Public Release: 

Duke Researchers Show "Editing" Can Fix Faulty Genes In New Approach To Gene Therapy

Duke University

DURHAM, N.C. -- Duke University Medical Center researchers have shown for the first time that enzymes can be used inside living cells to repair faulty genetic messages, instead of replacing them.

The finding, published in the June issue of Nature Medicine, opens up a new realm of possibilities for correcting genetic information, according to Bruce Sullenger, assistant professor of experimental surgery and genetics. The Duke team already has begun exploring use of these new therapeutic approaches for sickle cell anemia and even to "sabotage" the AIDS virus.

"This research proves that we can use nature's own processes to rewrite genetic instructions in mammalian cells," Sullenger said in an interview. "The results have encouraged us to go forward in exploring the use of this technology to correct disease-causing genetic defects."

The study was funded by a grant from the National Institutes of Health. Duke researchers Joshua Jones and Seong-Wook Lee also contributed to the work.

Sullenger's strategy is based on the discovery, more than a decade ago, that instead of being simply a passive carrier of genetic information, the genetic material known as RNA is an active participant in editing genetic messages before they are translated into protein.

The editing approach to gene therapy ignores the defective genes, which are encoded in DNA and stored in the chromosomes, in favor of focusing on the specific genetic RNA messages that are translated into protein. Such messages are copied from the chromosomes into a portable form called messenger RNA (mRNA). But mRNA copied from DNA is often full of superfluous information that has to be edited out before the mRNA is decoded into the final protein product. Cells have evolved an efficient system that uses RNA enzymes or "ribozymes" to cut junk out of mRNA and paste it back together again.

Sullenger reasoned that ribozymes could be adapted as a tool to recognize defective mRNA and splice in a corrected version. To accomplish this, he turned to the first ribozyme discovered, from the single-celled organism Tetrahymena thermophila. This ribozyme not only cuts other pieces of RNA at specific sites called recognition sequences, but after it cuts, it splices in a piece of RNA sequence attached to its tail end.

To test his idea of repairing faulty genes, Sullenger introduced a defective gene into mouse cells growing in a test tube. Then he engineered a ribozyme to recognize a short stretch of RNA near the genetic defect and splice in the corrected sequence, which Sullenger had produced artificially and attached to the ribozyme tail. When he introduced the ribozyme into the mouse cell, it recognized the defective RNA and swapped in the corrected version.

Although the technique is still in the proof-of-concept stage, Sullenger's twist on gene therapy addresses many of the problems that have complicated early gene therapy efforts.

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