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- ADVANCING PRION SCIENCE Guidance for the National Prion Research Program Committee on Transmissible Spongiform Encephalopathies: Assessment of Relevant Science Rick ErUtmann and Laura B. Sivitz, Editors Medical Follow-up Agency INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Insti- tute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. Support for this project was provided by the U.S. Department of Defense (Contract No. DAMD17-02-C-0094~. The views presented in this report are those of the Institute of Medicine Committee on Transmissible Spongiform Encephalopathies: Assessment of Relevant Science and are not necessarily those of the funding agencies. Library of Congress Cataloging-in-Publication Data Institute of Medicine (U.S.~. Committee on Transmissible Spongiform Encephalopa- thies: Assessment of Relevant Science. Advancing prion science: guidance for the national prion research program / Com- mittee on Transmissible Spongiform Encephalopathies: Assessment of Relevant Science, Rick Erdtmann and Laura B. Sivitz, editors. p.; cm. Includes bibliographical references. ISBN 0-309-09060-1 (pbk.) ISBN 0-309-52714-7 (PDF) 1. Prion diseases. 2. Prion diseases Government policy United States. EDNLM: 1. Prion Diseases prevention & control United States. 2. Food Supply- standards United States. 3. Health Policy United States. 4. Prion Diseases- diagnosis United States. WL 300 I591ad 2003] I. Erdtmann, Rick. II. Sivitz, Laura. III. Title. RA644.P93I55 2003 616.8'3 dc22 2003027266 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334- 3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2004 by the National Academy of Sciences. All rights reserved. Printed in the United States of America. The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin. COVER: The cover photograph, provided by Dr. David Asher, is a histopathology slide of brain tissue from a patient with a prion disease. Stained with the chemicals eosin (red) and hematoxylin (blue), the magnified tissue manifests microscopic holes (white circles) that illustrate why prior-infected tissue is described as spongiform. This report aims to guide scientists beyond histopathology toward new strategies to diagnose prion diseases noninvasively, rapidly, and early.

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"~nowin,g is not enough; we finest apply. Willtin,g is not enough; we must do." Goethe .......... ........ ........... ........ . ::::: :: INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES Shaping the Future for Health

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THE NATIONAL ACADEMIES Advisers to the Nation on Stienre, Engineering, and Medicine The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Acad- emy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Bruce M. Alberts is president of the National Academy of ~ . sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engi- neers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineer- ing programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Wm. A. Wulf is presi- dent of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its con- gressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy's purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Coun- cil is administered jointly by both Academies and the Institute of Medicine. Dr. Bruce M. Alberts and Dr. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council. www. nationa l-academies.org

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COMMITTEE ON TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES: ASSESSMENT OF RELEVANT SCIENCE Richard T. Johnson, Chair, Distinguished Service Professor of Neurology, Microbiology, and Neuroscience, Johns Hopkins University School of Medicine and Bloomberg School of Public Health Harvey l. Alter, Chief of the Infectious Diseases Section and Associate Director for Research, Department of Transfusion Medicine, National Institutes of Health Dean O. Cliver, Professor of Food Safety, Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis Linda D. Cowan, George Lynn Cross Research Professor, Epidemiology, Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, and Liaison from the Board of the Medical Follow-up Agency Roger Y. Dodd, Executive Director for Biomedical Safety, American Red Cross Holland Laboratory Frederick A. Murphy, Professor and Dean Emeritus, Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine. University of California. Davis Michael B.A. Oldstone, Professor, Department of Neuropharmacology, Division of Virology, The Scripps Research Institute David Relman, Associate Professor of Medicine and of Microbiology and Immunology, Stanford University Raymond P. Roos, Marjorie and Robert E. Straus Professor in Neurological Science, and Chairman, Department of Neurology, University of Chicago Medical Center David M. Taylor, SEDECON 2000 and retired Senior Scientist, Neuropathogenesis Unit, Institute for Animal Health, Edinburgh Reed B. Wickner, Chief, Laboratory of Biochemistry and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health Robert G. Will, Professor of Neurology, University of Edinburgh; Director, National Creutzfel~t-Jakob Disease Surveillance Unit; and Consultant Neurologist and Part-Time Senior Lecturer, Department of Neurosciences, Western General Hospital, Edinburgh v

