May 2007

NIAID Research on Prion Diseases

OVERVIEW

Prion diseases are a related group of rare, fatal brain diseases that affect animals and humans. Also known as transmissible spongiform encephalopathies (TSE), they include bovine spongiform encephalopathy (BSE, or "mad cow" disease) in cattle; Creutzfeldt-Jakob disease (CJD) in humans; scrapie in sheep; and chronic wasting disease (CWD) in deer and elk.

Much about TSE diseases remains unknown. The diseases are characterized by certain misshapen protein molecules that appear in brain tissue. Normal forms of these prion protein molecules reside on the surface of many types of cells, including brain cells, but scientists do not understand what normal prion protein does. On the other hand, scientists believe that abnormal prion protein, which clumps together and accumulates in brain tissue, is the likely cause of the brain damage that occurs in TSE diseases. Scientists do not have a good understanding of what causes the normal prion protein to take on the misshapen abnormal form.

The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), conducts TSE disease research in its Rocky Mountain Laboratories (RML) in Hamilton, Montana, and also funds prion disease research in university labs. Two other NIH institutes also fund prion disease research-the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA).

Variant Creutzfeldt-Jakob Disease

In some cases, TSE diseases appear to be infectious. For example, there is good evidence that a newly discovered TSE disease-variant Creutzfeldt-Jakob Disease (vCJD)-was first spread to humans from cattle infected with BSE. Identifying the transmissible agent is still an ongoing area of research.

A leading hypothesis about the origin of vCJD is that abnormal forms of prion protein ingested through diseased meat may sicken people by causing normal human prion protein to form incorrectly. This change from normal to abnormal prion protein spreads in the brain, where the misshapen protein aggregates in the spaces between brain cells and may produce disease. An alternative hypothesis is that the disease could be transmitted by a virus that subsequently triggers the process of forming abnormal prion protein.

Health officials in the United Kingdom have responded to evidence that beef infected with BSE may have spread vCJD to humans. Since the 1980s, when the BSE epidemic began in the United Kingdom, millions of cattle in Europe have been destroyed. In 1997, the U.S. Department of Agriculture (USDA) then reacted by outlawing feeding meat and bone meal products to cattle intended for U.S. consumption.

As of fall 2006, worldwide, there have been 200 reported cases of vCJD, according to the Centers for Disease Control and Prevention (CDC). All of these cases were among people who ate beef in a country with a BSE outbreak, and nearly all (164 cases) were in the United Kingdom. Three U.S. cases have been reported, though these individuals were likely exposed to BSE agent while in the United Kingdom.

The first North American case of BSE was found in Canada in May 2003. Discovery of the first U.S. case of BSE followed in December 2003 in a Washington State cow. In June 2005, a second cow in the U.S. tested positive for BSE in Texas. USDA ascertained that the cow was born in 2001, 4 years after the 1997 USDA ban. A third BSE-infected cow was found in Alabama in March 2006. No cases of endemic vCJD have been associated with consumption of domestic beef in the United States.

Another human type of TSE, CJD, is similar to vCJD but progresses much more quickly and affects older people. CJD is extremely rare with an estimated 1 case per million individuals. Although a majority of cases occur without a known cause, the disease may be inherited. Rare transmission of CJD through infection also has been documented.

CHRONIC WASTING DISEASE

A different TSE disease, called chronic wasting disease (CWD), has been detected in U.S. deer and elk populations in 11 states. So far, scientists have uncovered no evidence that deer or elk with CWD might transmit some form of TSE disease to people who consume or have close contact with deer or elk.

More research is necessary to determine whether CWD poses any risk to humans, particularly because it is spreading over a wider geographical area in the United States. There have been several reported cases of CJD in individuals who have consumed venison, most much younger than the typical age associated with CJD. In each of these instances, careful investigations by CDC have shown no causal link between CJD and CWD in deer and elk populations. Continued surveillance is important, however, to assess any possible risk of CWD transmission to humans.

BASIC RESEARCH

NIAID scientists at RML are examining how abnormal prion protein molecules cause TSE diseases. RML has had an active TSE research program since the 1960s. RML is one of the world's premiere laboratories for studying TSE diseases. Scientists there co-discovered and were among the first to clone the prion protein gene. NIAID scientists also discovered that abnormal prion protein can convert normal prion protein to the abnormal form. This may account for the disease process in the brain.

