Antibodies could combat prion-based diseases

LONDON A team from Imperial College School of Medicine are hopeful that they have discovered a way to prevent and destroy prion-based infections, such as scrapie, BSE and vCJD. A study, published in July 31 Proceedings of the National Academy of Sciences, found that treating cell cultures susceptible to mouse scrapie with an anti-prion antibody not only prevented infection of these cells but also cured chronically infected cultures (Proc Natl Acad Sci USA, 2001 198:9295-9299).Enari et al. suggested that their findings support the idea that immunisation could provide a feasible therapy for prion-based diseases; although they admit there still is a long way to go before this could become a clinical reality. "These are tissue culture cells, so we still have to find whether the same thing happens in animals, let alone in people," Charles Weissmann, who led the research at the Medical Research Council's Prion Unit at St Mary's Hospital, Imperial College School of Medicine, London, commented in the journal New Scientist.It is thought that the infectious agents causing certain degenerative disorders of the central nervous system consist solely of protein — called proteinaceous infectious particles, or "prions". These prion-based diseases are known as spongiform encephalopathies because the post mortem appearance of the brain shows large holes (vacuoles) in the cortex and cerebellum. Most mammalian species appear to develop these diseases, with the most well known examples being BSE, scrapie and the variant form of Creutzfeldt-Jakob disease (vCJD).The suggestion that proteins alone can cause and spread disease has provoked a great deal of scepticism within the scientific community. "This case is so unusual because although it is clearly an infective agent, scientists are still trying to prove that the agent is only a protein. Many scientists believe this is the case but others feel that transmissible diseases require some form of genetic material in order to establish an infection in a host," said Geoff Oldham, scientific assistant to the director at the Institute for Animal Health.To explain how prions can cause infection, the "protein only" hypothesis proposes that prions multiply in a very unusual way by converting normal protein molecules into harmful forms by inducing the molecules to change their shape. In the case of spongiform encephalopathies, the causative prion is thought to be similar to PrPC, the cellular form of the prion protein, which is found in most organs but most predominantly in the brain. It is thought that when the abnormal prion enters an organism, it can convert the alpha-helical structure of PrPC into a scrapie form of the prion protein, or PrPSC (which is thought to be in a beta-sheet form). It is not clear whether PrPSC is a major or the sole constituent of the causative prion.Previous studies have suggested that this abnormal form of the protein accumulates in the brains of people with vCJD, sheep with scrapie and cows with BSE; and also that suppressing PrP expression might be a successful approach to controlling and treating prion diseases. To examine ways of inhibiting prion infection, Weissmann and his team grew mice neuroblastoma cells in culture and infected them with a strain of mouse scrapie.As expected, the cells began producing prions but when the researchers exposed the infected cells to a monoclonal anti-PrP antibody — 6H4, this prevented the production of the prion proteins for up to six weeks after the antibody treatment had been given. They also found that the prion proteins that had accumulated before treatment also disappeared, which surprised them because prion proteins had previously been assumed to be virtually indestructible. They also treated infected neuroblastoma cells with the bacterial enzyme phosphatidylinositol-specific phospholipase C (PIPLC), which strips cells of all surface proteins, including PrPC. As observed with the antibody, PIPLC prevented the formation of PrPSC, implying that production of the prions was impossible once PrPC was no longer available.This suggests that the antibody works by blocking PrPC on the surface of cells, which both degrades existing PrPSC and prevents the formation of further PrPSC. They argued that this supports the theory that the contact between PrPC and PrPSC is key to the infective process.Weissmann said that although he was excited by the findings, there is a risk that the treatment might not work in people. "The next step is to try it in mice," he said. And even if it works in animals, scientists would need to develop different antibodies that mask the human PrPC protein. They would also need to find a way of getting the antibodies into the brain, which is not a trivial task."Despite this, he hopes that passive immunisation could one day be used to treat prion-based diseases. Passive immunisation involves administering antibodies to an animal to fight illness and is used when the organism is not making antibodies itself - as opposed to the conventional "active" immunisation, where an agent is delivered to raise antibodies.Studies have indicated this approach could be successful in other degenerative diseases. Using models for Alzheimer's disease it has been shown that antibodies against the Alzheimer's peptide — Aβ — can cross the blood-brain barrier and lead to the reversal of amyloid deposition - thought to be a hallmark of the disease.

Antibodies could combat prion-based diseases

The discovery that antibodies seem to be effective against prions could open the door to immunisation against spongiform encephalopathies.

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