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Consultants Adriano Aguzzi, Professor and Associate Dean for Research, Department of Pathology, Institute of Neuropathology, University Hospital at Zurich David M. Asher, Chief, Laboratory of Bacterial, Parasitic, and Unconventional Agents, Division of Emerging and Transfusion Transmitted Diseases, Office of Blood Research and Review, Center for Biologics Research and Evaluation, Food and Drug Administration Pieriuigi Gambetti, Professor and Director, Division of Neuropathology, Case Western Reserve University, and Director, National Prion Disease Pathology Surveillance Center David A. Harris, Professor, Department of Cell Biology and Physiology, Washington University School of Medicine Stanley B. Prusiner, Director, Institute for Neurodegenerative Diseases, and Professor of Neurology, University of California, San Francisco Elizabeth S. Williams, Professor, Department of Veterinary Science, University of Wyoming Project Staff Rick Erdtmann, Study Director, Medical Follow-up Agency Laura B. Sivitz, Research Associate, Medical Follow-up Agency Reine Y. Homawoo, Senior Project Assistant, Medical Follow-up Agency Karen Kazmerzak, Research Associate, Medical Follow-up Agency (through December 2002) Auxiliary Staff Richard N. Miller, Director, Medical Follow-up Agency Pamela Ramey-McCray, Administrative Assistant, Medical Follow-up Agency Andrea Cohen, Financial Associate Mary Poos, Senior Program Officer, Food and Nutrition Board Tina Rouse, Program Officer, Board on Agriculture and Natural Resources, Division on Earth and Life Sciences v'

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Reviewers This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the NRC's Report Review Committee. The purpose of this independent review is to provide candid and critical com- ments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their review of this report: Barbara Alving Deputy Director National Heart Lung and Blood Institute National Institutes of Health David C. Bolton Head, Laboratory of Molecular Structure and Function New York Institute for Basic Research Bruce W. Chesebro Chief, Laboratory of Persistent Viral Diseases Rocky Mountain Laboratories National Institutes of Health v''

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~ . . Vltt REVIEWERS Robert Finberg Professor and Chair of Medicine Professor of Molecular Genetics and Microbiology University of Massachusetts Colin Masters Professor of Pathology Center for Neuroscience University of Melbourne James Mastrianni Assistant Professor of Neurology Department of Neurology The University of Chicago Hospitals I. Glenn Morris Chair and Professor Department of Epidemiology and Preventive Medicine University of Maryland John E. VandeF~een Emeritus Scientist United States Food and Drug Administration Gerald A. H. Weds Consultant Veterinary Pathologist Head of Neuropathology (Retired) Central Veterinary Laboratory, United Kingdom Charles B. Wilson Senior Advisor Health Technology Center, San Francisco Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations, nor did they see the final draft of the report before its release. The review of this report was overseen by our coordinator, Morton N. Swartz, Chief, lackson Firm of Medical Service, and Chief Emeritus, Infectious Disease Unit, Massachusetts General Hospital; and our monitor, Linda Cork, Professor and Chair of Comparative Medicine, Stanford Uni- versity School of Medicine. Appointed by the National Research Council and the Institute of Medicine, Drs. Swartz and Cork were responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review com- ments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.

