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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 continues the funding of research on bio-safety in the field of prion.
In order to take into account the recent progress made into this field and to give the best chances to leverage promising results, the Foundation decided to focus its efforts on the detection of human prion proteins by opening a call for projects on the following theme  :

Development or validation of methods to detect prions (direct detection or indirect through biomarkers) in humans

14 projects have been received for this call for proposals; projects came from recognized team, mainly from Europe.
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.

13 projects were evaluated by two reviewers each; one project having not met the eligibility criteria has not been selected for evaluation.
The Scientific Council then met to finalize the selection which was approved at the Executive Committee of the Foundation.

5 projects were selected we present them following the main topics:

Detection of infectivity:

  1. Project « SAFE CJD »
    (Slice culture Assay For Express CJD agent Detection in blood and other biological products)

    • Investigators: Vincent Béringue (Principal Investigator), Sophie Halliez, INRA, Jouy-en-Josas, France
      • Olivier Andreoletti, INRA, Toulouse, France
      • Juan Maria Torres, INIA, Madrid, Spain
    • duration: 1 year
    • grant : € 50 000

    The SAFE CJD project is aimed at further developing the detection of human prions (notably those responsible of variant Creutzfeldt-Jakob disease) using organotypic brain slice cultures derived from transgenic mice expressing the human form of the prion protein. The ultimate goal is to obtain a sensitive, rapid ex vivo assay to detect these agents in biological fluids and tissues such as blood. In parallel, the neurotoxicity of human prions in these slices will be examined.

  2. Project « In vivo diagnosis of definite CJD » (Olfactory mucosa Brushing coupled with RT-QuIC: a potential and innovative test for intravital definite diagnosis of Creutzfeld-Jakob disease)

    • Investigators:Gianluigi Zanusso (Principal Investigator), Matilde Bongianni, Michele Fiorini, Department of Neurological and Movement Sciences University of Verona, Italy
    • duration: 1 year
    • grant : € 34  000

    Sporadic Creutzfeldt-Jakob disease (sCJD) is a not treatable neurological disorder and potentially transmissible. Thus, it is especially important to diagnose it, or rule it out, at the early onset of symptoms for eiher therapeutic or public health purposes. This project aims to develop and validate a diagnostic test for the definite diagnosis of sCJD in living patients based on the identification of the pathological prion protein (PrPCJD) in the olfactory mucosa (OM) collected by nasal brushing. Our rationale is based on our previous reports that olfactory epithelium specimens obtained from deceased sCJD patients have CJD-specific prion protein deposits (Zanusso et al., 2003; Zanusso et al. 2009). In order to easily and painlessly collect olfactory neurons from living patients we set up nasal brushing procedure which is currently performed in infants as a "gold standard" for primary ciliary dyskinesia diagnosis or in cystic fibrosis or allergic rhinitis, but it is an absolutely novel diagnostic procedure in prion or other neurodegenerative diseases. We coupled nasal brushing with an ultrasensitive assay for prion detection such real time quaking-induced conversion (RT-QuIC), showing in 14 sCJD affected patients and in 26 control subjects a 100% sensitivity and 100% specificity in discriminating sCJD patients from non-CJD patients.
    This diagnostic approach shows to have the prerequisites for substantially improving the practicality and certitude of intravital sCJD definite diagnosis. At present, the number of sCJD affected patients tested is limited and a validation of the procedure in larger group of patients with CJD is demanding. In addition, we wil also include also subjects with genetic CJD investigating the sensitivity and specificity of RT-QuIC coupled with OM brushing.

The use of exosome-based projects:

  1. Project « Detection of Exosomal PrPTSE in blood » (An exosomal misfolded prion protein (PrPTSE) in blood as an early diagnostic marker of transmissible spongiform encephalopathies (TSEs): detection by saPMCA)

    • Investigators:Larisa Cervenakova (Principal investigator), Paula Saa (co-PI), Oksana Yakovleva, Irina Vasilyeva, Jorge De Castro Blasco, Transmissible Diseases Department, Biomedical Services, American Red Cross, Rockville, USA
      • Andrew Francis Hill, Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Australia  
    • duration: 1 year
    • grant : € 32 800

