May 11, 2012 11:27 ET
ProMetic Life Sciences Inc.: P-Capt® Filtration Prevents Transmission of
Endogenous Blood-Borne Infectivity in Primates
LAVAL, QUEBEC, CANADA and LILLE, FRANCE--(Marketwire - May 11, 2012) -
ProMetic Life Sciences Inc. (TSX:PLI)
Compelling new infectivity data presented at the Prion 2012 conference in
Amsterdam
Macaques transfused with leuco-reduced red cells ("L-RBC") developed prion
disease
Animals transfused with P-Capt® filtered L-RBC remained asymptomatic after
45 months
P-Capt® filter efficacy proven beyond any doubt
Leuco filtration alone does not provide adequate protection
ProMetic Life Sciences Inc. (TSX:PLI) ("ProMetic or the "Corporation ") and
Macopharma SA ("Macopharma") announced today the presentation of new and
compelling data on P-Capt® filter performance at the Prion 2012 Congress being
held in Amsterdam, The Netherlands.
The lack of an established detection method for infectious prions (vCJD)
in human blood means animal bioassays must be used to demonstrate the ability of
the P-Capt® filter to capture and remove endogenous blood-borne infectivity from
leucoreduced red blood cell concentrate. The established 263k scrapie-adapted
hamster model is widely used for such studies and the successful removal of
endogenous prion infectivity from hamster blood was reported by ProMetic in 2006
[Lancet, Vol. 368, 2226-2230, 2006]. To eliminate any residual concerns
regarding P-Capt® filter efficacy and the applicability of the 263k hamster
bioassay as a model of vCJD in human blood, a further study has been conducted
in a cynomolgus macaque model.
The new study, undertaken by Macopharma and scientists from the CEA Prion
Research Group (Fontenay-aux-Roses, France), comprised the collection of blood
from cynomolgus macaques infected with BSE and the processing of the infected
blood to provide leucoreduced red cell concentrate (L-RBC) using standard
methods established for the processing of human blood. Leuco-reduced red cells
were transfused into two healthy primates and L-RBC that had been subjected to
P-Capt® filtration was transfused into three healthy primates. Both animals in
the L-RBC group exhibited symptoms of neurological disease after 30 months and
died two months later whereas all three animals in the P-Capt® filtered L-RBC
group remained asymptomatic after 45 months.
According to Dr Chryslain Sumian, Research and Development Manager for
Pathogen Safety at Macopharma, "this latest data proves beyond any doubt that
the P-Capt® filter is effective for reducing the risk of prion disease
transmission by blood transfusion". "The cynomolgus macaque bioassay developed
at the CEA is the most relevant model for human prion disease owing to the very
close genetic make-up of primates and our data demonstrates the ability of the
P-Capt® filter to retain endogenous infectivity if present in primate blood" he
added.
Dr Steve Burton (CEO of PLI's UK subsidiary ProMetic Biosciences Ltd)
commented "not only does this study prove the effectiveness of the P-Capt®
filter, it also demonstrates the inability of leucofiltration alone to provide
adequate protection against transmission of blood-borne prions". Dr Burton
continued "As currently leucofiltration represents the primary measure
implemented in the UK to reduce the risk of vCJD transmission by red cells, this
new study graphically illustrates the need for an effective prion safety measure
for RBC and we urge the UK Government to implement the P-Capt® filter, as
recommended by SaBTO in 2009, without further delay"
About variant Creutzfeldt-Jakob Disease
Variant Creutzfeldt-Jakob Disease ("vCJD") is characterized by the
accumulation of large deposits of misfolded prion protein in the brain and the
nervous system and the appearance of sponge-like holes in the brain causing a
fatal degenerative CNS disorder. Such abnormal prion proteins may be sufficient
to transmit the disease. Although some people's genetic make-up may protect
them, at least 89% of the population may be susceptible to vCJD. vCJD was
initially transmitted to humans from BSE infected cows presumably by the
consumption of BSE contaminated meat, but a secondary route of transmission by
the transfusion of blood units from asymptomatic vCJD individuals threatens to
increase the prevalence of the fatal disease.
About P-Capt®
P-Capt® is a single-use sterile device which was awarded CE mark approval
in September 2006. Red blood cells are passed through the filter under gravity
and a highly specific affinity adsorbent material captures and removes any vCJD
prion protein.
P-Capt® is the only approved product proven to be effective for the removal
of prion infectivity from red blood cell concentrate prior to transfusion. It
has been evaluated extensively by the UK Blood Services (including the National
Blood Service, the Northern Irish Blood Transfusion Service, the Welsh Blood
Service, and the Scottish National Blood Transfusion Service), the Irish Blood
Transfusion Service and the Health Protection Agency since production of the
first batches in 2006 and to date has achieved all of the required performance
and safety requirements and met all bench marks. The P-Capt® filter incorporates
the prion-specific affinity resin developed by PRDT and supplied by ProMetic to
MacoPharma and it is manufactured under licence and distributed by MacoPharma.
About ProMetic Life Sciences Inc.
