JACKSONVILLE, Fla. (March 2003) -- Mayo Clinic researchers have received a U.S. patent for their invention of a new way to use a synthetic molecule that specifically targets the genetic material of a cell. The technology will likely hasten development of novel gene therapy approaches for treating cancers, aging and behavioral diseases, infections and autoimmune diseases.

The Mayo Clinic team's discovery in 1997 of this technology both challenged existing protocols and opened new strategies in the field of gene therapy. Using molecules known as polyamide nucleic acid oligomers (PNAs), they became the first group to inject the substances into live animals -- rats -- and to get the desired biological results. As a bonus, the researchers also found that these molecules were able to slip past the brain's equivalent of a high-security defense system -- the blood-brain barrier -- thus allowing them to reach brain cells and fight diseases on a molecular level.

Says Elliott Richelson, M.D., a neuropharmacologist at Mayo Clinic in Jacksonville and the director of the Mayo team, "Based on the conventional wisdom at the time, we should not have been able to do the experiments that led to our discoveries. Thus, we were the first to give these types of molecules to whole animals and to look for biological effects. These molecules not only got into the brain when we injected them outside the brain, but also they caused a biological effect in the brain and elsewhere in the body."

The molecules reached their targets, worked as the researchers intended and consequently altered animal function. Adds team member Daniel McCormick, Ph.D., co-director of the Mayo Proteomics Research Center in Rochester, Minn., "We are very pleased with the biological activity of these new reagents, and with their ability to alter the expression of specific proteins in the brain. PNAs make it possible to modify the function of genes in virtually any tissue, and may serve as a "targeted genetic bullet' in the treatment of many human diseases."

Once inside cells, PNAs lock onto targeted structures to blunt or enhance a given biological response. The result: PNAs have a high potential to help researchers design drugs that specifically target important proteins involved in causing an array of diseases.

Background: What Are PNAs?

PNAs belong to a group of disease-fighting compounds called "antigene" and "antisense" agents. Research into these agents to treat diseases began more than 15 years ago with a first-generation DNA analog. The PNA molecules the Mayo Clinic is using belong to the second generation of antisense molecules --
a form that is chemically different from the first generation. This second generation group has been a topic of research at advanced laboratories around the world for about 10 years. The first antisense compound, which is a first-generation DNA analog, was approved for human use in 1998 by the U.S. Food and Drug Administration.

Antisense technology interferes with a cell's ability to make a specific protein by blocking the genetic code that directs the protein's formation. Working on the protein level is important because proteins do the actual work in cells -- not genes. Genes simply give directions, in the form of codes, of which proteins are to be made. Diseases result from such aberrations as overproduction of certain proteins or invasion of foreign proteins -- viruses, for example.

How Do They Work?

PNAs mimic many of the structural aspects of the body's natural DNA, but they are made differently. Composed of the individual bases that make up DNA, they are linked together by bonds that are found in peptides or proteins. From a drug-design point of view, this unusual structure and composition is an advantage: It makes them more resistant to enzyme degradation, gives them more stability and more capacity to be artificially modified than either natural DNA or the first generation of antisense compounds. As such, PNAs can be made to function like a kind of programmable, artificial piece of DNA -- a genetic code that researchers can program (design) to change protein production.

Significance of the Patents

The therapeutic potential for PNA technology is enormous and Mayo is seeking partners to help develop it. Once PNA technology is refined, researchers hope that any gene could be targeted by a PNA, and drugs specific to that disease gene could be delivered right to it to alter the production of the protein coded for it by its gene sequence. Says Dr. Richelson, "In theory, if we know the sequence of the gene that is producing the protein in an aberrant way, we could design the PNA to target the gene and correct it. These are truly "designer drugs.' What makes PNAs potentially so useful is their great stability, compared with the older generation molecules of this class. Unlike some older generation compounds, they are stable enough to be designed into a drug that can be taken by mouth."

Mayo's Breakthrough

While many researchers at other laboratories raced to refine PNA technology, their work largely excluded the use of live animals. Instead, they used isolated cells from animals. The Mayo team's innovation consisted of being the first to go directly to the animal to look for biological effects of PNAs. Their success in rats determined that PNAs did, in fact, have the intended biological effects even when inside the complex biological system of a living animal.

By looking for a biological effect of PNAs in live animals, Dr. Richelson and colleagues discovered that PNAs can do several things not previously known in this technology. Their PNAs can:

*be injected at a site other than the brain or spinal cord and still reach the brain
*pass both the blood-brain barrier and the cell membrane
*reach targeted genetic material in the brain
*alter the production of the protein
*obtain the desired behavioral response from a cell as a result of changing the production of this protein.

---Mayo Clinic

Back to The Science of Mental Health