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Proof Of Principle
CHORI Scientist Establishes mRNA as Potential Drug Target

The prestigious Proceedings of the National Academy of Sciences (PNAS) in its January, 2006 issue, has just published the results of a groundbreaking new study by CHORI Senior Scientist, Elizabeth C. Theil, PhD.

“It’s a new idea,” says Dr. Theil of PNAS paper on the upregulation of ferritin expression using a small-molecule ligand to the native messenger RNA (mRNA). “Throughout the 1980’s and even into the 90’s, there were many scientists who were always surprised you could even study mRNA.”Dr. Theil has been studying the ferritin mRNA for over two decades, and with her colleagues at University of North Carolina, for the last ten years.

“Many of the proteins for iron metabolism are coded in an mRNA with a 3-dimensional RNA structure that doesn’t have any protein code in it,” explains Dr. Theil. “These messages have both parts that code for protein, and non-coding parts that determine how fast the protein will be made.”

Dr. Theil and her colleagues hypothesized that they could use the molecular structure of non-coding mRNA to selectively target a molecule to change its properties. Test studies over the last few years have supported the hypothesis and showed that the RNA structure existed in living cells as well as in the test tube.

“We knew that even when you have a lot of iron in the cell and a lot of iron in the tissue, only 50 percent of the ferritin message is being used," explains Dr. Theil, pointing out that the ferritin protein is the only place in the body in which iron can be stored safely. "We also knew about the RNA structure, so we thought if we could upregulate or overcome what was repressing this mRNA, we could make more ferritin.”

This is exactly what Dr. Theil and her colleagues were able to do. By binding the naturally occurring small molecule, yohimbine, to a specific site in the ferritin mRNA, Dr. Theil and her colleagues succeeded in upregulating ferritin synthesis.

“It’s really proof of principle,” says Dr. Theil of the study, which essentially provides a model for utilizing small molecules to regulate protein biosynthesis. As more mRNA structures with non-coding structures are found, this approach could be a new key to developing better drug targets for treating all kinds of conditions.

“I don’t know of a single drug out there that is manipulates 3D mRNA structure, especially of normal cellular mRNA. One mRNA molecule makes many, many protein molecules, so if you can change just one mRNA, you have a much bigger effect."

Dr. Theil’s study not only has profound implications for research methodology, but also provides a new window into potential treatment options for iron overload. Currently, the only option for patients with sickle cell disease or thalassemia to treat iron overload is chelation therapy, an often painful and time consuming process. If Dr. Theil could identify an optimal drug to upregulate ferritin and store extra iron safely, it could minimize the need for chelation therapy.

Monday, May 16, 2011 11:33 PM

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