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Preface Why is the U.S. government concerned about prion diseases? Known scientifically by the descriptive term transmissible spongiform encephalopathies (TSEs), these diseases do not cur- rently represent significant public health problems in the United States. While it brings incalculable grief to affected families, CreutzielUt-Takob dis- ease (CJD), the primary human prion disease, causes only 1 in 10,000 an- nual deaths worldwide, and there is no evidence that this rate is growing. Bovine spongiform encephalopathy (BSE), the epidemic "mad cow" disease in Europe, has yet to be detected in the United States. Nevertheless, several compelling reasons exist for focusing greater re- search efforts on prion diseases. First, the sudden appearance of BSE in the United Kingdom in the mid-1980s represented a massive and unforesee- able contamination of the bovine and human food supplies. Hundreds of thousands of cattle died, and the infectious agent unexpectedly crossed the species-barrier to humans. In the past decade, more than one hundred young adults have developed a variant of CAD from exposure to BSE. The social, political, and economic impacts of those epidemics of cattle and human diseases in the United Kingdom and continental Europe have been enormous. Consequently, a number of policies have been instituted to ex- clude BSE from the United States and to limit its spread, should it enter the country. iED1TORS' NOTE: After this report was completed, the first U.S. case of BSE was identi fled in Washington State and was announced to the public on December 23, 2003. 1X

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x PREFACE In addition to concerns over the possible introduction of BSE into the United States and the occurrence of cases of variant COD, the presence in this country of a TSE of deer and elk, chronic wasting disease (CWD), has caused alarm. Might this disease spread to cows or humans? There is no evidence that it has, as yet, but European colleagues who have suffered through the BSE crisis are astonished at the paucity of attention that the United States has directed at CWD. They have told me, "You may be sitting on a time-bomb." The second rationale for expanding prion research in the United States is that the studies may provide insights into the pathogenesis of common neurodegenerative diseases, such as Alzheimer's, Parkinson's, and many hereditary neurodegenerative diseases. This is because the abnormal pro- cessing of altered neuronal proteins appears to be a feature of a variety of brain diseases, including TSEs. Prions are believed to be abnormally folded proteins that can replicate by converting normal prion protein into the al- tered conformation associated with disease. This generally insoluble, patho- genic isoform collects in the brain and spinal cord. Studies of the cellular transport of altered proteins, such as priors, could have broad pathogenetic . . . Imps Cations. All prion diseases have long incubation periods extending for years or decades, cause progressive and uniformly fatal neurological degeneration lasting for months, induce pathological changes limited to the nervous sys- tem, and evoke no inflammation or immune response. The idea that a dis- ease of this nature might be transmissible is revolutionary. Moreover, no RNA or DNA has been implicated thus far in the process of prion replica- tion a stunning affront to the central dogmas of biology. Unlocking the secrets of TSEs could advance a new disease paradigm that would help scientists develop treatments for a variety of neurological diseases that af- flict millions of people. The charge to the Committee on Transmissible Spongiform Encephalo- pathies: Assessment of Relevant Science emphasized sensitive and specific diagnostic methods. This emphasis stemmed from concerns about the safety of blood and meat products and the wish to detect prion infections during the incubation period of COD, BSE, or CWD. Diagnosis of infectious dis- eases has traditionally relied on the sensitive surrogate marker of antibodies formed by the host. As noted, however, priors, which are isoforms of a normal host protein, usually do not evoke an antibody response. Newer, highly sensitive tools to detect infectious agents in blood and spinal fluid use polymerase chain reaction to amplify nucleic acids, but this method is inapplicable to prion diseases because nucleic acid does not appear to be involved. Although tests are available to detect altered prion proteins in tissue obtained at death or by biopsy, a blood or spinal fluid test is needed to

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PREFACE Xt diagnose TSEs antemortem. Achieving the necessary level of acuity in such a test will probably require an innovative technology, not simply incremen- tal improvements to known methods of protein detection. More knowledge about the structure of prions and their normal cellular counterparts, about isoform conversion, the cellular trafficking of priors, pathogenesis, and other basic aspects of TSEs will probably be prerequisite to devising a diag- nostic method that increases sensitivity and specificity exponentially. Another issue that the committee was asked to address, the infrastruc- ture for TSE research in the United States, poses special problems. First, a limited number of investigators and laboratories here are dedicated to study- ing TSEs. Second, the usual investigator-initiated grants to universities or research institutes are ill suited for supporting the quantization and charac- terization of TSEs because this research generally involves animal hosts with incubation periods of months or years. Initial grants usually require re- newal and results after only 2 or 3 years, when many TSE studies are still in a preliminary stage. Third, laboratories and animal-holding facilities require varying degrees of complex and expensive biological containment equipment. Fourth, few host institutions can afford to commit faculty posi- tions and facility construction to TSE research. As a consequence of these challenges, new funding methods or the further expansion of government laboratories will be needed to meet the goal of increasing the number of U.S. investigations into prion diseases. In January 2003, our committee published an interim report that dealt primarily with basic biomedical research on TSEs, diagnostics, research infra- structure, and risks to the U.S. military. This final report has new chapters and recommendations on testing blood for evidence of TSEs, on TSE sur- veillance in the United States, and on strategies for TSE prevention and treatment. This report also updates and expands upon the information from the interim report. The broad array of topics discussed here will be of inter- est not only to the scientific and medical communities, but also to a range of readers who want to learn about the multidimensional impact of the bizarre, fascinating, and deadly maladies collectively called prion diseases. Richard T. Johnson, M.D. Chair

