer’s and diabetes.
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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