Scientists Find Way to Tame Rogue Proteins

Scientists Find Way to Tame Rogue Proteins

August 17, 2001 HealthScoutNews by Adam Marcus

THURSDAY, Aug. 16 (HealthScoutNews) -- Genetically engineered molecules that keep rogue proteins from spreading their bad influence may one day be a treatment for a family of degenerative brain disorders related to mad cow disease.

The engineered molecules -- immune proteins called antibodies -- appear to clear renegade infectious proteins by preventing them from binding to healthy cells.

Mad cow disease belongs to a group of deadly neurological maladies called transmissible spongiform encephalopathies, or TSEs. Neither bacterial nor viral, these "infections" are caused by a type of protein called a prion. Normally prions are harmless, but when they turn infectious, they are marked as killers by their folded shape change. Although these renegade prions don't spark an immune response, they're considered infectious because they can start a chain reaction of turning normal prions into the infectious form.

There is no cure or effective treatment for TSEs. They often take decades to cause symptoms, but once they do, they can kill a patient within a year. In this disease, the brain becomes increasingly filled with holes, causing personality changes, memory loss and myriad other symptoms of gross mental decline.

Although mad cow disease afflicts cattle, its human analog, new-variant Creutzfeldt-Jakob disease (news - web sites), can be transmitted to people who eat contaminated beef. More than 100 people in Europe have died from the condition. The United States so far has not had any cases of new-variant CJD. But a few hundred cases of conventional CJD are reported in this country each year. No one knows what caused most of them, but some of the infections are believed to be inherited.

The latest study, which appears in this week's issue of the journal Nature, focuses on proteins called antibody antigen-binding fragments, or Fabs. These sticky chains help antibodies, important immune molecules, glom onto antigens (foreign molecules) and, in doing so, help the immune system recognize infections.

A central problem is that prions don't spur the production of antibodies. But Anthony Williamson, an immunologist at the Scripps Research Institute in La Jolla, Calif., and his colleagues speculated that tying Fabs to normal prions might throw up a wall between the normal and infectious prions, preventing them from interacting with each other.

Williamson and his colleagues first used a trick of molecular genetics to convince mice -- or at least their immune systems -- that they didn't have any prions at all. This meant prions of any type were foreign to the mice's immune systems and therefore recognizable as interlopers. That meant that the mice produced antibodies against their own proteins, which Williamson's group collected and cloned. In a dish, they then screened seven Fabs from these antibodies for their ability to block prion binding in mouse cells.

One of those, which they dubbed Fab D18, stopped prion replication and quickly cleared the infectious particles from the mouse cells. Cells treated for a month with Fab D18 were free of prions a month after the treatment was stopped. "To our great surprise we found that the cells were actually able to degrade the pre-existing prions dramatically," says Williamson.

That finding undercuts the dogma about infectious prions, which have been thought to be almost indestructible, Williamson says. In reality, they may be merely engaging in a war of attrition against brain cells, overwhelming the healthy cells' ability to rid themselves of attackers.

The molecule also seemed to prevent the progression of infection in live mice, the researchers say. Animals injected with Fab D18-treated cells contaminated with infectious prions showed no traces of disease for at least 265 days, while animals injected with untreated cells or cells treated with a different Fab developed symptoms after about 165 days.

"We're fairly confident that the cells were cured of prion infectivity," says Williamson.

Williamson and his colleagues now plan to see whether their antibody treatment can cure other animals of prion infection, and if it can prevent the disease in unexposed creatures.

Earlier this week, a group led by Williamson's collaborator, Dr. Stanley Prusiner, found that two drugs now being used to treat malaria and psychological illness may also work against prion diseases. Prusiner, of the University of California at San Francisco, won a Nobel Prize in 1997 for his discovery that spongiform encephalopathies are caused by prions.

Although the researchers are in the process of preparing a clinical trial to test the drugs, quinacrine (used to sterilize women) and chlorpromazine (an antipsychotic drug), they say two patients with Creutzfeldt-Jakob disease are now being treated with one of the compounds.

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