Scientists Block Prions that Cause Mad Cow Disease

LA JOLLA, California, August 15, 2001 (ENS) - Scientists working at The Scripps Research Institute (TSRI) and at the University of California, San Francisco, have found a promising treatment for the dreaded mad cow disease and one form of the same disease in humans, called variant Creutzfeldt-Jakob Disease.

A malformed prion protein is the agent of infection. Not a virus or a bacteria, but instead transmissible spongiform encepalopathies such as mad cow disease, are caused by a malformed prion protein that is chemically the same as normal human proteins.


If fed grain contaminated with prion protein, cattle can develop bovine spongiform encepalopathy (BSE) or mad cow disease. (Photo courtesy
Pronounced (PREE-on), prions are known to cause new variant Creutzfeldt-Jakob disease, as well as numerous other rare neurodegenerative diseases in animals and humans.

Infection can occur from ingestion of prion-contaminated meats, contamination through biological and pharmaceutical products and, as seen in the past, from cannibalism.

In the current issue of the scientific journal "Nature" Professor Dennis R. Burton, Ph.D. describes an antibody that, in cell culture at least, clears prion infection. This finding may point the way to a treatment for mad cow disease and its human equivalent.

One antibody this group designed seems to halt the prion infection all together. The antibody - called Fab D18 - binds to the normal form of the prion protein and prevents the infectious form from binding in cell culture.

The normal cellular machinery degraded whatever infectious prions remained, suggesting that the antibody has the potential to cure established infection.

Dr. Burton says the antibody provides a potential therapeutic target, "a highly effective human drug might be designed to bind to the same place as Fab D18."

"Prions," says investigator Anthony Williamson, Ph.D., "have a Jekyll and Hyde personality."

Burton and Williamson, who are both in the Department of Immunology at TSRI, explain that infectious prions from an animal with mad cow disease will initially cause normal prion proteins in the brain of a healthy cow to misform into the infectious form.

Then these prions will act on more normal prion protein to produce more and more misfolded protein that accumulates and eventually leads to brain damage with a sponge-like appearance, Williamson says.


Stanley Pruisner, 1997 Nobel Prize in Medicine (Photo courtesy The Nobel Foundation)
The research article, "Antibodies inhibit prion propagation and clear cell cultures of prion infectivity," appears in the August 16 issue of the British journal "Nature" and is authored by David Peretz, R. Anthony Williamson, Klotoshi Kaneko, Julie Vergara, Estelle Leclerc, Gerold Schmitt-Ulms, Ingrid Mehlhorn, Gluseppe Legname, Mark Wormald, Pauline Rudd, Raymond Dwek, Dennis R. Burton, and Stanley Prusiner, a Nobel Prize winner honored for his work in identifying the prion.

The research was funded in part by the National Institutes of Health and is a collaboration between TSRI and the Prusiner laboratory at the University of California, San Francisco (UCSF).

In a related development, other UCSF researchers have determined that two drugs currently approved to treat either malaria or certain psychotic illnesses are effective in treating mouse cells infected with the infectious protein known as the prion.

Because the drugs have long been used, they are known to cross the difficult to penetrate "blood-brain barrier,"

The UCSF researchers have observed what they call "a dramatic response in the cells" to the two pharmaceuticals, quinacrine and chlorpromazine.

Carsten Korth, MD and his team report their findings and their recommendation for clinical trials in the August 14 issue of "Proceedings of the National Academy of Science." Korth is one of three founding scientists of Prionics Inc. a spin-off research company at the University of Zürich, Switzerland.

Korth advocates the immediate establishment of clinical trials to investigate the efficacy of the drugs in patients dying of prion diseases. He calls prion diseases "relentless and uniformly fatal."

"It's a big leap from findings in cell culture to those in humans, and we do not know if we will see a favorable response in humans. But the results we saw, in a cell model we consider valid, make this lead worth pursuing immediately," said Dr. Korth.

Korth is a postdoctoral scholar in the UCSF laboratory of senior author Stanley Prusiner, MD, UCSF professor of neurology and biochemistry and director of the UCSF Institute for Neurodegenerative Diseases.

UCSF neurologists, together with the researchers, are "in the final stages of developing a clinical trial to test the efficacy of the two drugs in the treatment of Creutzfeldt-Jakob disease (CJD) and other prion diseases." The two drugs, quinacrine and chlorpromazine, will be tested separately and in combination. The researchers hope to begin enrolling patients later this year. The trial will be the first to test the effectiveness of drugs to treat human prion diseases which can arise spontaneously, be inherited through a genetic mutation or develop through infectious transmission.