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Assessment of Strategies to - ~ Prevent and Treat Transmissible Spongiform Encepha/opathies The prospects for successfully treating an established prion disease are so disheartening at present that the most effective strategy for man-aging the threat of transmissible spongiform encephalopathies (TSEs) is to avoid preventable exposure to the infectious agents. This chap- ter begins, then, by describing the strategies and policies adopted by the United States to prevent human and animal exposure to the agent of bovine spongiform encephalopathy (BSE) through food and feed. Next, the chap- ter describes means of preventing human and animal exposure to the agent of chronic wasting disease (CWD) in food and the environment in the United States. 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 re- views the therapeutic agents used to date in attempts to treat TSEs. The development of a successful therapy will require a level of innovation and effort as exceptional as that needed for the development of antemortem diagnostics, described in Chapter 4. MEASURES TO PREVENT THE BSE AGENT FROM ENTERING THE U.S. FOOD CHAIN The United States has built a multilayered preventive barrier during the past 15 years against the introduction of the BSE agent into the U.S. animal 160

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ASSESSMENT OF STRATEGIES TO PREVENT AND TREAT TSEs 161 and human food chains.) This barrier has three components (PL 107-9 Fed- eral Inter-agency Working Group, 20031: 1. Prevent the agent of BSE from entering the United States and infect- ing U.S. cattle. 2. If the agent of BSE penetrates U.S. borders and infects cattle, prevent the amplification of the agent throughout the U.S. cattle herd. 3. Prevent the exposure of U.S. 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 Uni- versities, this trilayer barrier keeps animals and humans in the United States at very low risk of exposure to the BSE agent despite imperfect compli- ance with and enforcement of certain prevention strategies. "If BSE were somehow to arise in the U.S.," the study concludes, "few additional ani- mals would be infected, little infectivity would be available for human ex- posure, and the disease would be eradicated" (HCRA and TUCCE, 2001 :97-981. Although U.S. policies toward BSE effectively safeguard animal and human health, their effectiveness in protecting the U.S. economy is less cer- tain. According to a recent congressionally mandated analysis by the U.S. Department of Agriculture's (USDA) Economic Research Service, the iden- tification of just a single case of BSE in the United States could be more costly to this country than the BSE outbreak has been to the United King- dom to date (Mathews and Perry, 20031. The analysis does not give a dollar amount for the potential U.S. cost, but for perspective, farmers alone in the United Kingdom lost an estimated $700 million (Mathews and Perry, 2003), not to mention the losses to the beef processing and related industries. The authors of the USDA analysis based their prediction in part on the fact that the U.S. population is 5 times that of the United Kingdom, the U.S. beef sector is 10 times greater, and U.S. beef exports far exceed the amount of beef exported from the United Kingdom before the BSE outbreak. The very low risk that a case of BSE would enter the U.S. food chain and spread to other cattle would not mitigate the predicted financial im- pacts of a BSE case in the United States, the analysts forecasted, especially if the cow were a native-born animal (Mathews and Perry, 20031. Domestic consumption of beef products would likely decrease,2 U.S. renderers would iEDITORS' NOTE: After this report was completed, the first U.S. case of BSE was identi- fied in Washington State and was announced to the public on December 23, 2003. 2By contrast, the USDA Foreign Agricultural Service reports anecdotal evidence that Cana- dians responded to the BSE outbreak there by consuming more beef, not less (Myles, 2003).