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xvi ABBRE VIA TIONS AND A CR ONYMS DHHS U.S. Department of Health and Human Services DOD U.S. Department of Defense DOI U.S. Department of the Interior EC European Commission EEG electroencephalography ELISA enzyme-linked immunosorbent assay EU European Union FCS fluorescent correlation spectroscopy FDA U.S. Food and Drug Administration FFI fatal familial insomnia FLAIR fluid attenuated inversion recovery FSIS Food Safety and Inspection Service, U.S. Department of Agriculture GAO General Accounting Office GPI glycosy! phosphatidylinosito! GSS Gerstmann-Straussler-Scheinker disease HFSP Human Frontier Science Program HIV human immunodeficiency virus i.c. intracerebral(ly) iC}D iatrogenic Creutzfel~t-}akob disease ID50 a dose that infects 50 percent of the population exposed to the . , . infectious agent IGIV immune globulin to be given intravenously IHC immunohistochemistry IMAC immobilized metal ion affinity chromatography IOM Institute of Medicine i.p. intraperitoneal(ly) IU infectious unit i.v. intravenous(ly) kilodalton~s) LCGE laser-assisted capillary gap electrophoresis LD50 a dose that is lethal to 50 percent of the population exposed to an infectious agent ,ug micrograms MRI magnetic resonance imaging

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ABBREVIATIONS AND ACRONYMS MRMC Medical Research and Materiel Command, U.S. Army MUFS multispectral ultraviolet fluorescence spectroscopy NaPTA sodium phosphotungstate NASS National Agricultural Statistics Service, U.S. Department of Agriculture NIH nm NMR NPDPSC National Prion Disease Pathology Surveillance Center NPRP National Prion Research Program (DOD) and National Prion Research Project (congressional language) National Institutes of Health nanometer nuclear magnetic resonance xv't nvC}D new variant Creutzfel~t-}akob disease NVSL National Veterinary Services Laboratories PCR polymerase chain reaction pg programs PK proteinase K, an enzyme that digests cellular PrP PMCA protein misfolding cyclic amplification PRNP prion protein gene in humans Prop prion protein gene in animals other than humans PrP prion protein prpc pro/ease-sensitive cellular prion protein prpsc protein associated with prion disease; has limited resistance to proteinase K prpres pro/ease-resistant protein associated with prion disease PrPCwD protein associated with chronic wasting disease RIA radioimmunoassay sC}D sporadic Creutzfel~t-}akob disease sFI sporadic fatal insomnia SRM specified risk material TME transmissible mink encephalopathy TSE transmissible spongiform encephalopathy USDA U.S. Department of Agriculture vCJD variant Creutzfel~t-Jakob disease VMRD Veterinary Medical Research and Development Inc. WHO WorId Health Organization

