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2011 Call for projects in the field of viral safety for biological products
  » Outcome

Prions research Call for projects Results

The Alliance BioSecure Foundation under the aegis of the Fondation pour la Recherche Médicale pursues its funding of prions research with a focus on minimizing biological risk from prions.
2014 scientific themes were:

  • Innovative approach to detect and differentiate prion strains
  • Investigation of the risk of prion transmission from animals to humans

15 projects have been received for this call for proposals; projects came from recognized team, mainly from Europe and United States.
The process of selection of projects led by the Scientific Council that the Foundation warmly thanks. Chaired by the Pr Sylvain Lehmann it includes Pr Dominique Costagliola, Pr Jacques-Christian Darbord, Dr. Jean-Philippe Deslys and Pr Didier Guillemot, representing the FRM.
Two reviewers each evaluated 13 projects; two projects having not met the eligibility criteria have not been selected for evaluation.
The Scientific Council then met to finalize the selection, which was approved by the Executive Committee of the Foundation.

6 projects were selected

2 projects on detection:

  1. Project « RT- QuIC »
    (RT-QuIC and mass spectrometry approachs to prion strain detection and discrimination)
    • Investigators: Byron Caughey (Principal Investigator), Christina D. Orru (Co Investigator), Bradley R. Groveman, Roger Moore Laboratory of Persistent Viral Diseases, NIH/NIAID Rocky Mountain, USA
      Cristina Casalone, Cristiano Corona, Maria Mazza, Alessandra Favole, Istituto Zooprofilattico Sperimentale del Piemonte Liguria e Valle d'Aosta
      Gianluigi Zanusso, University of Verona, Italy.
    • Duration: 1 year
    • Grant: 60 000 €

    Pathological prions can lead to a variety of different mammalian brain diseases, also called transmissible spongiform encephalopathies (TSEs). The characteristics and symptoms of these diseases can be classified into strains. Identification of the prion strain in an infected individual is important in developing strategies for handling these diseases.
    A major challenge in prion disease management has been the lack of tests that are both practical and sensitive enough for routine prion detection and strain discrimination in medicine, agriculture and wildlife biology. Our group has helped develop the Real-Time Quaking Induced Conversion (RT-QuIC) test, a highly sensitive test for prions in infected tissues from multiple species. In preliminary experiments we have noticed that certain prion strains give different reactions in the RT-QuIC test. Thus, we propose to exploit these strain-dependent differences to identify and characterize certain prion types. As we anticipate that this approach might not be suitable for discriminating all prion strains of interest, we also propose to employ another biochemical technique, mass spectrometry, to aid in classifying important human sporadic CJD prion strains. The discrimination of sCJD types I and II has important implications for the pace of disease progression in the patient. We anticipate that these approaches could be used independently or in combination for diagnosing, screening, and researching these deadly, infectious diseases.

  2. Project « PDBvCJD »
    (Prion detection in blood samples of patients suffering from variant creutzfeldt-jakob disease)
    • Investigators: Fabio Moda (Principal Investigator), Claudio Sotto, Fabrizio Tagliavini, laboratoire de neuropathologie, "Carlo Besta" Neurological Institute, Milan, Italy.
    • Duration: 2 years
    • Grant: 60 000 €

    This project is aimed to establish and validate a diagnostic test for vCJD using blood samples from patients affected by this devastating disease. The small amount of infectious agent (named PrPSc) circulating in blood makes its detection very challenging. With an innovative technique called Protein Misfolding Cyclic Amplification (PMCA) we will make minute amount of PrPSc detectable with the conventional analitique techniques thus providing an important and highly sensitive test for vCJD.

    Worryingly, compelling evidences suggest that vCJD is transmissible from human-to-human through blood transfusion procedures. This alarmingly cases transmitted by blood transfusion confirms that prions exist in relatively small quantities in the blood of individuals silently incubating vCJD. Moreover, some infected patients my never develop clinical symptoms but remaining asymptomatic carriers who can potentially transmit the disease to other individuals.