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162 ADVANCING PRION SCIENCE have to find new ways to use or dispose of cattle offal3 and other edible waste if these materials were banned from use in animal feed, and countries with BSE policies similar to those of the United States would stop importing U.S. beef and ruminant products. In addition, such industries as cosmetics, pharmaceuticals, and medical supplies that use livestock by-products or rendered products might need to find alternative sources of these materials for a period of time. Later in this chapter, we discuss the impact of the single Canadian case of BSE on that country's beef, cattle, and related in- dustries. This section describes the policies behind each layer of the United States' preventive barrier against the infectious agent of BSE (with the exception of surveillance, which is discussed in Chapter 61. Table 7-1 provides a chrono- logical overview of the implementation of many of these policies. In the discussion that follows, we note salient criticisms regarding certain policies and describe how federal agencies have responded to those criticisms. While policy recommendations and cost-benefit analyses are beyond the scope of this committee's mandate, we recommend research that would further strengthen the present safeguards against BSE. 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) banned the importation of live ruminants4 and most ruminant products from all na- tions that had identified a case of BSE (USDA APHIS, 200331. Twenty- three countries fall into that category as of this writing (Office International des Epizooties, 20031. The Harvard/Tuskeegee risk assessment cites the import ban as one of the most effective tools for keeping the agent of BSE out of the United States (HCRA and TUCCE, 20011. USDA expanded the ban in 1997 to all of Europe, regardless of whether a country had reported a case of BSE (USDA APHIS, 200331. The ban was further expanded the following year to include any country "at risk" for BSE, meaning countries that conduct inadequate surveillance for BSE or regulate imports related to BSE in a less restrictive manner than does the United States (USDA APHIS, 19991. Subsequently, after the European Union 30ffal is the parts of butchered animals not processed into human food. These parts gener- ally include blood, internal organs, legs, heads, and spinal cords (Harlan, 2003). 4Ruminants are hoofed, even-toed, usually horned animals that characteristically have a four-chambered stomach and chew their cud.

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ASSESSMENT OF STRATEGIES TO PREVENT AND TREAT TSEs 163 (KU) announced in 2000 that feed made in EU countries from the offal of nonruminants may have been contaminated with the agent of BSE, USDA prohibited the import of all rendered protein and rendering wastes originat- ing from or processed in the KU, regardless of the animal species (USDA APHIS, 2003d). A 2002 report by the U.S. General Accounting Office (GAO) on U.S. vuinerabilities to BSE asserts that the United States lacks sufficient capacity to inspect all cattle imports, a weakness in the enforcement of the import bans (GAO, 2002~. USDA responded with a description of several efforts under way to remedy this problem: USDA proposed using a portion of its fiscal year 2003 budget to increase the number of its inspectors at ports of entry from 2,500 to 4,000 people (USDA and Department of Health and Human Services EDHHS], 2002~. To "strengthen coordination and documentation" among agencies that inspect products at U.S. ports of entry, USDA noted that it had ob- tained funds through the 2002 Defense Appropriations Act to integrate its computer technologies with those of the other relevant agencies (USDA, 2002:1~. USDA would invest in new detection systems, such as x-ray equip- ment (USDA and DHHS, 2002~. Feed Ban While the import bans described above attempt to keep BSE out of the United States, restrictions on the ingredients of feed products intended for ruminants aim to prevent BSE from spreading in the United States should it be introduced through imported goods, through a spontaneous case of BSE in a U.S. cow, or through other means. In 1997, the U.S. Food and Drug Administration (FDA) 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. There is a consensus among scientists that cattle can contract BSE by eating animal feed made from the offal of scrapie-infected sheep or of BSE- infected cattle. This opinion stems largely from epidemiological work by Anderson and colleagues (1996), who conclude that the widespread con- sumption of cattle feed contaminated with the infectious agents of scrapie and BSE was the most likely cause of the BSE epidemic in the United King- dom. The Harvard/Tuskegee risk assessment indicates that the feed ban is one of the most important elements of the U.S. barrier against BSE. In fact, the authors conclude, the effectiveness of the feed ban influences the risk of

