Advancing Prion Science Guidance for the National Prion Research Program (2004) / Chapter Skim
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7 Assessment of Strategies to Prevent and Treat Transmissible Spongiform Encephalopathies
7 Assessment of Strategies to Prevent and Treat Transmissible Spongiform Encephalopathies
Pages 160-213
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From page 160... ...
We then discuss the challenges of preventing exposure to TSE agents by inactivating them in blood, blood derivatives, and tissue, as well as on surfaces and in the environment; this section also addresses the potential for vaccination as a preventative strategy. The final section of the chapter reviews the therapeutic agents used to date in attempts to treat TSEs.
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From page 161... ...
residents to the agent of BSE through food and other products that come either partially or completely from cattle. According to a 3-year risk assessment by Harvard and Tuskegee Universities, this trilayer barrier keeps animals and humans in the United States at very low risk of exposure to the BSE agent despite imperfect compliance with and enforcement of certain prevention strategies.
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Restrictions on Imports It is widely believed that the exportation of BSE-infected cattle and cattle-derived products from the United Kingdom spread the infectious agent of BSE to countries in Europe and beyond. Beginning in 1989, therefore, USDA's Animal and Plant Health Inspection Service (APHIS)
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prohibited the use of most mammalian protein in animal feed intended for ruminants (FDA CFSAN, 19971. This prohibition is often termed simply the feed ban.
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Challenges of Enforcing the Feed Ban Before and during 2001,FDA had serious problems with monitoring and enforcing compliance with the feed ban. A significant percentage of animal rendering plants and feed mills failed to meet at least one major requirement from 1998 through 2000, according to an FDA report on the
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. For instance, the report states that 28 percent of the inspected rendering plants lacked a system to prevent commingling of mammalian protein with other materials, and 20 percent of the inspected, FDA-licensed feed mills did not place a required 5These include ruminant feeders (operations that feed and care for ruminants)
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of Irving, Texas, stated in February 2003 that FDA should take "more vigorous enforcement actions against violators" of the feed ban (Ransweiler, 2003:21. At the same time, industries affected by the feed ban have taken steps to monitor themselves and to make changes that reduce the risk of transmitting the BSE agent to ruminants.
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However, it is worth noting that additional precautions beyond those in the FDA feed ban would further reduce the risk of amplification of the BSE agent should the disease arise in the United States. For instance, FDA could prohibit the use of mammalian protein in feed for all animals, not just rumi
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From page 168... ...
How Beef Processors Prevent the BSE Agent from Entering the Food Chain The beef processing industry and USDA have developed procedures and regulations to prevent tissue infected with the BSE agent from entering the food chain should a cow infected with the BSE agent go undetected on the farm and be sent to slaughter. These measures are not foolproof, however.
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However, the committee sees little value in this sort of certification at present because only a neuropathological exam can establish the BSE-free status of a cow. An antemortem test would make the BSE-free certification of live cattle meaningful.
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Removal of CNS Tissue from Slaughtered Cattle BSE infectivity becomes concentrated in CNS tissue during the later stages of the disease. Therefore, in case a BSE-infected animal should fail to be detected by antemortem inspection, meat processors can reduce the risk of human consumption of the BSE agent by removing all CNS tissue from cattle.
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The use of AMR has created controversy, however. Opponents have asserted that the technology slices residual spinal cord tissue off neck bones and backbones, and that beef processors have mixed that CNS tissue with muscle tissue to sell as meat.
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[Priority 218 Rendering of Ruminant Tissue and the Potential Spread of the BSE Agent Many animal rendering plants use discarded tissue from multiple sources to manufacture a variety of edible products for animals and humans and inedible products for people. These products include meat-andbone meal (MBM)
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USDA APHIS acknowledges that if BSE or scrapie were present in the rendered tissue of dead-on-farm cattle, downer cattle, or sheep, and if that rendered material were used in cattle feed (deliberately or accidentally in violation of the feed ban) , healthy cattle could contract BSE (USDA APHIS, 2003b)
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Later in this chapter, we discuss the few successful methods of inactivating the TSE agent and recommend research to develop new approaches to this problem. Renderers, like beef processors, may reduce the risk of spreading the BSE agent by accepting tissue only from ambulatory cattle of U.S.
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From page 175... ...