ProMetic Life Sciences Inc. ("ProMetic") (www.prometic.com) is a
biopharmaceutical company specialized in the research, development, manufacture
and marketing of a variety of commercial applications derived from its
proprietary Mimetic Ligand™ technology. This technology is used in large-scale
purification of biologics and the elimination of pathogens. ProMetic is also
active in therapeutic drug development with the mission to bring to market
effective, innovative, lower cost, less toxic products for the treatment of
hematology and cancer. Its drug discovery platform is focused on replacing
complex, expensive proteins with synthetic "drug-like" protein mimetics.
Headquartered in Laval (Canada), ProMetic has R&D facilities in the UK, the
U.S. and Canada, manufacturing facilities in the UK and business development
activities in the U.S., Europe, Asia and in the Middle-East.
About Macopharma SA
Macopharma SA ("Macopharma") (www.macopharma.com) is an innovator in
global healthcare with expertise in the fields of transfusion and infusion. It
has become the largest supplier of in-line leucoreduction filtration sets in
Europe and is expanding its efforts into the cellular therapy field by
developing products for cell expansion, in addition to cell/organ processing and
freezing. Headquartered in the Lille metropolitan area (France), MacoPharma has
three manufacturing facilities in Europe and their products are sold into more
than 70 countries worldwide.
Forward Looking Statements
This press release contains forward-looking statements about ProMetic's
objectives, strategies and businesses that involve risks and uncertainties.
These statements are "forward-looking" because they are based on our current
expectations about the markets we operate in and on various estimates and
assumptions. Actual events or results may differ materially from those
anticipated in these forward-looking statements if known or unknown risks affect
our business, or if our estimates or assumptions turn out to be inaccurate. Such
risks and assumptions include, but are not limited to, ProMetic's ability to
develop, manufacture, and successfully commercialize value-added pharmaceutical
products, the availability of funds and resources to pursue R&D projects,
the successful and timely completion of clinical studies, the ability of
ProMetic to take advantage of business opportunities in the pharmaceutical
industry, uncertainties related to the regulatory process and general changes in
economic conditions. You will find a more detailed assessment of the risks that
could cause actual events or results to materially differ from our current
expectations on page 27 of ProMetic's Annual Information Form for the year ended
December 31, 2010, under the heading "Risk Factors". As a result, we cannot
guarantee that any forward-looking statement will materialize. We assume no
obligation to update any forward-looking statement even if new information
becomes available, as a result of future events or for any other reason, unless
required by applicable securities laws and regulations. All amounts are in
Canadian dollars unless stated otherwise.
Contact Information
Company Inquiries Pierre Laurin President and CEO ProMetic Life Sciences
Inc. p.laurin@prometic.com +1.450.781.0115
Frederic Dumais Director, Communications and Investor Relations ProMetic
Life Sciences f.dumais@prometic.com +1.450.781.0115
Macopharma contacts Ronald De Lagrange President and CEO Macopharma SA +33
320.118.400
Veronique Lutun Director communications Macopharma SA
Veronique.lutun@macopharma.com +33 320.118.400
In the published minutes of its meeting of 9th March 2012, SaBTO describes
a revised model for predicting future cases of vCJD by red cell transfusion
which is based on current assumptions of factors such as vCJD prevalence in the
UK and the amount of infectivity in human blood but which also assumes all
previous cases of vCJD transmitted by blood transfusion have been identified and
not missed or misdiagnosed. As a consequence the new model assumes a very low
amount of infectivity in human blood (1 infectious dose per unit of red cells
pre-leucodepletion) in order to make the model fit the actual number of vCJD
transfusion transmission cases reported. Even with these revised assumptions
discounting the possible missed and or misdiagnosed cases, the new model
indicates future vCJD transmission is very likely to occur and could therefore
be prevented. The potential for miss-diagnosis of vCJD is a real possibility as
the majority of cases to date have been individuals with the MM genotype with
very few cases identified for persons with MV or VV genotype. It has been
postulated that persons with different genotypes may show different symptoms and
rather worryingly the total number of cases of all forms of CJD reported by the
UK CJD Surveillance Unit have increased progressively over the last two decades
with no apparent explanation.
SaBTO meeting papers – 9 March 2012
24 April, 2012
At its meeting on 9 March 2012, Advisory Committee on the Safety of Blood,
Tissues and Organs (SaBTO) discussed topics including the importation of fresh
frozen plasma, prion filtration of red blood cells and double red cell
collection as measures to reduce the risk of potential vCJD transmission via
transfusion; and those born on/after 1 January 1996 as potential recipients of
blood transfusions, and blood donors.
Advisory Committee on the Safety of Blood, Tissues and Organs
16th Meeting: Friday 9 March 2012
Room 125A Skipton House,
80 London Road, London SE1 6LH
11am start
AGENDA
SABTO MINUTES 16th Meeting: Friday 9 March 2012
With the abolition of the Spongiform Encephalopathy Advisory Committee
(SEAC) on 30th March 2011, a new ACDP TSE Risk Assessment Subgroup has been
established.
The terms of references are:
“To provide ACDP as requested with scientifically based assessment of risk
from transmissible spongiform encephalopathies (TSEs) in relation to food
safety, public and animal health issues, taking appropriate account of
scientific uncertainty and assumptions in formulating advice."