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164 ADVANCING PRION SCIENCE TABLE 7-1 Measures Taken by the United States to Prevent the Introduction, Spread, and Consumption of the Infectious Agent of BSE Date Measure Taken 1987 BSE made a reportable disease. 1989 Ban on importation of live ruminants and most ruminant products from BSE- reporting countries instituted. 1990 USDA's Animal and Plant Health Inspection Service (APHIS) launches active surveillance for BSE and a BSE-education program.a 1992 U.S. Food and Drug Administration (FDA) recommends that manufacturers of dietary supplements avoid materials that could contain BSE or scrapie . . . . 1ntectlvlty. 1993 Nonambulatory cattle added to targets of BSE surveillance. FDA requests that most bovine source materialsb used in the manufacture of regulated products come from scrapie-free countries. 1994 FDA requests that bovine-derived materials for animals, cosmetics, or dietary supplements come from BSE-free countries. 1997 Ban on importation of live ruminants and most ruminant products from all of Europe instituted. FDA bans the feeding of most mammalian proteins to ruminants. FDA requests that bovine gelatin from countries reporting BSE not be used in certain products.c 1998 Ban on importation of ruminants and ruminant-derived products from countries at risk for BSE instituted.d Vermont quarantines two flocks of imported sheep possibly exposed to the BSE agent from contaminated feed in Europe. 1999 2000 USDA proposes a new rule to intensify scrapie-eradication efforts. Ban on import of rendered animal protein products originating from or processed in Europe instituted. BSE surveillance more than doubles from 1,300 to nearly 2,700 cattle brains tested. USDA seizes Vermont sheep after four die with an atypical TSE of foreign origin. BSE to the United States more than any other factor. They note: "A single breach of the feed ban can introduce . . . cattle to a substantial amount of BSE infectivity" (HCRA and TUCCE, 2001:97~. 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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ASSESSMENT OF STRATEGIES TO PREVENT AND TREAT TSEs TABLE 7-1 Continued 165 Date Measure Taken 2001 Precautions enacted to protect safe, edible ruminant products from contamination while passing through countries reporting or at risk for BSE en route to the United States. 2002 Food Safety and Inspection Service (FSIS) issues a directive for routine inspection of advanced meat recovery (AMR) systems and for regulatory actions if spinal cord is detected in beef products produced by AMR. 2003 USDA APHIS solicits public comment on ways to control the risk that dead and nonambulatory ruminants could facilitate the spread of BSE.e USDA APHIS closes a loopholef to prevent the importation of live ruminants from Canada immediately after the May 20 announcement of a BSE-positive cow in Canada. On August 8, USDA lifts part of the import ban on Canada by allowing the importation of hunter-harvested wild ruminant products intended for personal use and accepting applications for import permits for a number of ruminant products." aThe education provided involves teaching veterinarians, farmers, and others who work with cattle to recognize the clinical signs of BSE. bExcluding gelatin. CIncludes injectable, implantable or ophthalmic products. Also, FDA asked that manufacturers take special precautions when using gelatin for oral and topical use. An at-risk country is one that conducts inadequate surveillance for BSE or that regulates imports related to BSE in a less restrictive manner than does the United States (USDA APHIS, 1999). eSource: USDA APHIS (2003b). fThe original rule had exempted certain regions, including Canada, under certain circumstances, from the requirement to obtain a permit to import live ruminants into the United States (USDA APHIS, 2003a). The import ban automatically applies to ruminant meat, ruminant meat products, and ruminant by-products from Canada as of May 20. "Source: USDA (2003c). SOURCES: Adapted from Brown et al. (2001) and USDA APHIS (2003d). 9,947 inspections of the rendering plants, feed mills, and related businesses5 conducted during those years (FDA CVM, 2001a). 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), and protein blenders (GAO, 2000; FDA, 2001b).

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166 ADVANCING PRION SCIENCE caution label on animal feed containing mammalian protein. However, these data do not capture the true rate of compliance because, according to the report, state and FDA officials had not inspected 30 to 40 percent of all U.S. renderers and feed mills (FDA CVM, 2001a). The Harvard/Tuskegee risk assessment addressed these shortcomings and incorporated them into its analysis. Subsequently, FDA boosted its ef- forts by inspecting more firms that handled mammalian protein and by reinspecting more of the firms previously found to be out of compliance (FDA CVM, 2001b). FDA's Center for Veterinary Medicine (CVM) gave businesses easy access to the checklist used by inspectors to determine com- pliance with the feed ban by placing a link to the checklist on the center's Web site (FDA CVM, 2001c). CVM also hired a contractor to restructure the database used to manage the information reported by the state officials and FDA field officers who conducted inspections for compliance with the feed ban (FDA CVM, 2001b). Nevertheless, GAO's 2002 report sharply criticized FDA for its poor enforcement of the feed ban and for its "severely flawed" database, and recommended a number of ways in which the agency could improve compliance rates (GAO, 20021. FDA continued to improve its methods of enforcement. Feed mills that used mixed-species meat and bone meal came under increasing scrutiny because of the risk that mammalian protein could contaminate feed des- tined for ruminants (personal communication, D. Harlan, Excel Food Solu- tions Company, March 25, 20031. Some firms decided to stop using mam- malian proteins altogether. By March 2002, CVM reported, the compliance rate for 2,153 U.S. firms handling materials prohibited for use in ruminant feed had reached 95 percent (FDA CVM, 20021. The next month, CVM began using a new database to better manage the information on nation- wide