Development of a preclinical blood test for prion diseases
There are currently no tests for early prion diagnosis. Such tests would help:
Current tests are based on the identification of PrPSc or of characteristic pathologies in brain samples collected post mortem. Recent advances have shown that minute amounts of PrPSc exist in body fluids such as blood. Although these PrPSc levels are too low to be detected reliably by existing methods, they point to the feasibility of using these fluids with improved methods.
Backed by a powerful consortium of partners with proven clinical, experimental and industrial achievements, the AntePrion partners want to develop methods for the preclinical detection of prions in body fluids, based on (1) PrPSc and (2) novel surrogate (non-PrP) markers of prion diseases.
PrPSc detection in body fluids will be achieved by systematically optimising every step in the process:
Surrogate markers and molecular 'signatures' of prion diseases will be identified using novel sensitive proteomic and genomic approaches, including SELDI, MALDI and DNA microarrays. Proprietary software will be developed to analyse these emerging signatures.[+] Read More
Prions are infectious proteins. There is currently no effective therapy for prion diseases - collectively called the transmissible spongiform encephalopathies (TSEs) - and the disease is lethal. There is no sensitive and reliable preclinical or even ante-mortem diagnostic test for the detection of prions in blood or other body fluids. Post-mortem diagnosis relies on pathological findings in the CNS and especially on the detection of PrPSc. Due to the difficulty of detecting low levels of prion infectivity and PrPSc, little is known about prion infectivity and PrPSc in peripheral tissues.
The sensitivity of existing PrPSc detection methods is insufficient for the identification of PrPSc in body fluids (blood, CSF, milk) or in non-neural tissues. 14-3-3 and S-100 have been proposed as surrogate markers to PrPSc as the basis for diagnostic TSE tests, but such markers are not very specific. Therefore, the current project will endeavour to find new TSE-specific markers using novel mass spectrometric and genomic approaches, as well as immunological methods.
Thus, the search for non-PrP markers that is being carried out in parallel with improved procedures for detecting both the proteasesensitive (s) and -resistant (r) PrPSc may give rise to a reliable preclinical test.
AntePrion's goal is to use a combination of research and engineering approaches to:
Four types of activities can be discerned in AntePrion:
a. identify human TSE cases early
enough so that emerging therapies
can be administered on time (prior to
b. prevent transfusion of tainted human blood, and
c. remove TSE-tainted meat and animal products from the food chain.
Subpopulations of WBCs from humans and animals enriched for PrPSc will be isolated. The subcellular localisation of the PrPSc will be studied. A number of new antibodies and methods for concentrating and detecting PrPSc are being developed and tested. Enrichment of blood fractions containing high levels of PrPSc, combined with optimisation of methods for detecting PrPSc, may yield a blood test at a phase before any clinical symptoms of prion disease appear. Mass spectrometry will be used to obtain profiles of molecules from body fluids and tissues from prion-infected animals that bind to different chromatographic surfaces. The aim is to identify prion-infection specific biomarkers, most likely proteins. Measurements of such a biomarker might provide a target for development of a non-PrP based ante-mortem test. Alternatively, specific patterns of protein expression or 'signatures' detected by mass spectrometry might be used as the basis of such a test.
European countries aim at high standards of consumer protection and for high standards concerning the safety of blood and blood products. The presence of prion infections in cattle (sheep and goats) and the transmission of the disease to human beings are serious dangers to public health. Low levels of PrPSc have been detected in white blood cells (WBC) in the blood circulation of prion-infected animals. Moreover, recent data suggest that variant Creutzfeldt-Jakob disease (vCJD) can be transmitted from humans to humans via blood or blood products. The consortium's initiative will help to establish markers and methods for the early, preclinical diagnosis of prion infections in animals and human beings, and will lead to the development of a new and sensitive ante-mortem diagnostic test for prion diseases. Since several partners are involved in national and international research activities through networks and control/surveillance programmes on other infectious or transmissible diseases, AntePrion has a large impact on public health.