Papers
The CMV Position Statement
Download: Importation of fresh frozen plasma, effectiveness and
cost-effectiveness (PDF,755K)
Download Prion filtration & DRC, effectiveness & cost effectiveness
9 March 2012 (PDF,854K)
The Report of the PRISM A study will be published by the researchers in due
course
ACDP paper on blood-borne transmission of vCJD re-examination scenarios
Wednesday, May 9, 2012
Detection of Prion Protein Particles in Blood Plasma of Scrapie Infected
Sheep
SEE WEEKLY MAD COW BLOOD RECALLS IN USA ;
Enforcement Report for May 9, 2012
May 9, 2012 12-19 RECALLS AND FIELD CORRECTIONS: FOODS - CLASS I
PRODUCT Red Blood Cells Leukocytes Reduced. Recall # B-1110-12 CODE Unit:
GR84113 RECALLING FIRM/MANUFACTURER BloodCenter of Wisconsin, Inc., Milwaukee,
WI, by fax on August 31, 2007. Firm initiated recall is complete. REASON Blood
product, collected from a donor considered to be at increased risk for variant
Creutzfeldt-Jakob Disease (vCJD), was distributed. VOLUME OF PRODUCT IN COMMERCE
1 unit DISTRIBUTION MN
___________________________________
PRODUCT Recovered Plasma. Recall # B-1141-12 CODE Unit: W036510157983
RECALLING FIRM/MANUFACTURER LifeShare Blood Centers, Alexandria, LA, by
electronic notification on February 2, 2012. Firm initiated recall is complete.
REASON Blood product, collected from a donor who was at risk for variant
Creutzfeldt-Jakob Disease (vCJD), was distributed. VOLUME OF PRODUCT IN COMMERCE
1 unit DISTRIBUTION Switzerland
___________________________________
PRODUCT 1) Red Blood Cells Leukocytes Reduced. Recall # B-1166-12; 2)Whole
Blood Leukocytes Reduced. Recall # B-1167-12 CODE 1) Unit: 1620047; 2) Unit:
0890862 RECALLING FIRM/MANUFACTURER Hoxworth Blood Center University of
Cincinnati Medical Center, Cincinnati, OH, by letter dated October 10, 2006.
Firm initiated recall is complete. REASON Blood products, collected from a donor
who was at risk for variant Creutzfeldt-Jakob disease (vCJD), were distributed.
VOLUME OF PRODUCT IN COMMERCE 2 units DISTRIBUTION OH
___________________________________
PRODUCT 1) Plasma. Recall # B-1170-12; 2) Red Blood Cells Leukocytes
Reduced. Recall # B-1171-12 CODE 1) and 2) Units: 0857962; 0891897 RECALLING
FIRM/MANUFACTURER Recalling Firm: Blood Centers of the Pacific, San Francisco,
CA, by telephone on March 16, 2005. Manufacturer: Blood Center of the Pacific,
Redding, CA. Firm initiated recall is complete. REASON Blood products, collected
from a donor considered to be at increased risk for variant Creutzfeldt-Jakob
Disease (vCJD), were distributed. VOLUME OF PRODUCT IN COMMERCE 4 units
DISTRIBUTION CA, Switzerland
___________________________________
PRODUCT 1) Plasma. Recall # B-1173-12 2) Red Blood Cells Leukocytes
Reduced. Recall # B-1174-12 CODE 1) and 2) Unit: 8202523 RECALLING
FIRM/MANUFACTURER Blood Centers of the Pacific, San Francisco, CA, by telephone
on February 22, 2005. Firm initiated recall is complete. REASON Blood products,
collected from a donor considered to be at increased risk for variant
Creutzfeldt-Jakob Disease (vCJD), were distributed. VOLUME OF PRODUCT IN
COMMERCE 2 units DISTRIBUTION CA, Switzerland
___________________________________
now, what about that atypical L-type BASE BSE in the USA and Canada, human
exposure, and blood risk there from ???
Identification of a second bovine amyloidotic spongiform encephalopathy:
Molecular similarities with sporadic Creutzfeldt–Jakob disease
Cristina Casalone*†, Gianluigi Zanusso†‡, Pierluigi Acutis*, Sergio
Ferrari‡, Lorenzo Capucci§, Fabrizio Tagliavini¶, Salvatore Monaco‡ , and Maria
Caramelli* *Centro di Referenza Nazionale per le Encefalopatie Animali, Istituto
Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d’Aosta, Via Bologna,
148, 10195 Turin, Italy; ‡Department of Neurological and Visual Science, Section
of Clinical Neurology, Policlinico G.B. Rossi, Piazzale L.A. Scuro, 10, 37134
Verona, Italy; §Istituto Zooprofilattico Sperimentale della Lombardia ed Emilia
Romagna, Via Bianchi, 9, 25124 Brescia, Italy; and ¶Istituto Nazionale
Neurologico ‘‘Carlo Besta,’’ Via Celoria 11, 20133 Milan, Italy
Edited by Stanley B. Prusiner, University of California, San Francisco, CA,
and approved December 23, 2003 (received for review September 9, 2003)
Transmissible spongiform encephalopathies (TSEs), or prion diseases, are
mammalian neurodegenerative disorders characterized by a posttranslational
conversion and brain accumulation of an insoluble, protease-resistant isoform
(PrPSc) of the host-encoded cellular prion protein (PrPC). Human and animal TSE
agents exist as different phenotypes that can be biochemically differentiated on
the basis of the molecular mass of the protease-resistant PrPSc fragments and
the degree of glycosylation. Epidemiological, molecular, and transmission
studies strongly suggest that the single strain of agent responsible for bovine
spongiform encephalopathy (BSE) has infected humans, causing variant
Creutzfeldt–Jakob disease. The unprecedented biological properties of the BSE
agent, which circumvents the so-called ‘‘species barrier’’ between cattle and
humans and adapts to different mammalian species, has raised considerable
concern for human health. To date, it is unknown whether more than one strain
might be responsible for cattle TSE or whether the BSE agent undergoes
phenotypic variation after natural transmission. Here we provide evidence of a
second cattle TSE. The disorder was pathologically characterized by the presence
of PrP-immunopositive amyloid plaques, as opposed to the lack of amyloid
deposition in typical BSE cases, and by a different pattern of regional
distribution and topology of brain PrPSc accumulation. In addition, Western blot
analysis showed a PrPSc type with predominance of the low molecular mass
glycoform and a protease- resistant fragment of lower molecular mass than
BSE-PrPSc. Strikingly, the molecular signature of this previously undescribed
bovine PrPSc was similar to that encountered in a distinct subtype of sporadic
Creutzfeldt–Jakob disease.