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~ . . XVIII FIGURES, TABLES, BOXES, AND PLATES BOXES 1-1 3-1 3-2 3-3 3-4 5-1 5-2 6-1 6-2 6-3 7-1 7-2 2-1 2-2 4-1 7-1 Statement of Task, 32 Priority Research on the Structural Features of Protons, 58 Priority Research on Molecular Mechanisms of Prion Replication, 59 Priority Research on Mechanisms of TSE Pathogenesis, 61 Priority Research on the Physiological Function of PrPC, 63 Requirements for Testing Donors of Whole Blood and Blood Components, 108 Characteristics of New Blood-Donor Screening Tests Considered by the FDA Center for Biologics Evaluation and Research (CBER), 109 Tests that NPDPSC Performs on Suspected TSE Deaths, ~ ~ 7 Goals and Action Items for Nationwide Surveillance of CW]D, 13 ~ Priority Research on the Epidemiology and Natural History of TSEs, 133 Actions Taken by Game Processors to Minimize Contact with the Infectious Agent of CWD, 159 Therapeutic Strategies, 175 PLATES Cartoon of the three dimensional structure of the intact human prion protein, PrP (23-230), 43 Hypothetical models of PrP 27-30, the pro/ease-resistant segment of PrPSc superimposed on an electron micrograph of a two-dimensional crystal of PrP 27-30 after image processing, 44 The results of hematoxylin & eosin (H&E) staining and of immunohistochemistry on slides of human brain tissue from a normal brain, the brain of a patient with sCJD, and a patient with vCJD, 74 Effects of CpG on host immune cells, 179

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Contents EXECUTIVE SUMMARY SUMMARY Origins of This Study, 6 Prions and PrPSc: Definitions and Usage, 8 Basic Biomedical Research, 9 TSE Diagnostics, 10 Testing Blood for Evidence of TSEs, 13 Surveillance for TSEs in the United States, 14 Assessment of Strategies to Prevent and Treat TSEs, 17 Research Infrastructure, 22 The Risk of TSEs to the U.S. Military, 24 Conclusion, 25 References, 29 1 INTRODUCTION Charge to the Committee, 35 Organization of the Report, 35 References, 38 2 PRION DISEASES: AN OVERVIEW Origins and Development of Prion Science, 40 The Nature of Prions and Prion Protein, 43 The Epidemic of BSE and the Emergence of vCJD, 49 Global Impact of BSE and vC}D, 52 XtX 1 33 39

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xx The Spread of Chronic Wasting Disease in the United States, 53 Unique Challenges in Conducting TSE Research, 54 References, 55 3 BASIC BIOMEDICAL RESEARCH ON TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES Structural Features of Prions, 61 Molecular Mechanisms of Prion Replication, 62 Mechanisms of TSE Pathogenesis, 63 Physiological Function of PrPC, 67 References, 68 4 DIAGNOSTICS FOR TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES Clinical Diagnostics, 74 Current Laboratory Diagnostics, 79 Newer, Experimental Diagnostics for Laboratory Use, 89 Research Recommendations for TSE Diagnostics, 94 References, 101 CONTENTS 60 72 5 TESTING BLOOD FOR EVIDENCE OF THE AGENTS OF TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES 108 Animal Studies to Assess TSE Infectivity of Blood, 109 Risk of Human-to-Human Transmission of TSE Agents by Transfusion and Transplant, 112 Blood Tests for TSE Agents, 114 References, 122 6 SURVEILLANCE FOR TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES IN THE UNITED STATES U.S. Surveillance for Human TSEs, 126 U.S. Surveillance for TSEs in Animals, 137 Essential Research to Improve U.S. Capabilities to Conduct Surveillance for TSEs, 150 References, 154 7 ASSESSMENT OF STRATEGIES TO PREVENT AND TREAT TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES Measures to Prevent the BSE Agent from Entering the U.S. Food Chain, 160 Measures to Prevent the CWD Agent from Entering the U.S. Food Chain, 178 125 160

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CONTENTS Preventing TSE Transmission Through Blood, Blood Derivatives, and Transplanted Tissues, 184 Inactivation of Prions on Surfaces and in the Environment, 188 Vaccination as a Preventive Strategy, 195 Progress in Therapy for TSEs, 196 References, 205 8 INFRASTRUCTURE FOR RESEARCH ON TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES Present U.S. Infrastructure, 214 Need for Consistent, Science-Based Standards for Biological Safety Levels in TSE Laboratories, 216 Need for Standardized Reagents and Materials, 217 Opportunities for International Collaboration, 220 References, 221 9 RISKS OF TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES TO THE U.S. MILITARY Risk of Exposure to Beef Products Containing BSE Infectivity, 224 Risk of TSE Infection from Blood Products, 227 Summary of Overall Risk, 228 References, 229 APPENDIXES xxt 214 223 A AGENDAS OF OPEN SESSIONS OF COMMITTEE MEETINGS 233 B BIOGRAPHICAL SKETCHES GLOSSARY 243 250