    Prion diseases, also called transmissible spongiform encephalopathies (TSEs), are fatal pathologic conditions of the brain in humans and animals. These diseases are characterized by the accumulation of TSE-causing prion protein (PrPTSE), an abnormally shaped version of the normal cellular prion protein (PrPC) and have a very long silence period before symptoms develop. Reliable diagnostic tests would allow early detection and possible intervention for the potential treatment of these diseases. The absence of such a test poses a public health risk as infected but asymptomatic people may spread the disease through blood transfusions. In fact, this route has been implicated in the transmission of variant Creutzfeldt-Jakob disease (vCJD), a human version of the bovine spongiform encephalopathy. Exosomes, microscopic vesicles (fluid-filled pouches of lipid membranes) secreted by cells, have been found circulating in all biological fluids including blood. These vesicles contain nucleic acids and proteins and serve as messengers between cells. PrPTSE has been identified among the proteins present in exosomes. We are investigating the possibility that exosomes can facilitate the spread of infectious prions from tissue to tissue. Using a protein amplification method called PMCA that allows detection of minute levels of PrPTSE,, we have demonstrated the presence of PrPTSE in exosomes extracted from the blood of mice infected with TSEs. In the present study we will obtain exosomes from blood samples collected from experimentally infected squirrel monkeys and mice during the presymptomatic and symptomatic phases of the disease. Exosomes will be used in PMCA reactions to identify samples containing PrPTSE, allowing us to determine whether infectious prion proteins are carried in blood-derived exosomes. Detection of PrPTSE in blood during the incubation period may offer a target for an early diagnostic assay for TSEs and could facilitate early intervention for disease treatment.

  2. Project « ExoQuiC » (An exosome strategy for the diagnosis of  human prion diseases)

    • Investigators:Francesca Properzi (Principal investigator), Ilaria Cristofaro, Michele Equestre, Anna Ladogana, Anna Poleggi, Maria Puopolo,  department of Cellular Biology and Neuroscience, Istituto Superiore della Sanità, Rome, Italy
    • duration: 1 year
    • grant : € 35  000

    Exosomes are small vesicles released by cells, known to be involved in cell-to-cell communication and trafficking and in amplifying cellular functions. Viruses and RNAs also travel between cells via exosomes and indeed these particles have also been called “viral troyan horses”.
    Exosomes contain detailed molecular information representing a fingerprint of the cell type and status in both health and disease. For this reason and because they are released in easy accessible body fluids such as blood and urine, they represent precious biomedical tools. Indeed they are currently used in the diagnosis and prognosis of an increasing number of tumors.
    The finding of reliable diagnostic markers for prion diseases has been elusive for many years. Similarly to viruses, prions also travel via exosomes in vitro and there is increasing evidence that this is also occurring in vivo. The presence of prion-disease associated molecules in blood exosomes has been recently discovered by our group. This important finding provides the basis of a novel prion diagnostic strategy, named ExoQuIC, that is here proposed.

Micro RNA as biomarkers:

  1. Project « RNA editing in CJD »
    (RNA editing and modifications in Creutzfeldt-Jakob disease and other neurodegenerative diseases)

    • Investigators: Thedoros Sklaviadis (Principal investigator) University Laboratory of Pharmacology, Thessaloniki, Greece
      • Inga Zerr, University Medical Center, Göttingen Germany
    • duration: 18 months
    • grant : € 60 000

    The development of chronic neurodegenerative conditions is widely recognized as one of the major societal health problems of the 21st century. To date the focus of therapies for these conditions has been on symptomatic relief and efforts to develop disease modifying treatments have been unsuccessful.
    The traditional method of classifying neurodegenerative diseases is based on the original clinico-pathological concept supported by 'consensus' criteria and data from molecular pathological studies. Current problems in this classification results from the coexistence of different classificatory schemes, the presence of disease heterogeneity and multiple pathologies, the use of 'signature' brain lesions in diagnosis, and the existence of pathological processes common to different diseases.
    Twenty years ago the observation that rare familial forms of AD are caused by mutations in the APP genes [Scheuner et al. 1996] and PSEN [De et al. 1998], changed the direction of the field. Here we propose that RNA "mutations" in genes involved in Creutzfeldt-Jakob disease may provide a yet unexplored aspect of genomic variation, which though absent from the genome itself, directly affects the proteome, and therefore the phenotype as well. We also hypothesize that these changes might be far more prevalent than changes at DNA, and have more predictive power, as they allow the use of peripheral and easily accessible tissues or blood, thus providing a long-sought missing link between genomic information content and the onset and progression of neurodegenerative diseases.

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