Phenotypic Similarities Between BASE and sCJD. The transmissibility of CJD
brains was initially demonstrated in primates (27), and classification of
atypical cases as CJD was based on this property (28). To date, no systematic
studies of strain typing in sCJD have been provided, and classification of
different subtypes is based on clinical, neuropathological, and molecular
features (the polymorphic PRNP codon 129 and the PrPSc glycotype) (8, 9, 15,
19). The importance of molecular PrPSc characterization in assessing the
identity of TSE strains is underscored by several studies, showing that the
stability of given disease-specific PrPSc types is maintained upon experimental
propagation of sCJD, familial CJD, and vCJD isolates in transgenic PrP-humanized
mice (8, 29). Similarly, biochemical properties of BSE- and vCJDassociated PrPSc
molecules remain stable after passage to mice expressing bovine PrP (30).
Recently, however, it has been reported that PrP-humanized mice inoculated with
BSE tissues may also propagate a distinctive PrPSc type, with a
‘‘monoglycosylated- dominant’’ pattern and electrophoretic mobility of the
unglycosylated fragment slower than that of vCJD and BSE (31). Strikingly, this
PrPSc type shares its molecular properties with the a PrPSc molecule found in
classical sCJD. This observation is at variance with the PrPSc type found in
M V2 sCJD cases and in cattle BASE, showing a monoglycosylated-dominant pattern
but faster electrophoretic mobility of the protease-resistant fragment as
compared with BSE. In addition to molecular properties of PrPSc, BASE and M V2
sCJD share a distinctive pattern of intracerebral PrP deposition, which occurs
as plaque-like and amyloid-kuru plaques. Differences were, however, observed in
the regional distribution of PrPSc. While inM V2 sCJD cases the largest amounts
of PrPSc were detected in the cerebellum, brainstem, and striatum, in cattle
BASE these areas were less involved and the highest levels of PrPSc were
recovered from the thalamus and olfactory regions.
In conclusion, decoding the biochemical PrPSc signature of individual human
and animal TSE strains may allow the identification of potential risk factors
for human disorders with unknown etiology, such as sCJD. However, although BASE
and sCJD share several characteristics, caution is dictated in assessing a link
between conditions affecting two different mammalian species, based on
convergent biochemical properties of diseaseassociated PrPSc types. Strains of
TSE agents may be better characterized upon passage to transgenic mice. In the
interim until this is accomplished, our present findings suggest a strict
epidemiological surveillance of cattle TSE and sCJD based on molecular criteria.
Atypical BSE in Cattle
BSE has been linked to the human disease variant Creutzfeldt Jakob Disease
(vCJD). The known exposure pathways for humans contracting vCJD are through the
consumption of beef and beef products contaminated by the BSE agent and through
blood transfusions. However, recent scientific evidence suggests that the BSE
agent may play a role in the development of other forms of human prion diseases
as well. These studies suggest that classical type of BSE may cause type 2
sporadic CJD and that H-type atypical BSE is connected with a familial form of
CJD.
Thursday, August 12, 2010
Seven main threats for the future linked to prions
First threat
The TSE road map defining the evolution of European policy for protection
against prion diseases is based on a certain numbers of hypotheses some of which
may turn out to be erroneous. In particular, a form of BSE (called atypical
Bovine Spongiform Encephalopathy), recently identified by systematic testing in
aged cattle without clinical signs, may be the origin of classical BSE and thus
potentially constitute a reservoir, which may be impossible to eradicate if a
sporadic origin is confirmed.
***Also, a link is suspected between atypical BSE and some apparently
sporadic cases of Creutzfeldt-Jakob disease in humans. These atypical BSE cases
constitute an unforeseen first threat that could sharply modify the European
approach to prion diseases.
Second threat
snip...