    The fact that asymptomatic carriers far outnumber the clinically affected individuals, the difficulties on decontaminating prions and the evidence that prions are circulating in biological fluids indicate that vertical transmission of prion is a major concern for public health.

    Aim of this project is to identify and screen patients as well as blood samples (that might be collected from asymptomatic donors at the time of collection who subsequently died for vCJD) that carry infectivity and reduce the risk of human-to-human transmission of vCJD.

4 projects on prion transmission from animals to humans:

     - Research on « small ruminants »

  1. Project « Zoo- Scrapie »
    (Permeability of the human species barrier to Scrapie Prions)
    • Investigators: Olivier Andreoletti (Principal Investigator) UMR ENVT 1225 IHAP, INRA Toulouse, Vincent Beringue, UR 892 VIM, INRA Jouy en Josas, France.
    • Duration: 2 years
    • Grant: 60 000 €

    The Bovine Spongiform Encephalopathy (BSE) is the cause of variant CJD in human. While Scrapie in small ruminants is a disease that has been described for several centuries, the zoonotic potential of Scrapie prions had remained mostly unknown.

    Recently we demonstrated, for the first time, that a panel of sheep scrapie prions can transmit to several mice models that over-express the human prion protein with an efficiency comparable to that of cattle BSE. The serial transmission of different scrapie isolates in these mice led to the propagation of prions that are phenotypically identical to those causing sporadic CJD (sCJD) in humans. These results demonstrate that scrapie prions have an intrinsic zoonotic potential. They also raise some questions about the possible links between animal and human prions.

    Bioassay in mice expressing the human PrP protein can be considered as a reliable tool to gauge the permeability of the human species barrier. However, the time and the costs that are necessary to obtain results (over 5 years) are major limitations to their use.

    The main objective of the current proposal is to assess and characterize in-vitro and ex-vivo to estimate the permeability of the human species barrier towards animals’ prions.

    The development and the validation of in vitro or ex vivo tools as reliable and rapid alternative to bioassays for gauging the capacity of prions to cross the human species barrier will represent an important progress with important consequence for decision making in public health.

  2. Project « Prion- Zoonotic » ( Study of the zoonotic potential of the diversity of prions circulating in livestock ruminants using transgenic mouse models)
    • Investigator: Juan Maria Torres, INIA, Centro de Investigacion en Sanidad Animal, Madrid, Spain.
    • Duration: 3 years
    • Grant: 54 000 €

    Dietary exposure to bovine spongiform encephalopathy (BSE) contaminated bovine tissues is considered as the origin of variant Creutzfeldt Jakob (vCJD) disease in human. To date, BSE agent is the only recognized zoonotic prion.
    Despite the variety of Transmissible Spongiform Encephalopathy (TSE) agents that have been circulating for centuries in farmed ruminants there is no apparent epidemiological link between exposure to ruminant products and the occurrence of other form of TSE in human like sporadic Creutzfeld Jakob Disease (sCJD).
    However, the zoonotic potential of the diversity of circulating TSE agents has never been systematically assessed. The major issue in experimental assessment of TSEs zoonotic potential lies in the modeling of the ‘species barrier’, the biological phenomenon that limits TSE agents’ propagation from a species to another.
    Recently, we have developed new models based on transgenic mice expressing human PrP. These mice have proved essential in studying human TSEs and modeling the capacity of TSEs to cross the human species barrier.
    In this project, we propose to use these mouse models to evaluate the zoonotic potential of a collection of prion isolates from farmed ruminant species (cattle, sheep and goat). From each species, a panel of isolates will be selected on the basis of their phenotype diversity, trying to include the totality of the strain diversity circulating. The results will allow determining human susceptibility to these agents in comparison to BSE.