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Figures, Tables, Boxes, and Plates FIGURES 2-1 Diagram of the primary structure of normal human prion protein PrPC, 46 2-2 Mode! of PrPSc formation and deposition in a neuron infected with the agent of TSE, 47 2-3 Confirmed cases of BSE by month and year of clinical onset, 50 2-4 The best-fit curve for the observed quarterly incidence of vC.ID onsets in the United Kingdom through December 2002 is quadratic, 52 4-1 Electron micrograph of negatively stained fibrils composed of PrP 27-30 from scrapie-infected Syrian hamster brains, 81 6-1 The relative occurrence of sporadic, genetic, and iatrogenic forms of human TSEs in the United States, 1997-2002, 127 Percent distribution of vCID cases in the United Kingdom anal sCID cases in the United States by age group at death, 1995-2001, 128 Locations of 375 of 379 confirmed cases of scrapie reported to USDA APHIS's Veterinary Services during the 2002 fiscal year, 139 Number of cattle brains tested for BSE per year in the United States, 143 North American locations where CW1) had been diagnosed as of May 2003, 146 6-2 6-3 6-4 6-5 The 36.75 million U.S. cattle slaughtered in 2002, 169 . . XXtt

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FIGURES, TABLES, BOXES, AND PLATES . . . XXtt! 7-2 The path of the Canadian forward trace of rendered tissue from the BSE-positive cow found in Alberta, 176 7-3 Commercial processing of cervid tissues in the United States, 181 7-4 Paths taken by hunter-harvested cervid tissues during processing in the United States, 181 TABLES S-1 Committee Recommendations by Functional Area and Priority for the National Prion Research Program, 26 1-1 NPRP Award Mechanisms, 36 2-1 Classification of TSEs, 44 4-1 Clinical Differentiation of sC}D and vC}D, 75 4-2 Classification of Sporadic Prion Diseases, 76 4-3 Estimated Detection Limits of the First Three EC-Approved Post- mortem Tests for BSE, 82 4-4 Results of Field Trial Evaluations of Two New Rapid Postmortem Tests for BSE, 84 4-5 Diagnostic Tests for TSEs, 90 5-1 Studies of the Infectivity of Blood Components Transmitted Intrave- nously, 110 Risk of Transmitting Human TSE Agents Through Blood, Trans- planted Tissues, or Surgical Instruments, 113 5-3 The Predictive Value of a Positive Test Relative to the Prevalence of a Disease in a Population, 117 6-1 Annual Referrals and Diagnoses of Human TSE Cases in the United States, 1997-May 2003, 132 6-2 Actual and Expected Numbers of U.S. Cases of Human TSEs Con- firmed in 2001 and 2002, 133 6-3 Comparison of National Surveillance and Epidemiology Programs for Human TSEs in the United States with Those in the United Kingdom and Canada, 136 7-1 Measures Taken by the United States to Prevent the Introduction, Spread, and Consumption of the Infectious Agent of BSE, 164 7-2 Measures Taken in Response to Concern That TSE Agents May Be Transmissible via Human Blood Products, 185 7-3 Agents Used to Deactivate Prions, 190