Several transmission experiments in primate models were performed to
assess the risk of BSE for human health. Lemurs, marmosets, macaques and
squirrel monkeys developed spongiform encephalopathies after intracerebral
inoculation of brains from BSE-infected cattle (Baker et al., 1993; Bons et al.,
1999; Lasmezas et al., 1996; Williams et al., 2007). Secondary transmission to
the same host, i.e. conventional mice, of both macaque BSE and human vCJD
induced similar lesional profiles, bringing an additional evidence for the
similitude between BSE and vCJD agents (Lasmezas et al., 2001).
Subsequently, lemur and macaque models demonstrated the transmissibility of
BSE through the oral route (Bons et al., 1999; Lasmezas et al., 2005). In
macaque, 5 grams were sufficient to transmit the disease to one of two
inoculated animals (Lasmezas et al., 2005). Furthermore, risk of secondary
transmission through transfusion was assessed in the same primate models:
infectivity of blood components was demonstrated through intracerebral
inoculation in lemurs (Bons et al., 2002), the intravenous route was
demonstrated as an efficient way of transmission in macaques (Herzog et al.,
2004), and finally transmission was achieved through transfusion in this latter
model (Comoy et al., 2008a).
snip...
Intracerebral inoculation of brain from L-BSE-infected cattle to cynomolgus
macaque induced a spongiform encephalopathy distinct in all its aspects
(clinical, lesional and biochemical) from macaque BSE (Comoy et al., 2008b). In
the frame of a primary passage through inoculation of a same amount of infected
brain, incubation periods were shorter (23-25 months) than for BSE (38-40
months), suggesting that L-BSE may be more virulent than Classical BSE for
infecting primates. LBSE was also tranmissible to microcebes, with shorter
incubations than Classical BSE (Baron et al., 2008). Moreover, recent
experiments demonstrated the transmissibility of L-BSE to macaque by the oral
route (Comoy, 2010) with 5 grams of infected brain, this amount being similar to
the one used for oral transmission of Classical BSE in the macaque model.
Histology and biochemistry studies showed similarities between
L-BSE-inoculated macaques and MM2 sporadic Creutzfeldt-Jakob disease patients:
infected primates and those rare patients exhibited similar lesional profiles,
and their respective PrPres showed the same sensitivity of their N-terminal
parts to proteolysis. Moreover, a macaque inoculated with brain of a MM2 sCJD
patient showed similar lesional profile as L-BSE infected macaques (Comoy et
al., 2009).
snip...
The intracerebral inoculation of L-BSE field isolates produced TSE disease
in two lines of mice overexpressing human PrP (Met129), exhibiting a molecular
phenotype distinct from Classical BSE (Beringue et al., 2008a; Kong et al.,
2008). In one of them, the L-BSE agent appeared to propagate with no obvious
transmission barrier: a 100% attack rate was observed on first passage, the
incubation time was not reduced on subsequent passaging (Beringue et al.,
2008a), and the L-type PrPSc biochemical signature was essentially conserved
(Beringue et al., 2008a; Kong et al., 2008). The latter appeared
undistinguishable from that seen after experimental inoculation of MM2 sCJD in
these mice (Beringue et al., 2007). These transmission features markedly
differed from the low transmission efficiency of cattle BSE isolates to this
(Beringue et al., 2008a; Beringue et al., 2008b) and other (Asante et al., 2002)
human PrP transgenic mouse lines.
Conclusions:
• The true incidence and geographical distribution of atypical forms of BSE
has not been established.
• Both L-BSE and H-BSE have shown BSE-like characteristics on transmission
studies in some lines of mice. The precise relationship between Classical BSE,
H-BSE and L-BSE is not yet clear. However these experiments have shown that the
potential for interspecies transmission of Atypical BSE is high.
• Several elements indicate that the L-BSE agent has the potential to be a
zoonotic agent. Primates are highly permissive to L-BSE agents, even by the oral
route, and these can also propagate without any apparent transmission barrier in
transgenic mice overexpressing human PrP.
• In both primates and human PrP transgenic mice models the virulence of
the L-BSE agent is significantly higher than that of Classical BSE.
• To date, H-BSE has not been reported as transmissible to mice
overexpressing the Met allele of human PrP, nor to primates.
• To date, H-BSE has not been reported as transmissible to mice
overexpressing the Met allele of human PrP, nor to primates. ???
please see ;
P.4.23
Transmission of atypical BSE in humanized mouse models
Liuting Qing1, Wenquan Zou1, Cristina Casalone2, Martin Groschup3, Miroslaw
Polak4, Maria Caramelli2, Pierluigi Gambetti1, Juergen Richt5, Qingzhong Kong1
1Case Western Reserve University, USA; 2Instituto Zooprofilattico Sperimentale,
Italy; 3Friedrich-Loeffler-Institut, Germany; 4National Veterinary Research
Institute, Poland; 5Kansas State University (Previously at USDA National Animal
Disease Center), USA
Background: Classical BSE is a world-wide prion disease in cattle, and the
classical BSE strain (BSE-C) has led to over 200 cases of clinical human
infection (variant CJD). Atypical BSE cases have been discovered in three
continents since 2004; they include the L-type (also named BASE), the H-type,
and the first reported case of naturally occurring BSE with mutated bovine PRNP
(termed BSE-M). The public health risks posed by atypical BSE were largely
undefined.