inspections and enforcement activities related to the feed ban. While criticisms of enforcement of the feed ban had subsided by 2003, they had not been altogether eliminated. At least one major U.S. rendering firm, Darling International Inc. of Irving, Texas, stated in February 2003 that FDA should take "more vigorous enforcement actions against viola- tors" 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 rumi- nants. For instance, in 2001 the American Protein Producers Association and the American Feed Industry Association began to hire outside auditors to conduct inspections of plants and mills (Ransweiler, 20031. A number of firms subject to the feed ban stopped using mixed-species meat and bone meal (Harlan, 20031. Some producers voluntarily stopped feeding mamma- lian-derived meat and bone meal to all their livestock, reducing the risk that ruminants on a farm would accidentally be given the banned feed. The

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ASSESSMENT OF STRATEGIES TO PREVENT AND TREAT TSEs 167 combination of stronger FDA enforcement and self-monitoring by industry bolsters the effectiveness of the feed ban. Tools to Detect Mammalian Protein in Animal Feed An additional way to prevent ruminants from eating feed containing mammalian protein is for ruminant producers to test their purchased feed for the banned material. At least one test that detects some banned material has been on the U.S. market since 2002: Agri-Screen~ for Ruminant Feed, manufactured by Neogen Corp. of Lansing, Michigan (Neogen Corp., 2002a). According to Neogen, its product enables feediots, dairies, market- ers of feed products, regulators, and auditors to verify that ruminant feed and feed supplements do not contain ruminant muscle proteins, a marker for the presence of ruminant tissue. Since the product does not detect mam- malian muscle protein in general, however, the test cannot verify whether a sample of feed made for ruminants is in compliance with the feed ban. The company describes Agri-Screen as a single-step, lateral-flow immunochromatographic assay (Neogen Corp., 2002b). It consists of an absorbent strip with a reagent area containing color-tagged antibodies that are specific to heat-stable ruminant muscle protein, and a control area far- ther upstream. Like a pregnancy test, the strip wicks the extract through the reagent and control areas. Within about 10 minutes, a colored line always forms in the control zone, but a second line forms in the reagent zone only if the feed sample contains ruminant muscle protein. Although the com- pany claims the test can detect ruminant muscle protein present in concen- trations as low as 1 percent of a sample, an industry source who has used the test says its lower limit in practice ranges from 1 to 5 percent (personal communication, D. Harlan, Excel Food Solutions Company, May 20031. Feed tests such as Agri-Screen provide a worthwhile, additional line of defense against the introduction of BSE into the food chain. It would be even better to have a test that could detect mammalian protein, not just ruminant protein. The development of such products for an affordable price should be encouraged, as should their use by farmers. Additional Ways to Prevent the BSE Agent from Entering Ruminant Feed Policy recommendations are beyond the charge of this committee. How- ever, 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 pro- hibit the use of mammalian protein in feed for all animals, not just rumi-

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168 ADVANCING PRION SCIENCE nants. The United Kingdom instituted such a policy6 in 1996, and the EU7 followed in 2001 (Brown et al., 2001~. This more stringent measure makes sense in countries that, unlike the United States, have diagnosed cases of BSE or are at high risk for the disease. At least one challenge posed by the potential prohibition of mammalian protein in animal feed is to find alternative means of eliminating the 3.6 billion pounds of ruminant meat and bone meal left over from meat pro- cessing each year (Harlan, 2003~. Present U.S. research into alternative fu- els may offer at least a partial solution. Some scientists in this field are developing an experimental industrial boiler powered by agricultural by- products, including meat and bone meal, blood meal, and tallow (The En- ergy Institute, 2002~. Although the boiler may be a more efficient disposal mechanism than incineration, it would yield less energy than the amount required to create the meat and bone meal from producing feed, to raising animals, to processing parts into by-products (personal communication, D. Cliver, University of California, Davis, Tune 21, 2003~. The potential prohi- bition of mammalian protein in all animal feed also would challenge animal producers to find alternative affordable sources of nutrients for their live- stock. 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, how- ever. The sheer number of cattle involved U.S. beef processors slaughtered more than 36 million cattle in 2002 (see Figure 7-1) makes BSE detection at the slaughterhouse a formidable task. Beef processors reduce the risk of BSE-infected tissue entering the food chain by focusing on three aspects of their operation: procurement, antemortem inspection, and the removal of central nervous system (CNS) tissue. Specifically, the United Kingdom bans mammalian meat and bone meal from all animal feed and fertilizer (Brown et al., 2001). 7The EU prohibits the use of most animal protein in feed for any farmed animal species. Exempted proteins include those in milk, blood, and gelatin (Brown et al., 2001).

