Comparison of CR36, a new heparan mimetic, and pentosan polysulfate in the treatment of prion diseases.
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.
Larramendy-Gozalo
Claire
C
CEA, IMETI/SEPIA, 18 route du Panorama, BP6, 92265 Fontenay-aux-Roses cedex, France.
Barret
Agnès
A
CEA, IMETI/SEPIA, 18 route du Panorama, BP6, 92265 Fontenay-aux-Roses cedex, France.
Daudigeos
Estelle
E
CEA, IMETI/SEPIA, 18 route du Panorama, BP6, 92265 Fontenay-aux-Roses cedex, France.
Mathieu
Emilie
E
CEA, IMETI/SEPIA, 18 route du Panorama, BP6, 92265 Fontenay-aux-Roses cedex, France.
Antonangeli
Lucie
L
CEA, IMETI/SEPIA, 18 route du Panorama, BP6, 92265 Fontenay-aux-Roses cedex, France.
Riffet
Cécile
C
Laboratoire CRRET, CNRS FRE24-12, Université Paris XII-Val de Marne, Avenue du Général de Gaulle, 94010 Créteil, France.
Petit
Emmanuel
E
OTR3 Sarl, 4 Rue Française, 75001 Paris, France.
Papy-Garcia
Dulce
D
Laboratoire CRRET, CNRS FRE24-12, Université Paris XII-Val de Marne, Avenue du Général de Gaulle, 94010 Créteil, France.
Barritault
Denis
D
OTR3 Sarl, 4 Rue Française, 75001 Paris, France.
Brown
Paul
P
CEA, IMETI/SEPIA, 18 route du Panorama, BP6, 92265 Fontenay-aux-Roses cedex, France.
Deslys
Jean-Philippe
JP
CEA, IMETI/SEPIA, 18 route du Panorama, BP6, 92265 Fontenay-aux-Roses cedex, France.
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
D006497:Heparan Sulfate; D010426:Pentosan Sulfuric Polyester; D011328:Prions