Objectives: To investigate these atypical BSE types in terms of their
transmissibility and phenotypes in humanized mice. Methods: Transgenic mice
expressing human PrP were inoculated with several classical (C-type) and
atypical (L-, H-, or Mtype) BSE isolates, and the transmission rate, incubation
time, characteristics and distribution of PrPSc, symptoms, and histopathology
were or will be examined and compared.
Results: Sixty percent of BASE-inoculated humanized mice became infected
with minimal spongiosis and an average incubation time of 20-22 months, whereas
only one of the C-type BSE-inoculated mice developed prion disease after more
than 2 years. Protease-resistant PrPSc in BASE-infected humanized Tg mouse
brains was biochemically different from bovine BASE or sCJD. PrPSc was also
detected in the spleen of 22% of BASE-infected humanized mice, but not in those
infected with sCJD. Secondary transmission of BASE in the humanized mice led to
a small reduction in incubation time.*** The atypical BSE-H strain is also
transmissible with distinct phenotypes in the humanized mice, but no BSE-M
transmission has been observed so far.
Discussion: Our results demonstrate that BASE is more virulent than
classical BSE, has a lymphotropic phenotype, and displays a modest transmission
barrier in our humanized mice. BSE-H is also transmissible in our humanized Tg
mice. The possibility of more than two atypical BSE strains will be discussed.
Supported by NINDS NS052319, NIA AG14359, and NIH AI 77774.
P26 TRANSMISSION OF ATYPICAL BOVINE SPONGIFORM ENCEPHALOPATHY (BSE) IN
HUMANIZED MOUSE MODELS
Liuting Qing1, Fusong Chen1, Michael Payne1, Wenquan Zou1, Cristina
Casalone2, Martin Groschup3, Miroslaw Polak4, Maria Caramelli2, Pierluigi
Gambetti1, Juergen Richt5*, and Qingzhong Kong1 1Department of Pathology, Case
Western Reserve University, Cleveland, OH 44106, USA; 2CEA, Istituto
Zooprofilattico Sperimentale, Italy; 3Friedrich-Loeffler-Institut, Germany;
4National Veterinary Research Institute, Poland; 5Kansas State University,
Diagnostic Medicine/Pathobiology Department, Manhattan, KS 66506, USA. *Previous
address: USDA National Animal Disease Center, Ames, IA 50010, USA
Classical BSE is a world-wide prion disease in cattle, and the classical
BSE strain (BSE-C) has led to over 200 cases of clinical human infection
(variant CJD). Two atypical BSE strains, BSE-L (also named BASE) and BSE-H, have
been discovered in three continents since 2004. The first case of naturally
occurring BSE with mutated bovine PrP gene (termed BSE-M) was also found in 2006
in the USA. The transmissibility and phenotypes of these atypical BSE
strains/isolates in humans were unknown. We have inoculated humanized transgenic
mice with classical and atypical BSE strains (BSE-C, BSE-L, BSE-H) and the BSE-M
isolate. We have found that the atypical BSE-L strain is much more virulent than
the classical BSE-C.*** The atypical BSE-H strain is also transmissible in the
humanized transgenic mice with distinct phenotype, but no transmission has been
observed for the BSE-M isolate so far.
III International Symposium on THE NEW PRION BIOLOGY: BASIC SCIENCE,
DIAGNOSIS AND THERAPY 2 - 4 APRIL 2009, VENEZIA (ITALY)
I ask Professor Kong ;
Thursday, December 04, 2008 3:37 PM Subject: RE: re--Chronic Wating Disease
(CWD) and Bovine Spongiform Encephalopathies (BSE): Public Health Risk
Assessment
''IS the h-BSE more virulent than typical BSE as well, or the same as cBSE,
or less virulent than cBSE? just curious.....''
Professor Kong reply ;
.....snip
''As to the H-BSE, we do not have sufficient data to say one way or
another, but we have found that H-BSE can infect humans. I hope we could publish
these data once the study is complete. Thanks for your interest.''
Best regards, Qingzhong Kong, PhD Associate Professor Department of
Pathology Case Western Reserve University Cleveland, OH 44106 USA
END...TSS
Thursday, December 04, 2008 2:37 PM
"we have found that H-BSE can infect humans."
personal communication with Professor Kong. ...TSS
BSE-H is also transmissible in our humanized Tg mice.
The possibility of more than two atypical BSE strains will be discussed.
Supported by NINDS NS052319, NIA AG14359, and NIH AI 77774.
Research Experimental H-type bovine spongiform encephalopathy characterized
by plaques and glial- and stellate-type prion protein deposits
Hiroyuki Okada1*, Yoshifumi Iwamaru1, Morikazu Imamura1, Kentaro Masujin1,
Yuichi Matsuura1, Yoshihisa Shimizu1, Kazuo Kasai1, Shirou Mohri1, Takashi
Yokoyama1 and Stefanie Czub2
* Corresponding author: Hiroyuki Okada okadahi@affrc.go.jp
Author Affiliations
1 Prion Disease Research Center, National Institute of Animal Health, 3-1-5
Kannondai, Tsukuba, Ibaraki 305-0856, Japan
2 Canadian and OIE Reference Laboratories for BSE, Canadian Food Inspection
Agency Lethbridge Laboratory, Lethbridge, Alberta, Canada
For all author emails, please log on.
