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Novel ‘Antisense’ Technology Targets Thrush’s Molecular Machinery

Monday, September 16, 2002

Chemists have invented a new type of “antisense” technology that provides a simpler and less expensive method to knock out RNA. For their first demonstration the team disabled in the test tube an RNA molecule from a microbe that causes thrush, a fungal infection of the tongue, mouth and throat. The new technology, developed by chemists at the University of Rochester, throws off the dynamics of an entire RNA molecule, a bit like modifying the tail of a kite changes the way the kite flies in the wind. The University has filed for a patent on the work, which was published in the August 20 issue of the Proceedings of the National Academy of Sciences. The research is aimed at RNA molecules, which carry out the genetic instructions encoded in our DNA. RNA molecules are incredibly complex, with twists and turns and loops that put the most daunting roller coasters to shame. While an RNA molecule can assume many different shapes, it usually folds into the configuration that gives it what scientists call its lowest free energy – the shape that is “most comfortable” for the molecule. The molecule does its job only if it’s able to assume its preferred shape. “Antisense” technology involves using molecules, called oligonucleotides, that are made up of nucleotides which complement those on a targeted RNA strand. Conventional antisense technology aims at stopping a molecule’s function by attaching to the target strand and marking it for destruction by a protein. The new method is more subtle, aiming instead to change the dynamics of a folding RNA molecule by attaching a small oligonucleotide to it, causing a change in the molecule’s final shape. Scientists call the method Oligonucleotide Directed Misfolding of RNA, or ODMiR. “The technology makes it possible for us to force a molecule to assume a nonfunctional shape,” says team leader Douglas Turner, a chemist in the Center for Human Genetics and Molecular Pediatric Disease at the medical center, and a professor in the Department of Chemistry. “It’s like making the molecule change from a square knot to a slip knot. You change the dynamics of the RNA and cause it to fold into the wrong shape.” The research, funded by the National Institutes of Health, builds on previous work by Turner and Michael Zuker of Rensselaer Polytechnic Institute that predicts how RNA sequences fold up. The pair has developed a computer program available on the Web that other researchers use to analyze more than 50,000 RNA sequences each year. Turner’s team uses that knowledge to pinpoint sections of large RNA molecules that, if modified slightly, would cause the molecule to change shape. In the research described in the PNAS paper, Turner’s team – comprised of graduate students Jessica Childs and Matthew Disney – disabled a strip of RNA that plays matchmaker to two other key pieces of RNA. With the matchmaker out of the picture, a cell is unable to make crucial protein-making machinery. While the team’s work was done on RNA from the microbe Candida albicans, which causes thrush, Turner says it’s too early to know whether it might result in a new treatment. Because the team isn’t simply trying to match the base pairs of the strand, but instead strategically targets a location that will make the RNA fold up differently, the team is able to use shorter molecules than conventional antisense efforts. Turner’s team used very short molecules, just eight or 12 nucleotides long, to disable a piece of RNA 400 nucleotides long. In the expensive world of antisense technology, such short oligonucleotides would translate to savings for a pharmaceutical company producing an antisense drug, and could also result in fewer side effects, Turner says.

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