By David N. Leff

A crafty financial finagler named Charles Ponzi launched his famous get-rich scheme right after World War I. Ponzi bilked his gullible investors by paying their principal and dividends with money he raised from later easy marks ¿ and so on.

You, like many people, may have received a chain letter urging you to make X number of copies of the missive and send them, with a small cash enclosure, to friends and relatives, with the same request to keep the chain going. The circulation increased geometrically as long as all recipients played along.

When it comes to the prion diseases ¿ mad cow and Creutzfeldt-Jakob ¿ ¿prion¿ is spelled P-o-n-z-i.

¿The central event in prion propagation,¿ explained molecular immunologist R. Anthony Williamson, ¿is that the abnormal, infectious, form of the protein comes in, interacts directly with the normal cellular form, and causes its structural conformation to change. The end result of that contact is another infectious form of the prion molecule, which sets off a chain reaction ¿ a kind of geometric progression.

Williamson, an assistant professor at the Scripps Research Institute in La Jolla, Calif., is second author of a paper in today¿s issue of Nature, dated Aug. 16, 2001. Its title: ¿Antibodies inhibit prion propagation and clear cell cultures of prion infectivity.¿ Its senior author is Nobelist Stanley Prusiner, who discovered prions 20 years ago, and heads the prion laboratory at the University of California, San Francisco.

¿We believe we¿re inhibiting the interaction from taking place,¿ Williamson told BioWorld Today, ¿and thereby stopping prion propagation in its tracks.¿

In Britain, that infective prion propagation has led to the slaughter of 4 million cattle, to stem the spread of mad cow disease. It has also cost the lives of nearly 100 young men and women, struck down by Creutzfeldt-Jakob, acquired by eating beef from the infected bovines. (See BioWorld Today, July 25, 2001.)

Normal prion proteins, which exist on the surface of many different tissue types in healthy mammals ¿ in particular their brain cells ¿ carry the license-plate PrP^C. Once trapped in the infectious Ponzi scheme, the ensuing pathogenic prions wear the designation PrP^Sc with Sc standing for ¿scrapie¿ ¿ the ovine equivalent of mad bovine.

First Proof Antibody Can Curb Prion Disease

¿The overall finding of our paper in Nature,¿ Williamson said, ¿is that we¿ve used antibodies recognizing the normal form of the cellular prion protein to inhibit prion propagation in a scrapie-infected neuroblastoma cell line. In fact, the cells appeared to be cured of infection following antibody treatment.

¿Some of the antibodies were very effective,¿ he recounted, ¿whereas others were less so. By decorating prion PrP^C ¿ that¿s the normal form of the protein on the cell surface ¿ with antibodies, we think we¿re preventing the chain reaction of the infected form.

¿Having taken a system that was infected and prevented any new infectivity,¿ Williamson went on, ¿the important question is: What happens to the pre-existing infectivity that was in the system before treatment with antibodies?¿ And to our surprise, we found that the pre-existing infection was degraded quite rapidly by the antibody-treated cells. This showed for the first time that cells were able to degrade PrP^Sc, the infectious form of the protein. And that offers hope for therapeutic intervention in these diseases, where you have humans or animals with ongoing prion infection. Not only might you add antibody and prevent the formation of new infectivity, but then animal or human subjects could resolve the remaining infection itself.

¿We generated a panel of seven Fabs ¿ active antigen-seeking antibody fragments ¿ in knockout mice,¿ Williamson recounted. ¿Normally the prion protein is a self¿-antigen; so it¿s difficult to raise antibodies to it. But people have made KO mice in which they removed the prion gene. So those mice couldn¿t express PrP^c. But then we introduced prion protein back into these animals, which their immune systems regarded as foreign. So they raised antibody against it.

¿Then we tested those antibodies in vitro in a neuroblastoma cell line infected with mouse scrapie ¿ which will propagate that infection indefinitely. We put the antibodies into cultures of these cells, then measured the amount of infectious PrP^Sc present in the system. Those first results were very encouraging. They showed the most potent of our antibodies to be a powerful inhibitor of infectious prions.

¿So now we¿ve embarked on animal studies, with two questions: One: Can we take a mouse with an established prion infection, administer antibody, then resolve that existing infection?¿ Second: Can we give the antibodies to mice, then challenge them with infection, and prevent them from becoming infected in the first place?¿ That would be antibody prophylaxis, and prevention ¿ a therapeutic approach for man and beast. Probably within a year we should have some idea of how well we¿re doing.

Prion Principle May Work In Alzheimer¿s Too

¿Antibodies are emerging as viable drugs for various infectious diseases,¿ Williamson observed, ¿and also in diseases with protein conformation. Some of the data that¿s come out of the antibody to the invasive amyloid peptide in Alzheimer¿s disease,¿ he added, ¿is very encouraging. So we may be able to make use of antibodies emerging as a viable tool to treat or prevent diseases of protein conformation, such as prion disease of Alzheimer¿s.

¿Because we use a number of different antibodies, we are focusing in on particular areas of the prion protein that are reacting to inhibiting antibodies,¿ Williamson continued. ¿We may be able to use those protein sequences to screen for small molecules that have advantages over antibodies. Because one of the problems with antibodies is getting them past the blood-brain barrier, whereas small molecules would be orally administered.

¿It¿s not going to be a massive moneymaker,¿ Williamson pointed out. ¿There are maybe one in a million people in the world infected with classical Creutzfeldt-Jakob disease, and a limited number of individuals in the United Kingdom with variant ¿ prion-infected ¿ form. But what everybody is frightened of is that the epidemic is going to take off and perhaps extend to Europe. So it¿s only wise,¿ he concluded, ¿that we should try to develop therapies in order to tackle that eventuality.¿