Veterinary Research 2011, 42:79 doi:10.1186/1297-9716-42-79
The electronic version of this article is the complete one and can be found
online at: http://www.veterinaryresearch.org/content/42/1/79
Received:
5 January 2011
Accepted:
23 June 2011
Published:
23 June 2011
© 2011 Okada et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.
Abstract
Atypical bovine spongiform encephalopathy (BSE) has recently been
identified in Europe, North America, and Japan. It is classified as H-type and
L-type BSE according to the molecular mass of the disease-associated prion
protein (PrPSc). To investigate the topographical distribution and deposition
patterns of immunolabeled PrPSc, H-type BSE isolate was inoculated
intracerebrally into cattle. H-type BSE was successfully transmitted to 3
calves, with incubation periods between 500 and 600 days. Moderate to severe
spongiform changes were detected in the cerebral and cerebellar cortices, basal
ganglia, thalamus, and brainstem. H-type BSE was characterized by the presence
of PrP-immunopositive amyloid plaques in the white matter of the cerebrum, basal
ganglia, and thalamus. Moreover, intraglial-type immunolabeled PrPSc was
prominent throughout the brain. Stellate-type immunolabeled PrPSc was
conspicuous in the gray matter of the cerebral cortex, basal ganglia, and
thalamus, but not in the brainstem. In addition, PrPSc accumulation was detected
in the peripheral nervous tissues, such as trigeminal ganglia, dorsal root
ganglia, optic nerve, retina, and neurohypophysis. Cattle are susceptible to
H-type BSE with a shorter incubation period, showing distinct and
distinguishable phenotypes of PrPSc accumulation.
snip...
Discussion
This study demonstrated successful intraspecies transmission of H-type BSE
characterized by a shorter incubation period as compared with C-type BSE [19].
To the best of our knowledge, thus far, neuropathological and
immunohistochemical data for H-type BSE have only been reported from the medulla
oblongata at the obex in German, United States, and Swedish field cases
[10,13,24]. This is related to the fact that only the obex region is sampled for
BSE rapid tests and other brain regions are often unavailable due to marked
autolysis, limitations in collection infrastructure, or freezing artifacts
[10,13,24,25]. This is the first presentation of H-type lesion profiles
involving the whole CNS and additional nervous tissues, although of
experimentally infected animals. Incubation periods in the cattle challenged
with the Canadian H-type BSE (mean period, 18 months) were two months longer
than those reported in cattle challenged with German H-type BSE [20]. This
difference in incubation periods has several potential explanations, which
include differences in agents tested, inoculum titers, and breeding conditions.
Infectivity titer issues might be resolved by comparing second-passage infection
experiment results.
snip...
Since 2003, sporadic and discontinuous occurrence of atypical BSE has been
detected in Europe, North America, and Japan. Although, till date, the origin
and frequency of atypical BSE is unknown, a high prevalence is found in older
cattle over the age of eight years. This is the result of the active
surveillance programs using rapid screening tests, with the exception of a Zebu
case [38]. It has been reported that H-type BSE can be the result of a naturally
occurring, heritable variant caused by glutamic acid/lysine polymorphism at
codon 211 of the bovine PRNP gene (E211K) [11,58]. However, our cases, although
experimentally challenged via the intracranial route, and the original Canadian
H-type BSE field case [11,58] developed the disease without the Okada et al.
Veterinary Research 2011, 42:79 http://www.veterinaryresearch.org/content/42/1/79
Page 9 of 11
novel mutation E211K within PRNP. Therefore, atypical BSE seemed to be
sporadic rather than inherited with a higher risk in fallen stock than in
healthy slaughtered cattle [8,13,25], suggesting that young adult cattle
affected with atypical BSE might be dormant carriers. Further studies are
required to determine the epidemiological significance and origin of atypical
BSE.
The present study demonstrated successful intraspecies transmission of
H-type BSE to cattle and the distribution and immunolabeling patterns of PrPSc
in the brain of the H-type BSE-challenged cattle. TSE agent virulence can be
minimally defined by oral transmission of different TSE agents (C-type, L-type,
and H-type BSE agents) [59]. Oral transmission studies with H-type BSEinfected
cattle have been initiated and are underway to provide information regarding the
extent of similarity in the immunohistochemical and molecular features before
and after transmission.
In addition, the present data will support risk assessments in some
peripheral tissues derived from cattle affected with H-type BSE.
see ;
Experimental H-type bovine spongiform encephalopathy characterized by
plaques and glial- and stellate-type prion protein deposits
Hiroyuki Okada1*, Yoshifumi Iwamaru1, Morikazu Imamura1, Kentaro Masujin1,
Yuichi Matsuura1, Yoshihisa Shimizu1 , Kazuo Kasai1, Shirou Mohri1, Takashi
Yokoyama1 and Stefanie Czub2
MAD COW USDA ATYPICAL L-TYPE BASE BSE, the rest of the story...
***Oral Transmission of L-type Bovine Spongiform Encephalopathy in Primate
Model
***Infectivity in skeletal muscle of BASE-infected cattle
***feedstuffs- It also suggests a similar cause or source for atypical BSE
in these countries.