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ASSESSMENT OF STRATEGIES TO PREVENT AND TREAT TSEs 35 30 25 In o 20 . _ 15 10 5 o Calves Fed Cattle Mature Cattle 3% 80% 17% 169 Dairy > 8 yr 1% FIGURE 7-1 The 36.75 million U.S. cattle slaughtered in 2002 comprised calves (3 percent); fed cattle (80 percent); and mature cattle (17 percent), which included a small percentage of dairy cattle older than age 8. Fed cattle are 1 to 2 years old. Mature cattle are more than 2 years old. SOURCE: Harlan (2003~. Procurement Controls Some processors have limited their risk of exposure to BSE through company policies that specify the kinds of cattle that will or will not be purchased. For instance, a processor may decline to purchase nonambula- tory cattle (Harlan, 2003), that is, cattle that cannot rise from a recumbent position. These so-called downers can no longer stand because they are ill, and BSE is always suspect as the cause of illness in downer cattle. As noted in Chapter 6, nonambulatory cattle are the targets of active U.S. surveil- lance for BSE. Other procurement controls include buying only cattle of North Ameri- can origin (Harlan, 2003), although, as noted in Table 7-1, the United States banned the importation of cattle from Canada as of May 2003 because a case of BSE was discovered in Alberta (USDA and FDA, 20031. Buyers may also request that the producer certify the BSE-free status of an animal, and such certification is provided frequently. However, the committee sees little value in this sort of certification at present because only a neuropathologi- cal 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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170 Antemortem Inspection ADVANCING PRION SCIENCE Officials from USDA's Food Safety and Inspection Service (FSIS) in- spect all incoming cattle at all U.S. slaughterhouses for signs of neurological disease (USDA and FDA, 2003~. In general, if an animal shows such signs, it is condemned, and its meat may not be used for human consumption (HCRA and TUCCE, 2001~. However, if the signs are not pronounced or typical, an inspector may designate the animal as suspect but not condemned (personal communication, D. Cliver, University of California, Davis, July 2003~. After FSIS notifies USDA Veterinary Services of the suspect animal, laboratory staff at one of USDA's 15 National Veterinary Service Laborato- ries analyze the animal's brain tissue for evidence of BSE or some other TSE. FSIS tracks instances of antemortem or postmortem condemnation due to signs of disease (HCRA and TUCCE, 2001~. As mentioned earlier, no case of BSE has been identified in the United States to date. However, antemortem inspections can identify only clinical cases; they will not identify infected cattle during the incubation period, which lasts 2 to 8 years. The Harvard/Tuskegee risk assessment could not determine with certainty what percentage of clinical BSE cases inspectors might miss. In fact, the authors note that this was one of the most impor- tant sources of uncertainty behind the study's estimates of human exposure to the BSE agent. Condemned animals are rendered or incinerated (HCRA and TUCCE, 2001~. Rendered by-products could be turned into feed for nonruminant animals or an ingredient for cosmetics, among other products. 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. The air-injection captive bolt pistol, a too! used to render cattle uncon- scious before slaughter, has been implicated in the inadvertent spread of CNS tissue to the blood and thereby to the heart, lungs, and liver. The pistol would thrust a bolt under high pressure into the skull of an animal to render it unconscious (TSE BSE Ad Hoc Group,2001). Projecting a volume of air into the cranial cavity at high speed would displace small but visible pieces of brain into the bloodstream. Most U.S. meat processors have not used air-injection stunning devices since at least 2000 (HCRA and TUCCE, 2001~. FSIS plans to complete a direct final rule in 2003 prohibiting the use of those devices (USDA, 2003b). From the standpoint of BSE risk, a safer

