Understanding how prions move through the food chain is an important step in tackling the neurogenerative disorders with which they are linked. Two new pieces of research, one in Germany, the other in England, have shed light on how prions spread and how they can be disabled.
Prion diseases are a group of progressive neurodegenerative conditions that exist in both animals and humans. The first to be identified, in the 1730s, was scrapie. It affects sheep and goats.
More recently prion diseases have been seen in animals, the most common of which is bovine spongiform encephalopathy (BSE). Various forms of the disease have been identified since Creutzfeldt and Jakob first described the illness in 1920s.
With the onset of new forms of Creutzfeldt-Jakob disease, much research today is focused on how prions move through food chains and what can be done to stop them causing disease.
One of the most important recent developments came in May, with publication of the European Molecular Biology Organisation's journal. In it, researchers from the German Robert Koch Institute in Berlin report finding the pathological prion protein PrPSc in a wide range of skeletal muscles after feeding hamsters with prion-infected food.
PrPSc is believed to be an essential if not the sole constituent of the agent that causes BSE in cattle, scrapie in sheep and Creutzfeldt-Jakob disease in humans.
The researchers used Western blot analysis to analyse concentrated extracts from different muscles in the animals. They subsequently detected the pathological prion protein in various types of skeletal muscle of the terminally-ill animals. A control group of uninfected hamsters did not show pathological prion protein in their muscle tissue.
"These results support and expand on recent observations by Stanley Prusiner and his colleagues, who found scrapie agent in the hind limb muscles of mice whose brains had been injected with prions,“ says Michael Beekes, researcher at the Institute.
Until recently, PrPSc has normally been found in the central nervous system or in the lymphatic system, for instance, but never in skeletal muscle.
"However, we have to clearly state that these results in mice and hamsters do not necessarily mean that skeletal muscles of cows or sheep infected with BSE or scrapie, respectively, actually do contain prions. At present, the experiments only suggest that more research needs to be done in this area,“ he added.
Meanwhile, UK scientists have made a major scientific advance by establishing proof of principle that the development of prion disease can be prevented in mice using monoclonal antibodies (mAbs).
The work lays the foundation for further research to explore the potential of mAbs to treat specific prion diseases such as CJD and vCJD. The work was published on 6th March in Nature.
Mice in the 17-month study treated with mAbs remain clinically healthy almost a year after the untreated mice succumbed to the disease. Although the work is in its infancy and clinical studies with patients are some years away, the results raise the real possibility that mAb therapies might be effective against prion diseases.
Monoclonal antibodies are very versatile, forming the basis of many successful diagnostic tests, and an increasing number of therapeutic drugs. They are immune system molecules that bind very strongly to their target, in this case the prion protein.
A group of mice infected with scrapie prions (PrPSc) were given therapeutic doses of mAbs before they became ill with neurological signs of prion disease. The mAbs appear to have stopped the conversion of normal prion protein into the abnormal infectious form, preventing it accumulating. More importantly the mAb treatment appears to have delayed the onset of clinical disease indefinitely. The mice remain healthy.
A different group of mice were given mAbs for the first time once neurological symptoms of scrapie had developed and no therapeutic effect was seen. The mice later succumbed to the disease.
The work was funded by the UK's Medical Research Council (MRC) with additional support from the Department of Health. The research team was led by Simon Hawke at Imperial College London in collaboration with Professor John Collinge at the MRC Prion Unit at the Institute of Neurology and Professor David Anstee at the National Blood Service.
Research will now focus on achieving higher mAb concentrations in the brain when neurological symptoms and signs develop. Work will also be needed to ahumanise' the mAbs by genetically engineering them to more closely resemble human antibodies before they can be used for treating patients.
Hawke noted: "I'd like to urge caution about interpreting the results, as the work does not provide an immediate clinical preventative treatment or cure. 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.“
He added: "On one hand, if future tests can identify those who are ill before neurological disease sets in, then mAbs might form the basis of a useful preventative treatment. Of course, the success of this strategy will depend on the availability of a reliable test to diagnose CJD in pre-symptomatic patients, which doesn't yet exist. On the other hand, if large enough concentrations of antibodies can be achieved in the brain, then treatment of patients with neurological disease might be possible, but we can't even begin to contemplate this until we've done work to humanise the antibodies.“
According to the NHS National Prion Clinic website (http://www.st-marys.nhs.uk/specialist/prion/ index_prion.htm), a humanised mAb against prion protein could be used in patients. However, it cautions that there is no certainty about them working even outside the brain.
For this reason, the Clinic believes it is far too early to say whether such a treatment will eventually be offered. So for the moment, it is busy developing infrastructure to perform clinical trials in collaboration with the MRC Clinical Trials Unit and continue to study the drug quinacrine for experimental treatment of CJD.
It is expected that much will be learned in the course of ongoing studies about how better to monitor the progression of CJD and to design better clinical trials in the future which would allow us to assess therapeutic antibodies.
The site also cautions: "It is always important to emphasise that any new aexperimental' treatment caries risk and may do harm as well as good and careful assessment in a clinical trial is necessary to determine whether any new therapy offers overall benefit.“
