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_ executive Summary Transmissible spongiform encephalopathies (TSEs), or prion diseases, are inevitably fatal neurodegenerative diseases of long incubation affecting humans and animals. In this report, the Institute of Medicine's (IOM) Committee on Transmissible Spongiform Encephalopa- thies: Assessment of Relevant Science recommends research to close signifi- cant gaps in present knowledge of TSEs and techniques to strengthen the U.S. research infrastructure for studying these diseases. This report fulfills a request of the U.S. Army's Medical Research and Materiel Command for advice from the IOM on the most effective research agenda for the National Prion Research Program (NPRP), established by the U.S. Congress in 2002. Unlike all other known infectious diseases, TSE infectivity appears to be associated with a misfolded form of a normal cellular protein. The misfolded protein is either the primary or exclusive component of a prion, the infectious agent of TSEs. There is no cure, prophylaxis, or fail-safe antemortem diagnostic test for TSEs. To develop any of these tools to protect human and animal health, the committee determined, the scientific community must first answer fun- damental questions about TSEs and priors. Therefore, the committee rec- ommends that NPRP fund basic biomedical research on the structural fea- tures of priors; the molecular mechanisms of prion replication; the mechanisms of TSE pathogenesis; and the physiological function of prion protein, the normal form of the misfolded protein of priors. Moreover, the committee recommends that NPRP support research on the epidemiology and natural history of TSEs. 1

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2 ADVANCING PRION SCIENCE In addition to the lack of knowledge about TSEs, an impediment to the development of diagnostics and therapeutics for these diseases is the limited infrastructure available for studying them in the United States, the commit- tee found. Consequently, this report includes several recommendations for augmenting the U.S. infrastructure for TSE research. Notably, the commit- tee suggests that NPRP attract and train more investigators and provide grants of 5 to 7 years for research in animals (because prion diseases incu- bate for years). The report also recommends the expansion or upgrading of existing laboratories, animal facilities, and containment laboratories and the construction of new ones. Finally, the committee advises NPRP to sup- port new or established repositories for collections of materials and animals that investigators around the country could borrow for their experiments. As noted, no existing drugs are effective in treating TSEs, although many have been tried. NPRP should support research to develop new thera- peutic agents, including antibodies, that would either block the conversion of normal prion protein to the abnormally folded form or disrupt the mo- lecular mechanisms of TSE pathogenesis after conversion has occurred. The most promising approach appears to be the design of agents that attack a specific site on the target protein molecule. These same therapeutic agents may have applicability for detection as well. The development of TSE diagnostics will require quantum leaps rather than marginal improvements of existing tools, the committee concluded. Existing tests are several orders of magnitude less sensitive than is optimal. Thus, the committee advises NPRP to support the development of truly novel methods and reagents that detect or bind to priors, including new antibodies, peptides, nucleic acids, synthetic derivatives, and chimeric molecules. Because of the present limitations of prior-detection tools, it is un- known whether the blood of a human who has a prion disease is a vehicle for transmitting the disease to another individual. However, recent animal studies showed that two different TSE agents could be transmitted from TSE-infected sheep to uninfected sheep by the transfusion of sheep blood. Therefore, the committee recommends that NPRP support research to de- termine the risk of prion transmission through human blood. The outbreak of the TSE called bovine spongiform encephalopathy (BSE), commonly known as mad cow disease, in the United Kingdom and the consequent emergence of variant Creutzfel~t-Takob disease in humans demonstrated the importance of good surveillance for TSEs. The United States could strengthen its TSE surveillance systems through research into the natural history, prevalence, distribution, exposure and transmission characteristics, host susceptibility, and host range of TSEs, especially of chronic wasting disease (CWD), a TSE of elk and deer that is epidemic in this country. The committee recommends that NPRP support such studies.

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EXECUTIVE SUMMARY 3 Human TSEs in the United States are underrecognized and under- referred for definitive diagnosis, the committee found. It is recommended that NPRP support efforts to ensure that a greater proportion of suspected cases are identified and autopsied, because the only way to diagnose a TSE definitively at present is through a neuropathological exam. The most effective strategy for managing the threat of TSEs is to avoid preventable exposure to the infectious agent, the committee concluded. U.S. measures to prevent the tissue of cattle infected with the agent of BSE from entering the food chain are not foolproof, however, the committee found. Therefore, the committee recommends that NPRP fund research to improve rapid, accurate, and affordable screening assays for detecting central ner- vous system (CNS) tissue in processed meat products, since prions reside primarily in CNS tissue. In addition, the committee notes that a review of U.S. policy on specified risk materials, the mammalian tissues most likely to contain TSE infectivity, would be appropriate. Finally, the committee high- lights the potentially damaging economic effects of the discovery of even a single case of BSE in the United States. Studies evaluating the human risks associated with the infectious agent of CWD should also be funded, the committee recommends. There is no evidence to conclude that CWD is transmissible to humans; however, the theoretical risk of infection led the committee to advise people to avoid exposure to CWD-contaminated meat and meat products. The wide range of practices for processing venison, the paucity of regulation or oversight in this area, and the many opportunities for spreading the CWD agent influ- enced the committee's conclusions in this regard. There is a very small but unknown level of risk that U.S. forces and their dependents who were stationed in Europe during the 1980s and l990s acquired a TSE, the committee determined. Consequently, the committee recommends that the occurrence of TSEs in this population be monitored through established data systems in the Department of Defense and the Department of Veterans Affairs. Clearly, many unanswered questions remain regarding prions and TSEs. The recommendations in this report should provide a framework for re- search, especially basic research, leading to the development of effective diagnostics and therapeutics. Such research could advance scientific knowI- edge relevant to many neurodegenerative diseases in addition to TSEs. The reader is directed to the report summary for a more comprehensive and referenced discussion of all the committee's recommendations, only a por- tion of which are discussed above.

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