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ASSESSMENT OF STRATEGIES TO PREVENT AND TREAT TSEs 203 addition, the group receiving the 20 days of treatment survived without illness beyond 330 days. The investigators were unable to determine the mechanism for these effects, but speculated that they were due to the stimu- lation of toll-like receptor (TLR) 9-expressing cells, such as macrophages, monocytes, and dendritic cells (Seth) et al., 20021. A more direct approach is to modulate a specific protein of interest, such as prion protein, with a specific agent, namely antibodies. As previ- ously noted, there appears to be no natural antibody response by a host to priors. However, antibodies can be produced exogenously by novel meth- ods and administered prophylactically to the host organism. There are en- couraging studies showing that antibodies directed at PrP apparently block conversion to PrPSc. For example, researchers used a monoclonal antibody, 6H4, previously shown to bind PrP in the region spanning amino acid resi- dues 144 to 152 (Korth et al., 1997) to block infection of mouse neuroblas- toma (N2a) cells with mouse scrapie agent (Enari et al., 20011. When these cells were preincubated with 6H4 antibodies at the time of exposure to scrapie PrPSc, infection of the cells was not observed. When the antibody was added after the cells had been infected and were in a static state, the antibodies caused a reduction in the amount of PrPSc. This result suggested that equilibrium of PrPSc production and degradation existed and that it could be altered (Enari et al., 20011. Another study, also using scrapie-infected cells (ScN2a), screened sev- eral possible recombinant antibody fragments, known as Fabs, for their ability to clear PrPSc. The investigators noted significant activity associated with Fab 18, and also observed that the decrement of PrPSc was dose re- lated. They caution that future in vivo studies must recognize that Fabs have a short half-life in the body and do not cross the blood-brain barrier (Peretz et al., 20011. In vivo studies have proceeded using antibodies. One group examined the administration of several different monoclonal antibodies in mice. Mice were inoculated with antibodies i.p. at the same time they were inoculated i.p. with a mouse scrapie agent (Sigurdsson et al., 20031. The antibodies were readministered weekly until sacrifice. The antibodies prolonged sur- vival of the mice compared with controls given no antibody or standard IgG. The result of one antibody in particular, 8B4, was notable in that 10 percent of the animals receiving a diluted level of prions did not develop disease, and no toxicity was observed during the study (Sigurdsson et al., 20031. Another encouraging report was recently published by a group study- ing monoclonal antibodies in mice. In this study, using two different test antibodies, the investigators showed that even when the i.p. administration of the antibodies was delayed to 7 or 30 days after i.p. inoculation of the scrapie agent, all the mice survived and remained healthy for more than 500

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204 ADVANCING PRION SCIENCE days which was 300 days longer than control mice (White et al., 20031. While very hopeful, the researchers offer caveats that the antibodies did not work when given after the onset of symptoms, suggesting that the blood- brain barrier may limit their use to prophylaxis during the incubation pe- riod. The auhors note further that although they saw no evidence for au- toimmunity, it is a possibility to be considered (White et al., 20031. At least one research team combined concepts of gene therapy and an- tibody therapy by creating transgenic mice that could produce antiprion antibody endogenously. Using some clever genetic engineering, they trans- ferred genes into knockout mice. The transgene was derived from a hybri- doma that expressed monoclonal antibody to murine PrPC. Once in the mouse, the transgene expressed a single-chain variable antibody fragment (scFv) that had anti-PrP binding attributes (Heppner et al., 20011. Follow- ing i.p. inoculation of these transgenic mice with scrapie priors, no infectiv- ity was seen in either the knockout mice (Prnp/ ~ or mice that had one null allele and one Prnp allele (Pnrp/+~. Nor could PrPSc be detected in the spleen (Heppner et al., 20011. The study team observed no overt symptoms of autoimmune disease but were cognizant of that potential. 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. The most promising approach appears to be ratio- nal drug design, which begins with knowledge of the tertiary struc- ture of the protein or molecule that the therapeutic agent will tar- get. [Priority 11 Summary of Outlook for TSE Therapy The work in progress to develop therapeutic agents for TSEs is reveal- ing that, in cell culture and animal models, experimental agents can affect the accumulation of prions and prolong the survival of animals. At present, drug treatment in humans is limited to drugs that have been used for other medical conditions and been shown to be relatively safe. To date, no drugs or other agents have demonstrated consistent or prolonged success in treat- ing human TSEs. This failure relates in part to the use of candidate thera- pies very late in the course of disease. Also, it is unknown whether the efficacious outcome of one therapeutic agent for a particular TSE can be extrapolated to other TSEs.

