Advancing Prion Science Guidance for the National Prion Research Program: Interim Report (2003) / Chapter Skim
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Executive Summary
Executive Summary
Pages 1-16
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Unlike all other known infectious diseases, the infectious agent of TSEs appears to be associated with an abnormally folded protein known as a prion (Prusiner, 19821. There is no cure, prophylaxis, or fail-safe antemortem diagnostic test for TSEs, often called prion diseases.
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The origin of vCJD in prior-infected cattle raises the concern that chronic wasting disease, a prion disease spreading among North American deer and elk (Williams and Miller, 2002) , could cause disease in people who consume venison from the affected regions.
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. As part of the contract, MRMC asked the committee to produce an interim report advising the integration panel on the most promising avenues of research for developing antemortem TSE diagnostic tests.
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TSE DIAGNOSTICS Obstacles to Developing Antemortem Diagnostics for TSEs Conventional methods used to diagnose most infectious diseases, such as malaria, tuberculosis, hepatitis, and human irnmunodeficiency virus, fail to detect prion diseases for numerous reasons. A prion is a host protein with an altered conformation such that the immune system does not recognize it as foreign and does not produce antibodies against it.
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The tests must not only differentiate between normal and abnormal prion proteins, but also, for some purposes, discriminate between one or more strains of PrPSc a challenge resulting from basic deficiencies in the understanding of prion strain diversity and the nature of strain variation. This then introduces the ultimate objective of a prion detection test: find a single infectious unit while avoiding a falsely positive test result.
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Cells that have been injured by prion invasion perhaps produce other unique proteins or protein mixes that can be detected. The committee determined that the rapidly expanding field of proteomics may offer new tools for the development of highly sensitive prion detection tests that use such surrogate markers.
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Neuroimaging offers promise as a future clinical diagnostic tool for prion diseases. The committee concluded that newer magnetic resonance imaging techniques, positron emission tomography scanning applications, and multiphoton microscopy should be developed for antemortem detection of TSEs.
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, which may be easier to detect than prions themselves. These unidentified ancillary or chaperoning factors could serve as surrogate markers for prion detection and as drug targets for TSE therapeutics and prophylaxes.
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Investigators must clarify whether the basis for nerve cell dysfunction and death in prion disease is related to the toxicity of PrPSc, to the loss of function of prpc as a result of its conversion to PrPSc and its aggregation during a prion infection, or to other factors. The committee concluded that focusing too much on applied, rather than basic, research accounts for the European Union's slow progress in TSE diagnostics.
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For these reasons, the committee determined that programs funding TSE research should attract and train more investigators and should expand the granting periods for investigators conducting bioassay research to 5 to 7 years. The committee also encourages NPRP to provide funds to increase the capacities of animal facilities and containment laboratories (biosafety levels 2 and 3)
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Because experimental studies have demonstrated that the blood of animals can transmit prion disease by blood transfusion (Hunter et al., 2002) , caution dictates that individuals who have been exposed to BSE-tainted beef products be prevented from donating blood or organs.
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THE RISK OF BSE IN THE UNITED STATES Despite some assurance from a study commissioned by the U.S. Department of Agriculture that concluded that the United States is at very low risk of a BSE epidemic (Harvard Center for Risk Analysis, Harvard School of Public Health, Center for Computational Epidemiology, College of Veterinary Medicine, Tuskegee University, 2001)
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Identify surrogate markers or signatures for the detection of prions or prion diseases. Improve techniques for propagating prions in cultured cells and develop new in vitro cell systems as a means to assay and study priors.
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Provide funding for collaborative research and training with European investigators and facilities that provide unique opportunities for prion research. Establish a collection of reference materials and genetically engineered animals (including transgenic mice)
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2002. Imaging Abeta plaques in living transgenic mice with multiphoton microscopy and methoxy-X04, a systemically administered Congo red derivative.
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2001. Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding.
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