Development of new tools to identify cryptic prions in blood – UnmaskingBloodPrions
Despite a wide exposure of the population to the Bovine Spongiform Encephalopathy (BSE) agent (or “mad cow” disease: more than 2 millions of undiagnosed infected cattle would have entered the human food chain) in United Kingdom, and to a lesser extent in France, the number of related human cases (v-CJD, variant of Creutzfeldt-Jakob disease) reached a limited peak in 2000 and accordingly, those both countries that were the most impacted worldwide should cumulate less than 250 total human cases. However, with silent incubation periods exceeding several decades in humans, questions remain about the risks of secondary transmission through blood or medical and surgical practices. Blood donation is thus forbidden for British and French citizens in North America (USA and Canada) according to the principle of precaution.
In this context, the prevalence of healthy carriers, whose blood might be infectious, has been recently reevaluated in UK to around 1/2,000 (according to the presence of PrPres accumulation in appendices), i.e. close to 200-fold more than the total number of reported clinical cases, questioning the apparent containment of the BSE impact on public health. Moreover, after extended incubation periods, we have observed in primates exposed to those agents the occurrence of fatal, transfusion-transmissible neurological diseases that would not be identified as prion diseases according to the current diagnostic criteria. With new techniques of epitope unmasking, we have improved the sensitivity of detection of classical prion diseases and also observed new, yet undescribed forms of abnormal prion protein (PrPres) in the peripheral organs of BSE-exposed individuals, including those developing these atypical diseases.
We hypothesize that the field of human prion diseases might exceed the current opinion delimited by the classical techniques for PrPres detection. It is therefore compulsory to explore new technological issues allowing a rational evaluation of the risk linked to healthy carriage, together with the development of large-scale screening tests whether the protection of blood transfusion would be subsequently needed.
The UnmaskingBloodPrions project aims to provide the operational proofs of concept of new diagnostic tools able to detect classical and atypical forms of abnormal prion protein in biological samples, notably blood. The UnmaskingBloodPrions project federates the main French teams involved in the development of sensitive blood tests, already able to blindly detect blood samples derived from clinical v-CJD patients. We propose to optimize those techniques by coupling them with techniques of epitope unmasking according to the previously developed concepts. Once validated with calibrated samples, the best techniques will be used to detect the different forms of abnormal PrP accumulation in several categories of biological samples (blood and tissues), in order to draw a panorama of the real impact of BSE on human health. The diagnostic tests developed in the frame of this project should provide the basis for a complete system including rapid screening and highly sensitive tools to identify and limit the risks of secondary transmission, notably through transfusion.
Project coordination
Emmanuel Comoy (Service d'Etude des Prions et des Infections Atypiques / Institut des Maladies Emergentes et des Thérapies Innovantes / Commissariat à l'Energie Atomique)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
Partner
CEA / iMETI / SEPIA Service d'Etude des Prions et des Infections Atypiques / Institut des Maladies Emergentes et des Thérapies Innovantes / Commissariat à l'Energie Atomique
INSERM UMR ICM Institut National de la Santé et de la Recherche Médicale - INSERM
HCL Hospices Civils de Lyon
EFS-TransDiag Etablissement Français du Sang - Laboratoire TransDiag
INRA IHAP UMR 1225 IHAP INRA-ENVT
Help of the ANR 655,720 euros
Beginning and duration of the scientific project:
December 2015
- 36 Months