Silence Of The Genes: Researchers Provide Unique View Of Inherited Disorders And Cancer

Many genes in our bodies are permanently turned off as part of normal development. But sometimes that process goes awry, turning off genes that should otherwise remain active. The new field of epigenetic therapy, put forth by the USC researchers in their Nature review paper, aims to switch these genes back on.

In their article, Peter Jones, Ph.D., director of USC/Norris and Distinguished Professor of Biochemistry and Molecular Biology and Urology at the Keck School of Medicine of the University of Southern California, and his colleagues lay 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. They add that a number of chemical compounds have been found that have an affect on some form of epigenetic gene change, and note that "several of these agents are currently being tested in clinical trials," including trials being conducted at USC/Norris.

This Nature review comes just days after the U.S. Food and Drug Administration (FDA) approved the epigenetic inhibitor azacitidine (Vidaza(tm), Pharmion Corporation) for the treatment of a pre-leukemic bone-marrow disorder known as myelodysplastic syndrome, or MDS. MDS, which is characterized by the production of abnormal, immature blood cells, affects between 10,000 and 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.

Azacitidine was first synthesized in the 1960s in Czechoslovakia; it received its first exposure in the United States in the Childrens Hospital Los Angeles laboratory of then-fellow Peter Jones. 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 down 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, who is one of the world's pre-eminent epigenetics experts, says that azacitidine's approval is bigger than its role in MDS.

"This is the first approved drug in a new kind of therapy-epigenetic therapy," Jones notes. "That gives it tremendous potential importance not just in this disease, but in a host of others as well."

Indeed, cancer and its relatives are far from the only conditions that may be affected by epigenetic gene silencing, Jones notes. A number of other 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 epigenetics to combat disorders caused by aging, providing the opportunity to turn on the genes shut down by the aging process.

And the search for the right drugs to undo the epigenetic damage is equally wide-ranging. Jones is involved in research into the utility of a compound called azadeoxycytidine--a more specific version of azacitidine that only affects DNA and thus potentially carries fewer side effects. Many of the major pharmaceutical companies have at least one methylation inhibitor trial ongoing, Jones adds, and there are dozens of additional compounds being screened for their potential utility.

"It is apparent that we are just at the beginning of understanding the substantial contributions of epigenetics to human disease, and there are probably many surprises ahead," 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 direct therapeutic concepts into new directions."

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Gerda Egger, Gangning Liang, Ana Aparicio, Peter Jones, "Epigenetics in human disease and prospects for epigenetic therapy." Nature, 429:457-463, 27 May 2004.