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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.
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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
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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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Representative terms from entire chapter:
molecular mechanisms