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xxtv FIGURES, TABLES, BOXES, AND PLATES 7-4 Drug Classes and Agents Used Experimentally to Treat TSEs, 199 9-1 DOD Active Duty Personnel and Dependents in Europe, 226 9-2 Comparison of Deferral Policies, 229 BOXES 1 -1 Statement of Task, 34 Priority Research on the Structural Features of Prions, 61 Priority Research on Molecular Mechanisms of Prion Replication, 62 3-3 Priority Research on Mechanisms of TSE Pathogenesis, 64 3-4 Priority Research on the Physiological Function of PrPC, 67 5-1 Requirements for Testing Donors of Whole Blood and Blood Components, 121 5-2 Characteristics of New Blood-Donor Screening Tests Considered by the FDA Center for Biologics Evaluation and Research (CBER), 121 6-1 Tests That NPDPSC Performs on Suspected TSE Deaths, 129 6-2 Goals and Action Items for Nationwide Surveillance of CWD, 149 6-3 Priority Research on the Epidemiology and Natural History of TSEs, 151 7-1 7-2 Actions Taken by Game Processors to Minimize Contact with the Infectious Agent of CWD, 182 Therapeutic Strategies for TSEs, 198 COLOR PLATES Depiction of the three-dimensional structure of the intact human prion protein, PrP (23-230) Hypothetical models of PrP 27-30, the pro/ease-resistant segment of prpsc 4-1 The results of hematoxylin and eosin (HOE) staining and of immu- nohistochemistry staining (IHC) of PrP are visible in microphoto- graphs of human brain tissue from a normal brain, the brain of a patient with sC}D, and the brain of a patient with vC}D 7-1 Effects of CpG on host immune cells

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ADVANCING PRION SCIENCE

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XXVI PrPC: Normal cellular prion protein digestible by proteinase K. GLOSSARY PrPCwD: Abnormally folded prion protein associated with a TSE called chronic wasting disease (CEDE, which is kno~m to occur in elk, mule deer, and white-tailed deer. The disease's name derives from the observation that infected animals at the clinical stage lose muscle mass and appear wasted. PrPreS: Abnormally foldeUprion protein that is highly resistant to proteinase K digestion and is strongly associated with prion disease. It is sometimes used synonymously with PrPSC . PrPSc: Abnormally foldeUprion protein that has a gradient of resistance to proteinase K digestion. It is associated with infectious potential and with prion disease even in circumstances where it may be sensitive to proteinase K digestion. PrPSen: Prion protein that is sensitive to proteinase K digestion. Sometimes used synonymously with PrPC. rational drug design: The development of a drug based on foreknowledge of the three- dimensional structure and behavior of a specific molecule involved in a disease process. With this knowledge, drug developers can target a specific binding site on the molecule to disrupt, enhance, or redirect its normal activity, thus interrupting the disease process. By contrast, traditional drug development typically begins with a range of potentially therapeutic chemical compounds that are narrowed down to the best candidates through empirical observation of their effects. Applying rational drug design to transmissible spongiform encephalopathies (TSEs) would begin with the knowledge of differences between the tertiary structures of cellular prion protein (PrPC) and its misfolded isoform (PrPsC) as well as the identification of one or more epitomes on these proteins. Blocking or activating the epitope(~s) could potentially disrupt an essential step in TSE pathogenesis, such as the conversion of prpc to PrPSc. scrapie: A TSE of sheep and goats. The TSE was first described by Scottish veterinarians in the 1 700s, centuries before prions were first recognized. The modes of transmission are thought to be contact with infected sheep or goats or their placentas, contact with a scrapie-contaminated environment, or oral intake of scrapie agent-contaminated material. The "Sc" in the term PrPSC refers to scrapie. PrPSc is used to refer to the abnormal isoform of prPc associated with TSEs. species barrier: The genetic, metabolic, physiological, and physical differences among species that result in variable susceptibility to an infectious agent. --a -a sporadic Creutzleldt-]akob disease (sCJD): The most common variety of CAD. The cause is unknown. sCID appears to occur worldwide at a rate of approximately ~ case per ~ million population. Most cases involve older adults. transgene: A gene from one organism that has been transferred and integrated into the DNA of another organism of the same or different species such that the transferred gene is expressed in _ ~ ~ ~ .. . . . ~ .. . . .. . . . . . .. . the host organism. Investigators conducting prion transmission studies use transgenes to convey unnatural molecular characteristics to experimental animals so as to circumvent the species barrier. For example, it is easier to transmit BSE to a transgenic mouse with a bovine transgene