***Also, a link is suspected between atypical BSE and some apparently
sporadic cases of Creutzfeldt-Jakob disease in humans.
full text ;
atypical L-type BASE BSE
Tuesday, May 1, 2012
BSE MAD COW LETTERS TO USDA (Tom Vilsack, Secretary of Agriculture) and FDA
(Magaret Hamburg, Commissioner of FDA) May 1, 2012
Wednesday, May 2, 2012
ARS FLIP FLOPS ON SRM REMOVAL FOR ATYPICAL L-TYPE BASE BSE RISK HUMAN AND
ANIMAL HEALTH
Friday, May 4, 2012
May 2, 2012: Update from APHIS Regarding a Detection of Bovine Spongiform
Encephalopathy (BSE) in the United States
Sunday, March 11, 2012
APHIS Proposes New Bovine Spongiform Encephalopathy Import Regulations in
Line with International Animal Health Standards Proposal Aims to Ensure Health
of the U.S. Beef Herd, Assist in Negotiations
Wednesday, April 4, 2012
Bovine Spongiform Encephalopathy; Importation of Bovines and Bovine
Products APHIS-2008-0010-0008 RIN:0579-AC68
Sunday, May 6, 2012
Bovine Spongiform Encephalopathy Mad Cow Disease, BSE May 2, 2012 IOWA
State University OIE
SPONTANEOUS ??? NOT...
How the California cow got the disease remains unknown. Government
officials expressed confidence that contaminated food was not the source, saying
the animal had atypical L-type BSE, a rare variant not generally associated with
an animal consuming infected feed.
However, a BSE expert said that consumption of infected material is the
only known way that cattle get the disease under natural conditons.
“In view of what we know about BSE after almost 20 years experience,
contaminated feed has been the source of the epidemic,” said Paul Brown, a
scientist retired from the National Institute of Neurological Diseases and
Stroke. BSE is not caused by a microbe. It is caused by the misfolding of the
so-called “prion protein” that is a normal constituent of brain and other
tissues. If a diseased version of the protein enters the brain somehow, it can
slowly cause all the normal versions to become misfolded.
It is possible the disease could arise spontaneously, though such an event
has never been recorded, Brown said.
USA FDA TRIPLE FIREWALL I.E. MAD COW FEED BAN ?
nothing but ink on paper. see ONE DECADE, TEN YEARS, POST PARTIAL AND
VOLUNTARY MAD COW FEED BAN USA ;
10,000,000+ LBS. of PROHIBITED BANNED MAD COW FEED I.E. BLOOD LACED MBM IN
COMMERCE USA 2007
Date: March 21, 2007 at 2:27 pm PST
RECALLS AND FIELD CORRECTIONS: VETERINARY MEDICINES -- CLASS II
PRODUCT
Bulk cattle feed made with recalled Darling's 85% Blood Meal, Flash Dried,
Recall # V-024-2007
CODE
Cattle feed delivered between 01/12/2007 and 01/26/2007
RECALLING FIRM/MANUFACTURER
Pfeiffer, Arno, Inc, Greenbush, WI. by conversation on February 5, 2007.
Firm initiated recall is ongoing.
REASON
Blood meal used to make cattle feed was recalled because it was cross-
contaminated with prohibited bovine meat and bone meal that had been
manufactured on common equipment and labeling did not bear cautionary BSE
statement.
VOLUME OF PRODUCT IN COMMERCE
42,090 lbs.
DISTRIBUTION
WI
___________________________________
PRODUCT
Custom dairy premix products: MNM ALL PURPOSE Pellet, HILLSIDE/CDL Prot-
Buffer Meal, LEE, M.-CLOSE UP PX Pellet, HIGH DESERT/ GHC LACT Meal, TATARKA, M
CUST PROT Meal, SUNRIDGE/CDL PROTEIN Blend, LOURENZO, K PVM DAIRY Meal, DOUBLE B
DAIRY/GHC LAC Mineral, WEST PIONT/GHC CLOSEUP Mineral, WEST POINT/GHC LACT Meal,
JENKS, J/COMPASS PROTEIN Meal, COPPINI - 8# SPECIAL DAIRY Mix, GULICK, L-LACT
Meal (Bulk), TRIPLE J - PROTEIN/LACTATION, ROCK CREEK/GHC MILK Mineral,
BETTENCOURT/GHC S.SIDE MK-MN, BETTENCOURT #1/GHC MILK MINR, V&C DAIRY/GHC
LACT Meal, VEENSTRA, F/GHC LACT Meal, SMUTNY, A- BYPASS ML W/SMARTA, Recall #
V-025-2007
CODE
The firm does not utilize a code - only shipping documentation with
commodity and weights identified.
RECALLING FIRM/MANUFACTURER
Rangen, Inc, Buhl, ID, by letters on February 13 and 14, 2007. Firm
initiated recall is complete.
REASON
Products manufactured from bulk feed containing blood meal that was cross
contaminated with prohibited meat and bone meal and the labeling did not bear
cautionary BSE statement.
VOLUME OF PRODUCT IN COMMERCE
9,997,976 lbs.
DISTRIBUTION
ID and NV
END OF ENFORCEMENT REPORT FOR MARCH 21, 2007
2006, was such a banner year for banned mad cow protein in commerce, it
was measured in TONNAGE, not pounds. ...TSS
