Richelson and his colleagues in the Neuropsychopharmacology and Neurochemistry labs at Mayo Jacksonville and the Department of Biochemistry and Molecular Biology at Mayo Clinic Rochester described their findings in the June 8 issue of the Proceedings of the National Academy of Sciences.
Richelson has been studying neurotensin, a small piece of protein, or peptide, found in the brain and involved in pain perception and lowering body temperature. For the last few years, scientists worldwide have been testing the theory that interfering with a protein's production on a molecular level might stop it from carrying out its job in humans. Scientists were trying to interfere with protein production by creating special "antisense" molecules designed to block a cell's ability to make specific proteins.
To better understand the brain peptide he was researching, Richelson and his colleagues used peptide nucleic acids (PNAs), a new type of molecule, to create antisense compounds targeting neurotensin. When they injected the PNA antisense molecules into the brains of rats, the molecules worked. They blocked neurotensin's ability to lower body temperature and reduced its ability to block the sensation of pain.
"Then we injected PNA in the belly of the rat to see what would happen, and we got the same result," Richelson says. "Nobody had ever shown that you could inject this type of molecule or any type of antisense molecule in the belly and get a biological response in the brain."
That's important because not only is the molecule locking onto its intended target, it's also getting past the blood-brain barrier. This barrier blocks the action of many drugs on brain cells, making diseases that affect the brain often so difficult to treat.
To prove further that the PNA had reached the brain, Richelson's group developed an assay to measure the chemical's presence in brain cells.
The work is so unique that Mayo Clinic has applied for five U.S. and international patents on PNAs and the assay.
"It's absolutely mind boggling to see what these molecules did in animals," Richelson says. "What we've presented here goes totally against the grain. The medical literature tells us it shouldn't work. A huge skepticism for antisense molecules has developed because they seem to be unpredictable in that they're not binding to what you expect them to.
"The PNA field has been waiting for a major breakthrough in getting molecules into cells," Richelson says. "We're saying it's here. Inject PNAs and look for a biological response."
These findings have implications for treating many illnesses that are caused by overproduction of a protein normally found in the body and for treating diseases caused by foreign proteins invading the body (for example, viral infections). Scientists are just beginning to identify the specific proteins that are involved in certain diseases. But once the proteins are recognized, it will be possible to find the genes responsible for creating those proteins and develop antisense molecules to stop the proteins' function.
"We made a discovery that's totally unexpected, and it's taken us down a path we never dreamed of," Richelson says.
Contact: Evelyn Tovar 904-953-7347 [email protected]
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