Futures and commodity markets in beef, cattle, and feed products were affected in the United States, Canada, and elsewhere. Because the BSE-positive cow, dubbed the index case, was condemned during antemortem inspection, Canadian policies prevented its meat from entering the human or ruminant food chains (Evans, 20031.
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In August 2003, USDA partially lifted the import ban by allowing several types of ruminant products from Canada back into the United States.
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For example, one beef processor and exporter to the United States laid off 75 to 100 employees just a day after the announcement (Olsen et al., 20031. Another consequence of the case of BSE in Canada was the decision by CFIA to ban SRMs from the rendering process to help prevent the inadvertent spread of the BSE agent (CFIA and Health Canada, 2003; Government of Canada, 2003b)
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These likely effects underscore the importance of preventing even one case of BSE in the United States. Plans for Responding to a BSE Outbreak in the United States The Harvard/Tuskegee risk assessment concluded that if the BSE agent were to enter the United States and infect a cow, the trilayer barrier described in this chapter would very likely prevent the agent from entering the human food supply.
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As is the case with other TSEs, however, a significant amount of infectivity develops in CWD-positive animals before the onset of clinical disease. The brain, spinal cord, lymph nodes, and spleen of a CWD-positive cervid would contain infectivity at various stages of the disease.
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From a food-safety standpoint, the commercial processing of venison is probably safer than any other method. Most game processors use a technique called boneless fabrication, which minimizes contact with the brain, spinal cord, and lymph nodes if the animal was not quartered first.
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181 FIGURE 7-4 Paths taken by hunter-harvested cervid tissues during processing in the United States. SOURCE: Adapted from Means (2003~.
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The traditional method of field processing is to remove the head and quarter the animal. In the process, the hunter bisects the spinal cord, exposing CNS tissue.
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Recommendation 7.2: Fund risk assessments that characterize the exposure of hunters, cervid processing establishments, and consumers to the infectious agent of chronic wasting disease. [Priority 31
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Preventing TSE Transmission Through Blood Products Regulatory bodies throughout the world, including FDA, have taken steps to prevent the potential transmission of TSEs among humans through blood, blood components, and blood derivatives (Foster, 20001. FDA has instituted a number of policies, listed in Table 7-2, to prevent the infectious agents of human TSEs from entering U.S.
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1995 (Aug.) FDA extends donor deferral to those with a family history of CJD and to recipients of aura mater.
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Recommendation 7.3: Fund research to develop novel methods for removing prions from or inactivating prions in blood products and tissues in vitro, using physical, chemical, or immune mechanisms alone or in combination. [Priority 21 Preventing Transmission of TSE Agents in Transplanted Human Tissues As previously noted, many iatrogenic CJD cases have been attributed to infected processed aura mater allografts and a small number to infected corneal transplants (Hogan et al., 19991.
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Since then, FDA's Center for Devices and Radiological Health (CDRH) has issued guidelines, not regulations, to minimize the risk of TSE transmission by processed human aura mater implantation (FDA CDRH, 1999~.
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Today, hospitals lack both an antemortem test for human TSEs (except a brain biopsy) and satisfactory methods to disinfect medical equipment potentially contaminated with a TSE agent.
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Finally, as mentioned in Chapter 6, most pathologists in the United States will not perform an autopsy on suspect TSE cases mainly for fear of contaminating their equipment (Belay, 2003~. Clearly, the lack of a safe, routine, affordable procedure for inactivating the TSE agent on surfaces has significant consequences.
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190 TABLE 7-3 Agents Used to Deactivate Prions ADVANCING PRION SCIENCE Evidence for Complete Inactivation Class of Agent Agent/Conditions Not Successful Successful Radiation Microwave X Ultraviolet X Ionizing X Dry Heat 600°C/5-15 mina X 360°C/24 hr 220°C/20 min X 160°C/24 hr X Moist Heat (autoclave) Gravity displacement 121°C/90 min X 132°C/90 min Xb 132°C/4.5 hr xc Porous loading 134-138°C/18 min X (debated)
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. NOTE: GD = gravity displacement autoclave; M = molar; NaOH = sodium hydroxide.
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Unfortunately this procedure also reduced the prion levels so that infectivity was not detected. Failure to identify fully satisfactory methods for inactivating prions with a single type of deactivation treatment led investigators to believe that combination methods might be a more effective approach.