RML scientists have recently published findings from significant TSE studies. One study showed that when prion protein was modified to remove a membrane "anchor" in laboratory animals, scrapie infection caused formation of abnormal prion protein, but remarkably, did not result in disease. Researchers believe that without the membrane anchor, the abnormal prion protein is unable to damage the brain cells. These results suggest that drugs aimed at blocking interactions between normal and abnormal prion protein might be able to halt the progress of disease. In these same mice where the membrane anchor was removed, scrapie infection led to an accumulation of abnormal prion protein in heart tissue resulting in heart stiffness and malfunction. This research indicates that cardiac infection may be a new and previously overlooked feature of TSE diseases.

In another study, RML scientists used a new methodology to determine the size of the smallest infectious prions. These results demonstrate that the minimal size of the infectious material is equivalent to 5 to 10 prion protein molecules. It is possible, though not yet proven, that these smallest fractions are more infectious than the larger aggregates.

At Colorado State University in Fort Collins, NIAID has established an emerging diseases research center focused on studying CWD. This center is investigating the mechanics of CWD infection in deer and elk. Such studies underlie the search for improved diagnostics and therapies. The researchers also will seek to better understand the entire spectrum of disease transmission and under what circumstances CWD might "jump" to other species.

One recent study concluded that infectious prions are present in skeletal muscles of CWD-infected deer, demonstrating that humans consuming or handling meat from CWD-infected deer are at risk for prion exposure. Though there is no causal proof that CWD is capable of spreading to humans, researchers suggest that individuals use caution when handling infectious material or consuming any part of the animal that may be infected. More recently, the research group at Colorado State University has reported that infectious prions capable of transmitting CWD are found in the saliva and blood of affected deer. This helps to explain the ease of transmission of CWD among deer and suggests caution concerning contact with body fluids of infected animals.

CROSS-SPECIES TRANSMISSION

At RML, studies are ongoing to understand the mechanisms by which TSE infections cross species. Experiments have demonstrated that species once thought to be resistant to certain TSE strains can be life-long carriers of the infection without ever becoming sick. RML scientists also are investigating whether CWD can be transmitted from deer or elk to other species after eating brain matter from deer or elk that are infected with CWD. That knowledge would provide valuable insight into whether this disease could possibly be transmitted to humans.

THERAPEUTIC APPROACHES

Although there are no known ways to cure TSE diseases, scientists around the world are working to develop treatments. Using infected tissue culture cells for fast initial screening, NIAID researchers have tested thousands of compounds and identified hundreds of molecules that inhibit the formation of the abnormal form of prion protein. Further testing of the most potent of these inhibitors has revealed several that can prolong the lives of rodents if treatments begin soon after infection.

In collaboration with NIAID scientists and through a contract with NIAID, researchers at RML and at Utah State University in Logan are testing these compounds in animals. Other groups are further testing two of the inhibitors in CJD patients. New research at RML has shown increased survival times in mice given combination drug treatment therapy 14 to 28 days after scrapie inoculation. Although this will need further exploration, it is a positive step in treatment after the onset of clinical signs of TSE diseases.

RML researchers also have identified antibodies and short synthetic protein molecules (fragments of prion protein) that can block the conversion of normal prion protein to the abnormal form. If successful, these investigations will lead to safe and effective methods to prevent prion infections as well as therapies that work in either the pre-symptomatic or symptomatic phases of disease.

DIAGNOSTICS

Improved diagnostic tests for TSE diseases are critical for the success of both therapeutic strategies and eradication programs. NIAID scientists are exploring various approaches to creating new tests. In addition, NIAID has given CDC funds to better monitor TSE disease incidence and to improve collection of tissue specimens for TSE disease-related diagnostics.

MORE INFORMATION

Other Federal agencies work on prion issues from standpoints of research, public health, food supply safety, and animal health. The following links provide more information.

National Institute on Aging
31 Center Drive, MSC 2292
Bethesda, MD 20892
1-800-222-2225 or 301-496-1752

National Institute of Neurological Disorders and Stroke
P.O. Box 5801
Bethesda, MD 20824
1-800-352-9424 or 301-496-5751

National Library of Medicine
MedlinePlus
8600 Rockville Pike
Bethesda, MD 20894
1-888-FIND-NLM (1-888-346-3656) or 301-594-5983

Centers for Disease Control and Prevention
1600 Clifton Road NE
Atlanta, GA 30333
1-800-311-3435 or 404-639-3534

Food and Drug Administration
Center for Food Safety and Applied Nutrition
5100 Paint Branch Parkway
College Park, MD 20740-3835
1-888-SAFEFOOD (1-888-723-3663)

U.S. Department of Agriculture
1400 Independence Avenue, SW
Washington, DC 20250

World Health Organization
Avenue Appia 20
1211 Geneva 27
Switzerland 41-22-791-21-11

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