Gene Silencing Technique Offers New Strategy for Treating, Curing Disease

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Gene Silencing Technique Offers New Strategy for Treating, Curing

Disease

http://www.medicalnewstoday.com/medicalnews.php?newsid=28408

01 Aug 2005

A new technique aimed at directly controlling the expression of genes

by turning them on or off at the DNA level could lead to drugs for

the treatment or cure of many diseases, say researchers at UT

Southwestern Medical Center.

" Virtually every disease starts at the level of malfunctioning gene

expression, or viral or bacterial gene expression, " said Dr.

Corey, professor of pharmacology and biochemistry. " This is an

approach that could theoretically produce a drug for the treatment or

cure of almost any disease. "

In two papers appearing in the online edition of the journal Nature

Chemical Biology, Dr. 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 Dr. 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, " Dr. Corey

said. " Those types of things now look a lot more feasible. "

Genes are segments of DNA housed in the chromosomes in the nucleus of

every cell. Genes carry instructions for making proteins, which in

turn carry out all of life's functions. Faulty or mutated genes lead

to malfunctioning proteins, which cause disease.

The information in a gene is not directly converted 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 create a protein.

Current techniques for turning genes on or off focus on controlling

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.

While that's certainly possible, a more efficient way to staunch the

streams of water would be to turn off the faucet. By targeting the

chromosomal DNA directly, that's just what Dr. Corey and his

colleagues accomplished.

The researchers targeted chromosomal DNA in two ways. First, they

developed a synthetic molecule called a peptide nucleic acid, or PNA,

which physically binds to DNA and blocks enzymes from copying, or

transcribing, the DNA into messenger RNA.

More importantly, the researchers also employed RNA itself as a

silencing agent. Previous work by other scientists had shown that RNA

might be able to target chromosomal DNA, so once Dr. Corey and his

team saw that 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, " 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, " Dr. Corey

said.

So far, the researchers have inhibited the expression of nine

different genes in cancer cell cultures. Dr. 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.

Other UT Southwestern researchers involved in the studies were lead

author on both papers Dr. Bethany Janowski, research assistant

professor in pharmacology; Dr. Kunihiro Kaihatsu, former pharmacology

postdoctoral research fellow; Dr. Huffman, pharmacology

postdoctoral research fellow; Schwartz, pharmacology research

assistant; lyn Ram, pharmacology research associate; Dr.

Hardy, biochemistry postdoctoral researcher; Shames, student

research assistant; Dr. Carole Mendelson, professor of biochemistry;

and Dr. Minna, professor and director of the B. and Jake

L. Hamon Center for Therapeutic Oncology Research and the W.A. " Tex "

and Deborah Moncrief Jr. Center for Cancer Genetics.

The study was supported by the National Institutes of Health and The

Welch Foundation.

UT Southwestern Medical Center

5323 Harry Hines Blvd.

Dallas, TX 75390-9060

United States

utsouthwestern.edu/news