title: Comparison of CR36, a new heparan mimetic, and pentosan polysulfate in the treatment of prion diseases.
abstract: Sulfated polyanions, including pentosan polysulfate (PPS) and heparan mimetics, number among the most effective drugs that have been used in experimental models of prion disease and are presumed to act in competition with endogenous heparan sulfate proteoglycans as co-receptors for prion protein (PrP) on the cell surface. PPS has been shown to prolong the survival of animals after intracerebral perfusion and is in limited use for the experimental treatment of human transmissible spongiform encephalopathies (TSEs). Here, PPS is compared with CR36, a new heparan mimetic. Ex vivo, CR36 was more efficient than PPS in reducing PrPres in scrapie-infected cell cultures and showed long-lasting activity. In vivo, CR36 showed none of the acute toxicity observed with PPS and reduced PrPres accumulation in spleens, but had only a marginal effect on the survival time of mice infected with bovine spongiform encephalopathy. In contrast, mice treated with PPS that survived the initial toxic mortality had no detectable PrPres in the spleens and lived 185 days longer than controls (+55%). These results show, once again, that anti-TSE drugs cannot be encouraged for human therapeutic trials solely on the basis of in vitro or ex vivo observations, but must first be subjected to in vivo animal studies.
authors.affiliation: CEA, IMETI/SEPIA, 18 route du Panorama, BP6, 92265 Fontenay-aux-Roses cedex, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Larramendy-Gozalo
authors.affiliation: CEA, IMETI/SEPIA, 18 route du Panorama, BP6, 92265 Fontenay-aux-Roses cedex, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Barret
authors.affiliation: CEA, IMETI/SEPIA, 18 route du Panorama, BP6, 92265 Fontenay-aux-Roses cedex, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Daudigeos
authors.affiliation: CEA, IMETI/SEPIA, 18 route du Panorama, BP6, 92265 Fontenay-aux-Roses cedex, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Mathieu
authors.affiliation: CEA, IMETI/SEPIA, 18 route du Panorama, BP6, 92265 Fontenay-aux-Roses cedex, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Antonangeli
authors.affiliation: Laboratoire CRRET, CNRS FRE24-12, Université Paris XII-Val de Marne, Avenue du Général de Gaulle, 94010 Créteil, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Riffet
authors.affiliation: OTR3 Sarl, 4 Rue Française, 75001 Paris, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Petit
authors.affiliation: Laboratoire CRRET, CNRS FRE24-12, Université Paris XII-Val de Marne, Avenue du Général de Gaulle, 94010 Créteil, France.
authors.forename: Dulce
authors.initials: D
authors.lastname: Papy-Garcia
authors.affiliation: OTR3 Sarl, 4 Rue Française, 75001 Paris, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Barritault
authors.affiliation: CEA, IMETI/SEPIA, 18 route du Panorama, BP6, 92265 Fontenay-aux-Roses cedex, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Brown
authors.affiliation: CEA, IMETI/SEPIA, 18 route du Panorama, BP6, 92265 Fontenay-aux-Roses cedex, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Deslys
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D006497:Heparan Sulfate / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010426:Pentosan Sulfuric Polyester / Q000009:adverse effects / Q000627:therapeutic use*; D017096:Prion Diseases / Q000188:drug therapy*; D011328:Prions / Q000037:antagonists & inhibitors*; D013154:Spleen / Q000737:chemistry; D016019:Survival Analysis
chemical_list: D006497:Heparan Sulfate; D010426:Pentosan Sulfuric Polyester; D011328:Prions