BioWorld International Correspondent
LONDON - An experimental therapy for people with Creutzfeldt-Jakob disease that involves infusing humanized monoclonal antibodies into patients' brains might be available within five years, a new study in mice suggests.
Researchers who carried out the mouse study emphasize that they do not have a cure for Creutzfeldt-Jakob disease (CJD), and that much work remains to be done before the therapeutic strategy can be applied to humans.
Simon Hawke, clinical senior lecturer in neurology and neuroimmunology at Imperial College in London, told BioWorld International, "The exciting aspect of this work is that we have shown that targeting the process by which normal, healthy prion protein is converted into infectious prions is a very effective strategy for turning off the underlying disease process in living animals."
Hawke, who led the study, predicted that his team's results would give a boost to groups and companies worldwide that have drug discovery programs searching for molecules that target the conversion process. Small molecules that interfere with the conversion would be preferable to antibodies because they might be easier to deliver to the brain, Hawke added.
The study is reported in the March 6, 2003, issue of Nature in a paper titled "Monoclonal antibodies inhibit prion replication and delay the development of prion disease."
Normal cellular prion protein is widely expressed in the mammalian central nervous system and immune system. Little is known about the function of the normal protein, although it might play a role in copper metabolism and the activation of lymphocytes. Mice that have been genetically engineered to not express prion protein appear to be normal except for subtle differences in neuronal excitation.
Prions - the infectious agents that cause the transmissible spongiform encephalopathies such as CJD and bovine spongiform encephalopathy (BSE) - are abnormally folded isoforms of cellular prion proteins. While the normal protein has an open structure with alpha helices, prions are largely made up of beta sheets, which form polymers, aggregates and fibrils in the brain. The accumulation of these deposits eventually leads to the characteristic spongiform changes in the brain.
People with variant CJD (vCJD) are presumed to have eaten food containing the prions responsible for BSE in cattle. There also are inherited forms of CJD, in which the gene encoding the normal prion protein has a mutation that, researchers have speculated, might make it more likely to spontaneously flip from the normal to abnormal form.
Hawke, in collaboration with John Collinge at the Medical Research Council Prion Unit at the Institute of Neurology in London, and David Anstee of the National Blood Service in Bristol, UK, evaluated a therapy to treat a mouse model of CJD. They manufactured monoclonal antibodies that could bind to both normal prion protein and infectious prions.
First, the researchers inoculated normal mice with infectious prions. Normally, mice begin to fall ill about 195 days after the inoculation. At either day seven or day 30 following inoculation, Hawke and his colleagues treated the mice with one of the two monoclonal antibodies.
He said, "We found that this treatment could reduce substantially the evidence that infectious prions were present in the animals' spleens and that it could reduce the animals' infectivity, as measured with an appropriate bioassay." With one of the antibodies, signs of infection were virtually undetectable, he said. The mice are still alive 520 days later and are still being treated. All mice that received control antibodies were dead by day 200.
"These antibodies presumably stabilize the normal form of the prion protein and stop it from converting into the infectious form," Hawke said. "Or it is possible that they somehow cap the prions and stop them from interacting with the normal protein."
Mice that had already started to show symptoms of disease, however, did not respond to the treatment. Hawke says that is probably because the large-molecule antibodies were not able to cross the blood-brain barrier.
A difficulty in developing the strategy as a treatment for people with CJD is that mouse antibodies would provoke immune reactions in humans. To combat that, the team is planning to engineer hybrid monoclonal antibodies in which the bulk of the antibody molecule is encoded by human genes, and only the binding site is encoded by a murine gene.
That approach is likely to take at least two years. Once the humanized antibody is available, Hawke and his collaborators would investigate whether it can be given as a long-term treatment into the brains of people with CJD.