By Dean A. Haycock

Special to BioWorld Today

Prion diseases are unique in the world of infectious disease. Also known as transmissible spongiform encephal opathies (TSEs), they affect sheep, cattle, mink, deer, elk and humans. They are called spongiform encephalopathies because autopsies reveal large vacuoles, or empty spaces, in the brain cells of those infected. An intriguing feature of TSEs can be traced to the nature of the disease-causing entity itself: an infectious protein that, most likely, has no nucleic acid component.

Another unusual aspect of TSEs is the notion that they can be either infectious or hereditary diseases. Some TSEs appear to be sporadic, with no obvious risk factor involved, while others can be acquired via hereditary transmission as a non-sex-linked, dominant trait. The seemingly sporadic cases very likely may be the result of acquired infections following surgical procedures, corneal or other transplants or injections of growth hormones. In the case of one TSE, Kuru ¿ now very rare ¿ the route of transmission turned out to be cannibalism.

Four years ago, the first hints appeared that the twisted little proteins have crossed species barriers by hitching rides in cattle byproducts, which are present in a remarkable number of items used in Western society. The prion disease that affects cattle is called bovine spongiform encephalopathy. This is the source of "Mad Cow" disease, which has affected more than 40 individuals and may affect many more in coming years. Mad Cow disease is a variant of Creutzfeld-Jacob disease, a TSE that affects approximately one person in a million per year. Other human diseases caused by prions are Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia and Alpers syndrome.

There are no effective treatments to prevent the loss of motor control, paralysis, wasting, dementia and eventual death produced by these infections. But there are some promising leads, such as those described in "Porphyrin and Phthalocyanine Antiscrapie Compounds," an article by Suzette Priola and her colleagues in the February 25, 2000, issue of Science.

Disease-causing prions appear to be modified forms of normal cellular proteins known as PrP-sen (sen for protease sensitive). They are found on the surface of neurons and can be degraded by protein-eating enzymes, proteases. The infectious prion is designated PrP-res (res for protease resistant). It is resistant to the action of proteases and accumulates in the brain cells of infected animals and humans. Introducing abnormal, "diseased" PrP-res into a brain is believed to induce the conversion of normal, "healthy" prions, PrP-sen, into PrP-res proteins. This process very likely involves a conformational change in PrP-sen to produce PrP-res.

A class of compounds called cyclic tetrapyrroles can selectively bind to proteins and prevent conformational changes. This makes them obvious candidates as anti-TSE drugs. Priola, an Investigator with the National Institute of Allergy and Infectious Diseases, National Institutes of Health at the Rocky Mountain Laboratories in Hamilton, Mont., and her collaborators demonstrated this in an animal model of TSE. The model is a transgenic mouse that overexpresses hamster PrP-sen. The investigators injected high doses of hamster scrapie, a form of prion first recognized in sheep, into these mice.

Starting on the same day of infection, they injected the mice three times a week for a month with one of three structurally different cyclic tetrapyrroles: DPG2-Fe3+, TMPP-Fe3+ or PcTS. All significantly increased the survival time of infected mice and delayed the disease compared to untreated controls. The better the compounds inhibited PrP-res formation in vitro, the better they worked in vivo. So, the least effective compound in test tubes increased survival in mice by a mean of 37 days whereas the stronger inhibitor in vitro, TMPP-Fe3+, prolonged survival by 90 days. The strongest inhibitor in vitro, PcTS, increased mean survival time by 135 days compared to untreated controls.

"We have shown that three structurally different forms of these compounds all work, suggesting that now there may be a lot of these [compounds] that can work," Priola said. "We are not saying that we have the best one right off the bat, but there may very well be far better ones or we could make far better ones."

Such compounds may have a prophylactic use. "Ongoing experiments suggest that we can give them quite a ways before infection and they work," Priola said. No compound has yet been identified that works after the disease has had a chance to spread in the brain.

Robert Petersen, associate professor of pathology at Case Western Reserve University in Cleveland and vice president of Prion Developmental Labs in Buffalo Grove, Ohio, commented on the research for BioWorld Today. "If you can find a chemical compound that can inhibit the ability of the converted prion protein [PrP-res] to transmit disease, then you potentially have a way of securing the safety of the blood supply," he explained. "Secondarily, if you have a chemical that you can use to block the transmission of the disease which is believed to occur by one protein causing another protein to change its shape, ultimately you should be able to find an appropriate chemical that would be able to get to the cells in the brain that have this process occurring."

It will be important, Petersen added, that such a treatment be used in conjunction with early diagnostics. "Early diagnostics is one component that also needs to be developed in order for this to be a really significant part of our program to deal with these diseases in a therapeutic manner," he said.

Priola and her colleagues are continuing to study different chemical structures. "We are taking the best inhibitor that we have so far, PcTS, and looking at modified forms to see if any work better or can work later, for example," she said. She and her collaborators also are testing the compounds in different animal model systems.

"Many of them [cyclic tetrapyrroles] bind to proteins and interact with proteins," Priola said. "The logical extension of that is that they 'might' be useful in other diseases where protein accumulation is a problem. That could be something like Alzheimer's disease or Huntington's disease. I don't know if it will turn out that way, but it is a logical thing to think about."