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ASSESSMENT OF STRATEGIES TO PREVENT AND TREAT TSEs 205 Significant acceleration in identifying effective therapeutic agents for TSEs will require scientific breakthroughs. The main obstacle to rapid progress is the same as that which is constraining rapid development of diagnostics (see Chapter 41: fundamental knowledge gaps with regards to the molecular mechanisms, immunobiology, and pathogenesis of prion dis- ease. The heartening news, however, is that breakthroughs in TSE diagnos- tics will likely translate quickly into progress in the development of thera- peutic agents because both diagnostics and therapeutics will target the structural peculiarities of priors. Diagnostics and therapies are inextricably linked for another vital reason: Therapies will likely be more successful if administered early in the preclinical stage of infection, when prions exist in the host at very low titers. 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 be- ing treated for prion diseases. REFERENCES Agrawal S. Kandimalla ER. 2002. Medicinal chemistry and therapeutic potential of CpG DNA. Trends in Molecular Medicine 8(3):114-121. Agriculture and Agri-Food Canada. 2003. Fact SI7eet: Trade. [Online]. Available: http:// www.agr.gc.ca/cb/trade/factsheet_e.phtml [accessed June 8, 2003]. Anderson RM, Donnelly CA, Ferguson NM, Woolhouse ME, Watt CJ, Udy HJ, MaWhinney S. Dunstan SP, Southwood TR, Wilesmith JW, Ryan JB, Hoinville LJ, Hillerton JE, Aus- tin AR, Wells GA. 1996. Transmission dynamics and epidemiology of BSE in British cattle. Nature 382(6594):779-788. APHIS and FSIS (Animal and Plant Health Inspection Service and Food Safety and Inspection Service). 2002. Bovine Spongiform Encepl7alopatI7y (B. SK) Response Plan Summary. Washington, DC: USDA APHIS. Asher DM, Pomeroy KL, Murphy L, Gibbs CJ Jr, Gajdusek DC. 1987. Abstract: Attempts to Disenfect Surfaces Contaminated witI7 Etiologic Agents of tI7e Spongiform Encepl7alopa- tI7ies. Presentation at the VIIth International Congress of Virology, Alberta, Canada. Asher DM, Pomeroy KL, Murphy L, Rohwer RG, Gibbs CJ Jr, Gajdusek DC. 1986. Abstract: Practical Inactivation of Scrapie Agent on Surfaces. Presentation at the IX International Congress of Infectious and Parasitic Diseases, Munich. Barret A, Tagliavini F. Forloni G. Bate C, Salmona M, Colombo L, De Luigi A, Limido L, Suardi S. Rossi G. Auvre F. Adjou KT, Sales N. Williams A, Lasmezas C, Deslys JP. 2003. Evaluation of quinacrine treatment for prion diseases. Journal of Virology 77(15):8462- 8469. Belay E. 2003. CJD Surveillance in tI7e United States. Presentation to the IOM Committee on Transmissible Spongiform Encephalopathies: Assessment of Relevant Science, Meeting 4. Washington, DC: National Academy Press. Bernoulli C, Siegiried J. Baumgartner G. Regli F. Rabinowicz T. Gajdusek DC, Gibbs CJ Jr. 1977. Danger of accidental person-to-person transmission of Creutzieldt-Jakob disease by surgery. Lancet 1(8009):478-479. Brown P. 2002. Drug therapy in human and experimental transmissible spongiform encepha- lopathy. Neurology 58(12):1720-1725.

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