Gene Silencing Used to Treat Disease

David Corey, professor of pharmacology and biochemistry at University of Texas (UT) Southwestern Medical Center (Dallas, TX, USA). "This is an approach that could theoretically produce a drug for the treatment or cure of almost any disease.”

In two studies published in the August 2005 online edition of the journal Nature Chemical Biology, Dr. Corey and coworkers reported how they effectively turned off gene expression in cultured cells by suppressing the ability of chromosomal DNA to be copied into RNA and made into proteins. The studies, which Dr. Corey said signify the most important findings so far in his career, are the most definitive to date demonstrating that chromosomal DNA is accessible to, and can be controlled by, natural and synthetic molecules.

"With this information, one could easily turn on or off gene expression, as well as think about ways to correct genetic disease by changing mutant gene sequences back to normal,” Dr. Corey said. "Those types of things now look a lot more feasible.”

The information contained in a gene is not directly transformed into proteins, but first is copied by special enzymes into many copies of messenger RNA, which then move out of the nucleus and into the body of the cell, where they go on to produce a protein. Current methods for activating and inactivating genes center on controlling the messenger RNA once it is already made. But blocking all the copies of messenger RNA before they can produce a protein within a cell is similar to using a pail to catch all the streams of water coming out of a yard sprinkler before they can hit the ground. Whereas this is definitely possible, a more effective way to stem the streams of water would be to turn off the faucet. By targeting the chromosomal DNA directly, that is just what Dr. Corey and his coworker accomplished.

The scientists targeted chromosomal DNA in two ways. First, they developed a synthetic molecule called a peptide nucleic acid (PNA), which physically binds to DNA and stops enzymes from copying, or transcribing, the DNA into messenger RNA. More significantly, the scientists also utilized RNA itself as a silencing agent. Earlier studies by other researchers had demonstrated that RNA might be able to target chromosomal DNA, so once Dr. Corey and his team saw that the PNAs were working, they decided to try RNA as well.

"The RNA is more important because it may reflect the body's own natural mechanism for controlling gene expression, while the PNAs are synthetic,” Dr. Corey said. "The experiments worked beautifully. It's hard to believe that this strategy would work so well if nature wasn't doing it already.”

The investigators designed their RNA to correspond with and target specific genes. "It's possible that the body is making the RNAs that we are using, and that will be an exciting topic for further research, to determine whether the human body or viruses and bacteria make RNA sequences like this to control gene expression,” Dr. Corey noted.

Up to now, the scientists have suppressed the expression of nine different genes in cancer cell cultures. Dr. Corey said it is still not certain whether the RNA is in actuality binding to the DNA itself, as the PNAs do, but it is apparent the effects are occurring at the DNA level.


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University of Texas Southwestern Medical Center