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operatorles. Recommendation 7.4: Fund research to develop standard assays for the detection of PrPSc or TSE infectivity on the surfaces of reusable medical instruments and materials, as well as research to develop better methods to disinfect such instruments and materials.
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Recommendation 7.5: Fund research to develop standard test methods for detecting prion contamination in environmental samples. [Priority 31 The longevity of TSE infectivity, specifically in soil, has tremendous implications for the proper disposal of animals infected with a TSE agent, as well as the offal and rendered material from these animals.
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Recommendation 7.6: Fund research to identify safe, cost-effective disposal mechanisms for animals and rendered waste infected with agents of transmissible spongiform encephalopathies. This research would best be conducted with a multidisciplinary approach involving experts in such fields as prion biology, biochemistry, environmental engineering, and commercial disposal technology.
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The reasons for this limited success are multiple and include uncertainty regarding the underlying pathophysiology of prion diseases, the difficulty of identifying disease at an early preclinical stage without sensitive detection tests, the problem of getting any treatment agent past the blood-brain barrier, the toxicity associated with therapeutic agents, and the enormous challenge of translating gains from cell culture or animal studies to human
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However, research directed at this protein-folding disorder would likely have crossover value in advancing understanding of other, more common neurodegenerative disorders, such as Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, and Parkinson's disease. And fortuitously for sufferers of prion diseases, the reverse is also true.
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From page 198... ...
Also, because of the rarity of human TSEs, the ability to test a candidate drug in hundreds of individuals, as is done in clinical trials, is limited. The dilemma of not having an approved drug to treat human TSEs, yet having drugs in the formulary that have shown some positive effect against prions in cell or animal testing, has led to some controversial decisions on the appropriateness of administering such drugs to patients dying from CJD.
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g~ven to t" ,~s pat~ent. Despite the controversy over using existing formulary drugs for human prion diseases, research continues to offer new possibilities.
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They caution that different prion strains can respond differently to therapeutic agents tested in the same animal species (Collins et al., 20021. Barret and colleagues (2003)
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A mutant Prep gene was engineered that resulted in the deletion of eight amino acids between residues 114 and 121 of the prpC prion protein. This deletion spanned most of the central amyloidogenic region of PrPSc.
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Agents That Modulate or Augment Immunity In the near term, a more promising treatment strategy is based on the use of agents that affect immune mechanisms. Such strategies might involve a broad effect on the host's innate immune system or highly specific synthesized antibodies designed to attack a precise epitope on prion protein or its .
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to block infection of mouse neuroblastoma (N2a) cells with mouse scrapie agent (Enari et al., 20011.
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The investigators are hesitant to recommend such complex gene-altering strategies as those they described but are optimistic about the potential for active and passive immunization strategies used in prophylaxis or therapy for prion diseases (Heppner et al., 20011. Recommendation 7.7: Fund research to develop new therapeutic agents, including antibodies, that either block the conversion of prpc to PrPSc or disrupt the molecular mechanisms of pathogenesis of transmissible spongiform encephalopathies after this conversion has taken place.
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Thus, having a diagnostic test sensitive enough to detect prions very early in the incubation period, long before the onset of symptoms, will likely lead to the best outcomes for persons or animals being treated for prion diseases. REFERENCES Agrawal S
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1998. The distribution of infectivity in blood components and plasma derivatives in experimental models of transmissible spongiform encephalopathy.
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Presentation at the conference, Molecular Agents of Transmissible Spongiform Encephalopathies (Prion Disease)
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2002. Mad Cow Disease: Improvements in the Animal Feed Ban and Other Regulatory Areas VDould Strengthen U.S.
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2003. Spinal cord tissue detection in comminuted beef: comparison of two immunological methods.
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Presentation to the IOM Committee on Transmissible Spongiform Encephalopathies, Assessment of Relevant Science, Meeting 5. Washington, DC.
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02N-0273. Advance notice of proposed rulemaking: substances prohibited from use in animal food or feed: animal proteins prohibited in ruminant feed.
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1994. Decontamination studies with the agents of bovine spongiform encephalopathy and scrapie.
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Managing the risk of nosocomial transmission of prion diseases. Current Opinion in Infectious Diseases 15(4)
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