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OCR for page 160
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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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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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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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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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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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.
OCR for page 205
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.
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Representative terms from entire chapter:
treat tses