     - Research on bovine strains

  1. Project « RESATYPBSE » (Strain features and seeding properties by Protein Misfolding Cyclic Amplification of L-BSE and sporadic CJD (type 2) prion strains following disease transmission in an ovine transgenic mouse model with co-expression of a resistance allele (R171))
    • Investigators: Thierry Baron (Principal Investigator ), ANSES Lyon, Vincent Beringue, UR 892 VIM, INRA Jouy en Josas, France.
    • Duration: 2 years
    • Grant: 30 000 €

    L-type bovine spongiform encephalopathy (BSE), one of the two known forms of atypical BSE in cattle, has a surprising capacity to change its “structural clothes” when transmitted to another species.
    We notably found that sheep known to be highly resistant to scrapie or classical BSE due to the sequence of their normal prion protein (RQ171) were relatively susceptible to L-BSE, but then showed a quite unexpected molecular change of the disease-associated prion protein, strikingly different from that found in cattle or in sheep expressing only the highly susceptible QQ171 normal protein. However, the biological properties of the infectious agent examined by transmission studies in mice seem to be unchanged.
    We propose some experiments reproducing this phenomenon in transgenic mice that will express both the Q171 and the R171 ovine normal prion proteins.
    These mice will be experimentally infected with L-BSE, as well as with another prion strain derived from human sporadic Creutzfeldt-Jakob disease that shares some molecular similarities with L-BSE. Features of the diseases will be studied in mice by ANSES, including survivals of mice, distribution of the brain lesions and detailed analyses of the molecular properties of the disease-associated prion protein. Properties of the infectious agents in these mice will be studied by INRA using the recently developed approach of Protein Misfolding Cyclic Amplification (PMCA).
    This will allow examining how the infectious agent from these mice behaves, compared to that in transgenic mice expressing only the Q171 prion protein, regarding its capacity to transform either ovine or human normal prion proteins in their disease-associated counterparts.
    Beside the importance of L-BSE which appears easily transmissible to a humanized host, this example of LBSE is a unique opportunity to study this unexpected capacity to change its properties and increase its adaptation during cross-species transmissions.

     - Research on cervidae

  1. Projet« CWDVHM »
    (Transmission of CWD deer isolates to voles and transgenic PrP-humanized mice )
    • Investigators: Luisa Gregori (Principal Investigator), Food and Drug Administration, Christopher J. Johnson, USGS National Wildlife Health Center, USA.
    • Duration: 1 year
    • Grant: 40 000 €

    Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy fatal brain infection of deer, elk and moose. Epidemiological evidence does not suggest CWD is readily transmitted to humans, but the true risk is still uncertain.
    In this proposal, we aim to investigate the risk posed by the infectious agent of CWD from white-tailed deer that have different forms of a cellular protein called the prion protein.
    Preliminary studies indicated that white-tailed deer with prion protein of one kind injected into the meadow vole gave rise to multiple types of CWD infections, whereas CWD from deer with another kind of prion protein resulted in just one type of CWD infections in voles. These results suggest two distinct kinds of deer caused two different types of infections in the voles. These data led us to hypothesize that naturally occurring types of CWD agents may have a “host range” different in voles and perhaps also in humans.
    To test our hypothesis we have challenged a small group of mice that have genetically modified to express the human form of the prion protein (humanized mice), as surrogates for human susceptibility, with the two types of deer brain.
    We seek support to 1.) Continue and further expand the study to include more mice and additional isolates as well as CWD 96SS; 2.) Conduct tests with an in vitro assay using vole and transgenic mouse brains amplified with deer CWD samples.
    The results from the in vitro study will be compared to the results from the animal bioassay (aim 1) to establish the degree of correlation between the two very different methodologies.
    These studies will investigate the question of transmissibility of CWD to humans from a less
    common kind of deer that may be more easily transmit the disease to humans.
    If our hypothesis is correct, our results might explain why the studies so far conducted with the more common CWD type have failed to show transmission to mice with human prion protein.

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