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Researchers discover possible diagnosis, treatment, vaccine for mad cow, prion diseases

02.06.2003


Research led by scientists at the U of T and Caprion Pharmaceuticals have uncovered the basis for a diagnostic, immunotherapy and vaccine, providing a way to detect and treat the brain-wasting damage of infectious prions like those found in mad cow disease and its human version, Creutzfeldt-Jakob Disease.


Microscopic image of a tissue sample from a human brain that shows a clump of infectious prions (dark pink area).
Credit: Dr. Neil Cashman of the University of Toronto.


representation showing the tyrosine-tyrosine-arginine amino acid sequence (the yellow, green and purple clumps) on the infectious prion.
Credit: Dr. Neil Cashman of the University of Toronto.



Dr. Neil Cashman, a principal investigator at U of T’s Centre for Research in Neurodegenerative Diseases and professor in the Department of Medicine (neurology) and a Caprion founder, says a vaccine approach - which would likely be of most use in animals and livestock - could prevent animals from becoming infected. For humans with diseases like classical or variant Creutzfeldt-Jakob, an immunotherapeutic would provide patients with antibodies that bind infectious prions, enabling the immune system to recognize and attack them. For both humans and animals, the diagnostic screening potential of this discovery could significantly improve the safety of the human blood and food systems.

Cashman, who also holds the Jeno Diener Chair in Neurodegenerative Diseases at U of T, says his team tried a new approach in studying infectious prions, which are particles thought to be composed of normal prion proteins that have been compromised and folded into rogue shapes. "The usual way of raising antibodies in the immune system is to grind the infectious agent up and inject it into a mouse to see if it prompts antibody production," he says. "Scientists have tried this method with prions over the past 15 years, all without success. My group decided to examine it from the sub-molecular level to determine if antibodies would recognize and react to the amino acids exposed at the surface of a prion. It was a novel idea, and when we found that our hypothesis actually worked, we were surprised and pleased." The researchers’ findings are reported online in the June 1 version of Nature Medicine.


All mammals have prion proteins, the highest levels of which are present in the brain, explains Cashman, a senior scientist at Sunnybrook and Women’s Research Institute and a neurologist in the Department of Medicine at Sunnybrook and Women’s College Health Sciences Centre. Mammals can contract prion diseases by ingesting abnormal or infectious prions. From the digestive system, these prions make their way to the brain. When an abnormal prion comes in contact with a normal prion protein, it causes the protein to misfold, thus creating a copy of the infectious prion. Cashman says the process is more akin to co-opting than replication. However, since the abnormal prion has similar characteristics to the original host protein, the immune system does not recognize it as a foreign invader and does not attack it.

In their study, Cashman and his colleagues examined the role of chemical groups in amino acids, which are called side chains. "We wanted to see whether there were side chains accessible on abnormal prions that were not accessible on the normal protein. We hypothesized that in a normal prion protein, there will be side chains buried in the interior of the molecule. When the protein converts to the abnormal form, we thought that some of these side chains would then be exposed on the molecular surface. We discovered that the newly exposed side chains of abnormal prions include a sequence composed of three amino acids - tyrosine, tyrosine and arginine (Tyr-Tyr-Arg). By raising antibodies against the Tyr-Tyr-Arg amino acid sequence, the immune system became able to recognize the abnormal prion as an invader and attack it."

"It was a ’Eureka!’ moment," he recalls. "Significantly, while the antibodies recognized the abnormal prions, they left the normal prion proteins intact."

Cashman and his team further found that the tyrosine-tyrosine-arginine amino acid sequence appears to be common among species. "Different species have different sequences of prion proteins," he says. "But this Tyr-Tyr-Arg motif appears to be the same in every species that we’ve been able to look at - humans, cattle, mice, hamsters, sheep and elk. When we applied our antibodies to the infected tissues and cells of our samples, they only bound to the abnormal prion protein in all these species."

The researchers are currently testing a possible vaccine to prion disease in mice. They plan to immunize mice with the Tyr-Tyr-Arg sequence and then infect them with prions.

"In order to treat prion diseases in the most effective way possible, it is necessary to understand the manner in which prion proteins fold into a pathological form," says Dr. Bhagirath Singh, scientific director of the Institute of Infection and Immunity of the Canadian Institutes of Health Research. "Dr. Cashman’s discovery is a vital step in understanding the causes of prion diseases and will play key a role in developing vaccines and a new generation of drugs to combat this condition."

The immediate commercial applications of the discoveries are diagnostics, as global health authorities urgently seek to ensure that beef and transfused blood are safe from Mad Cow-related infections. "Neil’s discovery represents the single most promising hope for diagnosing and treating this fatal disease," notes Lloyd M. Segal, president and CEO of Caprion. Caprion has already announced collaborations with Johnson & Johnson and IDEXX Laboratories to apply these technologies for the development of diagnostics for prion-related diseases, he adds.


Caprion provided the major funding and support for this pioneering research and own all commercial applications of the discoveries. This research was also supported by the Canadian Institutes of Health Research and McDonald’s Corp.

CONTACT:

Janet Wong
U of T Public Affairs
416-978-5949
jf.wong@utoronto.ca

Neil Cashman
Centre for Research in Neurodegenerative Diseases
416-978-1875
neil.cashman@utoronto.ca

Kathie Darlington
Caprion Pharmaceuticals Inc.
514-940-3608


Janet Wong | EurekAlert!
Further information:
http://www.caprion.com
http://www.utoronto.ca/

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