In findings that could portend ways to stymie a host of deadly and bizarre brain disorders, British researchers have shown that a synthetic version of nature's prime disease-fighting weapon can foil agents implicated in "mad cow" disease, its human equivalent and related neurological ailments.
The team observed that injections of monoclonal antibodies -- laboratory-produced proteins made in the image of the body's own health-protecting mechanisms -- kept infected mice alive and well nearly a year after their untreated counterparts had succumbed to the incurable degenerative disorder.
In the experiments, the front that typically defends against harmful foreign invaders, such as bacteria, toxins and viruses, appeared to stand its ground against powerful new antagonists: prions. The strangely folded proteins, which can wreak havoc with the nervous system, have a poisonous effect, killing brain cells and, ultimately, the patient.
Injections of monoclonal antibodies -- which apparently can block replication of the misfit protein -- significantly lowered prion levels in rodents suffering from a form of scrapie, a prion affliction that normally affects sheep, investigators discovered.
Their report, to be published in the March 6 issue of the British journal Nature, is the first to show the versatile immune system molecules can stop the misshapen proteins from duplicating in an animal infected with prion disease, said lead study author Simon Hawke of Imperial College London.
"This is the first time (researchers have shown) that a treatment works even when it starts after infection," Jiyan Ma, assistant professor of molecular and cellular biochemistry at Ohio State University in Columbus, told United Press International.
"This makes antibody treatment more feasible as a real treatment."
Hawke warned against reading too much into his findings, however.
"I'd like to urge caution about interpreting the results, as the work does not provide an immediate clinical preventative treatment or cure," he emphasized. "The work is a key scientific advance, but there is much more development work to be done before we can begin to think about translating this research to the clinic. The good news is we're making promising advances towards a possible treatment."
The results from the 17-month study lend support to a growing body of evidence pointing to the potential of besting disorders formerly beyond medical reach with the antibody molecules. The tools already have proven their worth in an impressive array of medical applications, from pregnancy testing kits to medical imaging to drugs designed to prevent rejection of transplanted organs to therapies for cancer, autoimmune disease, cardiovascular disorders and infections.
In the new study, the researchers sought to establish a proof of principle they could attempt to use to target the prion protein and suppress the disease process.
"These findings are encouraging and have shown this approach has the potential to develop into a therapeutic method," said Ma, who was not involved in the research.
Prions set the course to destruction when a single molecule folds the wrong way and starts a lethal chain reaction that decimates nerve cells in the brain and destroys neurological function.
There is no cure for the resulting fatal diseases, called transmissible spongiform encephalopathies.
TSEs can affect most mammals. In humans, the disorders include Creutzfeld-Jakob disease, Kuru, fatal familial insomnia and Alpers syndrome. In animals, prions can bring on scrapie in sheep, chronic wasting disease in deer and bovine spongiform encephalopathy in cattle. In England in the late 1990s, an epidemic of BSE, commonly called mad cow disease, forced the slaughter of 3.7 million cattle and nearly annihilated the country's beef industry.
Prion diseases in humans can be hereditary and linked to a genetic flaw. Or, they can occur sporadically at a rate of about one case per million individuals. The ailments also can take on a contagious form, spreading like an infection. At least 93 people died after exposure to BSE in England caused them to develop its human equivalent, called variant Creutzfeldt-Jakob disease.
Although the antibodies lowered prion levels and stopped development of the disorder in the mice, they did not work when disease symptoms appeared, the study authors stressed. Also, the molecules cannot pass into the brain where prions act to cause CJD and vCJD, they cautioned.
"This is the first time that any agent has effectively suppressed prion replication once it has taken hold," Hawke told UPI. "But it didn't work late in the incubation period when animals started to develop neurological disease."
Nevertheless, the results should encourage researchers to refine this therapeutic strategy against specific prion diseases, the authors asserted.
Adriano Aguzzi, professor at the Institute of Neuropathology in Zürich, Switzerland, told UPI the study added little new information of significance to his analysis -- published in Trends in Molecular Medicine in November 2001 -- of the prospects for anti-prion vaccines. That review included his own experiments that involved inoculating genetically engineered mice against scrapie.
Ma disagreed.
"Prion diseases were considered not treatable only a few years ago," he said. Ma recently uncovered the prions' killer mechanisms and described the details in the journal Science.
"This is the first successful example of post-exposure prophylaxis, which is very encouraging," he added.
The success of an antibody strategy will depend on the availability of a reliable test to diagnose the disease before symptoms appear -- something not yet on hand, Hawke noted.
In his study, one group of mice received antibody injections twice a week beginning either seven or 60 days after being infected with scrapie prions but before showing any neurological signs of the disease.
The antibodies seemed to stop the conversion of the normal prion protein into the abnormal infectious form, preventing its dangerous accumulation. The antibodies also appeared to delay the onset of disease, the researchers found, noting the rodents showed no symptoms more than 300 days after untreated animals had died from the disorder.
Other mice, first treated 150 days after the appearance of the scrapie symptoms -- which can include changes in behavior, mobility and sensitivity and wool/hair and weight loss -- failed to improve and died.
"The results indicate that targeting the conversion process is a very useful strategy," Hawke told UPI.
The researchers already have begun tests to determine whether the disease in the survivors was suppressed or eradicated and whether the illness will recur once treatment stops. They also want to learn how much medicine they should give and for how long.
The study animals showed no ill effects from the treatment, but it is premature to rule out the possibility of such in humans, the researchers said. In the next phase, they hope to boost the antibody levels in animals when symptoms develop.
"If large enough concentrations of antibodies can be achieved in the brain, then treatment of patients with neurological disease might be possible," Hawke said, "but we can't even begin to contemplate this until we've done work to humanize the antibodies."
That process will involve genetically engineering the man-made mouse molecules to resemble human antibodies more closely. If successful, they might then be used as drug treatments. Because the technology required for such a feat already is well established, the researchers expect the deed to be done within two years.
"We do plan to do this, and then we plan to pump these humanized antibodies directly into the brains of patients with CJD," Hawke said, adding the researchers will not know the effectiveness of the strategy until they try it.
"By demonstrating that monoclonal antibody technology could work for illnesses like CJD," Hawke concluded, "we've made a promising start."
