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Posted 12-8-00
CLEVELAND -- Researchers at Case Western Reserve University have joined a test that seeks to develop a rapid, sensitive, and inexpensive screening test to identify for prion diseases in animals and humans.
Prions are the infectious agents that cause a family of fatal neurodegenerative diseases, most notably "Mad Cow Disease" in cattle and a new variant of Creutzfeldt-Jacob Disease (CJD) in humans.
Prion Developmental Laboratories (PDL) of Maryland is leading the effort. It has established research collaborations with three major U.S. research institutions -- including CWRU's School of Medicine -- that are considered leading centers in prion diseases and diagnostic test development.
Leading PDL's scientific advisory board for this project is Robert Gallo, who discovered the AIDS virus. Gallo is professor of virology at the University of Maryland and director of the Institute of Human Virology.
CWRU's Robert Petersen will coordinate the product development collaboration. Petersen is chief scientific advisor to PDL and an associate professor in the Department of Pathology at CWRU's School of Medicine.
"Prion diseases in humans and animals are of increasing concern because these diseases are fatal and cannot be diagnosed early," said Gallo. "The availability of a diagnostic test to detect prion in presymptomatic humans and animals would help to relieve concern about the safety of the blood supply and assist in maintaining the safety of products from animals. Our approach is to assemble novel and highly sensitive diagnostic techniques and adapt them to detect the abnormal prion protein in blood."
"Unfortunately, at present the only way to diagnose 'Mad Cow Disease' in cattle or the human form of the disease, known as new variant CJD (nvCJD), is after the symptoms have developed and the disease is entering its late stages. By then it's usually too late to ensure that infected meat or beef products have not entered the human food supply," Petersen said.
"There is still no treatment for prion diseases, ... but a reliable and sensitive diagnostic would permit the testing not only of cattle, but also of human blood products and tissues before they are used in another person," Petersen added. "This diagnostic would provide a great deal of peace-of-mind among consumers, agricultural and public health officials worldwide."
Among other key scientists involved in the product development program are Pierluigi Gambetti and Man-Sun Sy, professors of pathology at CWRU's School of Medicine; Niel Constantine of the Institute of Human Virology at the University of Maryland; and Richard Kascsak and Richard Rubenstein of the Institute for Basic Research.
Each of these scientists is a recognized expert in human and animal prion diseases, or in the development of sensitive diagnostics for hard-to-detect infectious agents.
"The PDL scientific team is composed of an unparalleled group of prion scientists spanning immunology, virology, neuropathology, protein chemistry, molecular biology, and immunodiagnostic development and testing," said David Grosky, chairman and CEO of PDL. "We are pleased that PDL was able to bring together such a highly qualified group of research scientists to develop this urgently needed diagnostic test."
Prion diseases are a family of fatal neurodegenerative disease that are caused by a prion, an "infectious proteinaceous particle." These diseases occur in humans in both sporadic (or randomly occurring) and genetic forms at a very low incidence, primarily affecting persons older than 50 years of age. Infectious forms of prion disease are also known in animals, including scrapie in sheep and "Chronic Wasting Disease" in mule deer and elk.
In all forms of prion disease, the underlying cause appears to be that the prion protein can occur in two different three-dimensional shapes: normal and misfolded. The abnormal form can induce other normal prion proteins to mimic their shape, thereby leading to dementia and eventual death.
These diseases are characterized by the formation of plaques, which are deposits of misfolded prion proteins accumulating in the brain. The brain becomes spongy and full of holes, leading to the fatal neurodegenerative symptoms. Based on these changes to brain structure, prion diseases are also known as "spongiform encephalopathies" (spongy-like brain diseases).
Prion diseases are difficult to diagnose since they are not amenable to standard detection methods used for identifying bacteria and viruses and since it is difficult to distinguish the normal form of the prion protein from the disease-causing form.
Prion diseases became a worldwide concern with the outbreak in the United Kingdom of Bovine Spongiform Encephalopathy (BSE) or "Mad Cow Disease" in the 1980s among cattle. It appears that cattle were first infected by feed that was supplemented with protein from sheep infected with scrapie. This probably occurred after changes were implemented in the 1970s to the process for preparing animal feed that resulted in infectious prions surviving the rendering process.
Subsequent to BSE appearing in cattle in the UK, a new variant of Creutzfeldt-Jakob disease (nvCJD) was diagnosed in humans. The first reported case of nvCJD was in 1996 when a 19 year old individual died of this rapidly fatal form of prion disease. To date, there have been over 80 deaths reported in the UK, Ireland and France. This is particularly alarming, as it is believed that nvCJD is transmitted to humans by eating infected beef or byproducts from cattle infected with BSE, yet there is still no diagnostic test that can detect the low levels of prions in pre-symptomatic cattle. Since the incubation period for both BSE in cattle and nvCJD in humans is a number of years, the need for a diagnostic is urgent.
Currently there are no rapid, sensitive screening tests that can detect the presence of infectious prions before symptoms appear. There are several tests being used in Europe that can diagnose the disease in cattle once an animal is infected, but these require that a sample of brain tissue be removed at the slaughterhouse and tested in a laboratory. There is an urgent need for a more rapid and sensitive diagnostic that could detect the presence of infectious prions at an earlier stage of the disease and provide accurate results without requiring post-mortem brain samples.
The PDL prion diagnostic test will be developed first in a format that can be used to test cattle at the slaughterhouse, and then secondly for testing human blood at the point of collection, either at a blood bank or plasma center.
In the United States each year over 37 million head of cattle are slaughtered and 25 million units of human blood collected. This prion test will be designed to detect BSE before the overt symptoms appear in cattle, with the objective of ensuring that infected meat or cattle byproducts are removed from the market.
In the United States, a panel of advisors have recommended to the Food and Drug Administration that individuals who have spent more than six months in the United Kingdom between 1980 and 1996 be prohibited from donating blood. In addition, there is consideration being given to banning organ or tissue donations from the same category of people.
While no cases of BSE have been reported in the United States, "Chronic Wasting Disease", a prion disease similar to BSE, has appeared in deer and elk in Colorado and Wyoming.