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Development of TSE therapies based onprion proteinbinding oligosa ccharides

Objective



There is currently no therapy for prion diseases. However, much data indicates that polyanions in general, and sulfated sugars in particular, inhibit prion propagation both in animals and in cultured cells. For instance, the sulfated polysugars pentosan polysulfate and dextran sulfate, the amyloid-binding dye Congo red (CR), and the anthracycline iododeoxyrubicin (IDX) prolong BSE incubation time when inoculated prophylacticaly. Although the mechanisms of action of these reagents remain to be clarified, several lines of evidence connect most of the anti-prion agents with molecules of the heparin family. Heparan sulfate has been shown to be a component of every brain amyloid, and interestingly, the amyloid binding dye CR, a known amyloid stain, is among the most effective anti prion agents. Endocytosis of PrPc, the normal prion protein and precursor of PrPSc is stimulated by sulfated glycans. All anti prion polyanions seem to inhibit the binding of PrPc to heparin sepharose, demonstrating a clear connection between the heparin binding activity of PrPc and inhibition of prion replication. Prion inhibition was tested by several investigators in scrapie infected neuroblastoma cells (ScN2a), a mouse line permanently infected with scrapie prions. In these cells, inhibition criteria is defined as reduction in PrPsc synthesis as well as reduction of prion titer for cell extracts. We propose to initiate a systematic search for more efficient anti-prion agents of the polyanionic class and to determine their mode of action.

Our research will focus especially, but not exclusively,on sulfated sugars, and is expected to result in the development of effective anti-prion therapeutic approaches. We will screen both natural and artificial libraries of carbohydrates, as well as other available polyanions, and determine their anti-prion potential in a series of tests both in-vitro, in cultured cells, and in animal models of experimental scrapie. To achieve these objectives, four groups of prion researchers have recruited the collaboration of two leading teams that specialise in proteoglycan research and oligosaccharide chemistry. We believe that the resulting consortium has the expertise needed to succeed in this task.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

HADASSAH MEDICAL ORGANIZATION
Address
Hadassah University Hospital
91120 Jerusalem
Israel

Participants (5)

COMMISSARIAT A L'ENERGIE ATOMIQUE
France
Address
60-68,Route Du Panorama 18
92265 Fontenay Aux Roses
LUDWIG-MAXIMILIANS UNIVERSITY OF MUNICH
Germany
Address
25,Feodor-lynen-strasse 25
81377 Muenchen
The Hebrew University of Jerusalem - The Authority for Research and Development
Israel
Address
Hadassah Medical Centre
91120 Jerusalem
University of Birmingham
United Kingdom
Address
Edgbaston
B15 2TT Birmingham
Université Paris Val-de-Marne
France
Address
Avenue Du Général De Gaulle
94000 Créteil