Gene Silencing Offers New Strategy For Treating Disease

In two papers published in the online edition of the journalNature Chemical Biology, researchers at UT Southwestern Medical Center say they have developed a technique that can control gene expression by turning them on or off at the DNA level. In doing so, the research team may have paved the way for the development of new drugs designed to treat many serious diseases.

As diagnoses and gene research improves, scientists are consistently finding that nearly all diseases start at the genetic level. “Virtually every disease starts at the level of malfunctioning gene expression, or viral or bacterial gene expression,” said Dr. David Corey, professor of pharmacology and biochemistry.

Corey and his colleagues describe how they efficiently shut down gene expression in cultured cells by blocking the ability of chromosomal DNA to be copied into RNA and made into proteins. The studies, which Corey said represent the most significant findings thus far in his career, are the most definitive to date showing that chromosomal DNA is accessible to and can be controlled by synthetic and natural 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,” Corey said.

Genes are segments of DNA housed in the chromosomes in the nucleus of every cell. Genes carry instructions for making proteins, which are then copied by special enzymes into many copies of messenger RNA. The RNA then move out of the nucleus and into the body of the cell, where they go on to create the proteins needed for everyday life. Faulty or mutated genes lead to malfunctioning proteins that cause disease.

Current methods of turning genes on or off involve trying to block copies of the messenger RNA once it’s already produced. But blocking all the copies of messenger RNA before they can make a protein within a cell is akin to using a bucket to catch all the streams of water coming out of a yard sprinkler before they can hit the ground. Corey’s technique is a much more effective solution because it turns off the streams of water at the faucet. By targeting the chromosomal DNA directly, this is effectively what Corey and his colleagues have accomplished. “This is an approach that could theoretically produce a drug for the treatment or cure of almost any disease,” said Corey.

Corey and his team targeted chromosomal DNA in two ways, which involved both synthetic and natural molecules. First, a synthetic molecule called a peptide nucleic acid, or PNA, was used. PNA physically binds to DNA and blocks enzymes from copying, or transcribing, the DNA into messenger RNA.

The second stage employs RNA itself as a silencing agent. “The RNA is more important because it may reflect the body’s own natural mechanism for controlling gene expression, while the PNAs are synthetic,” Corey said. Previous work by other scientists had shown that RNA might be able to target chromosomal DNA, so once Corey and his team saw that PNAs were working, they decided to try RNA as well. “The experiments worked beautifully,” he said. “It’s hard to believe that this strategy would work so well if nature wasn’t doing it already.”

The researchers designed their RNA to match up 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,” Corey explained. So far, the researchers have inhibited the expression of nine different genes in cancer cell cultures. Corey said it’s not clear whether the RNA is actually binding to the DNA itself, as the PNAs do, but it’s clear the effects are occurring at the DNA level.

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