NR AWES
AU Farquhar,C.F.; McConnell,I.; Cumming,S.; Herd,S.; Marshall,A.; Barclay,R.; Pepper,D.S.; Prescott,R.J.; Turner,M.L.; Bruce,M.E.
TI Sodium pentosan polysulphate use in rodent models of scrapie and BSE
QU International Conference - Prion 2006: Strategies, advances and trends towards protection of society - 3.10.-6.10.2006, Torino, Italy, Lingotto Conference Centre - Oral sessions ORAL-50
PT Konferenz-Vortrag
AB There is no proven treatment for TSEs. Sodium pentosan polysulphate (PPS) is a heparin analogue with anti-coagulant, anti-thrombotic, anti-inflammatory and anti-viral activity. We and others have shown that PPS increases survival time and reduces susceptibility if given parenterally within days to weeks of scrapie inoculation in rodents. The aim of this study is to evaluate, in rodent models of scrapie and BSE, whether PPS has general efficacy in reducing susceptibility to TSEs at doses, and by routes, that are both clinically relevant and without deleterious effects. The effectiveness of PPS is model dependent, with route, dose and timing of delivery also influencing outcome. PPS increases survival time by the greatest amount in those models where the lymphoid phase plays a significant role in pathogenesis. Repeated parenteral delivery of drug can further increase survival time, even to normal lifespan. Proof of concept of oral efficacy is surprising given the low oral bioavailability of PPS. Per oral PPS is licensed in the USA for interstitial cystitis, is well tolerated long-term and avoids the effects on haemostasis seen with parenteral delivery. Oral PPS may therefore have potential as a post-exposure prophylactic where, for example, a blood donor is identified as having vCJD shortly after their blood has been used for transfusion. In addition, we found that where rodents survived PPS entering the CNS compartment hours after inoculation with ME7 scrapie, they lived significantly longer than untreated controls. PPS may therefore have efficacy even after neuroinvasion. In scrapie infected cell lines PPS appears to inhibit or disrupt de novo conversion of PrP to PrPsc, with no significant reversion to PrPc detected in its presence. This may explain the general finding from experimental animal models that the later PPS therapy is initiated the smaller the increase in survival obtained. As a result of this work we have designed a generic TSE model screening platform to test whether novel therapeutics, pre-selected in vitro, outperform PPS and to reduce animal use. This work is funded by the Department of Health, UK
AD C.F. Farquhar, I. McConnell, S. Cumming, S. Herd, A. Marshall, M.E. Bruce: Institute for Animal Health, Neuropathogenesis Unit, Edinburgh, Scotland, UK; R. Barclay, D.S. Pepper, M.L. Turner: Edinburgh & South East Scotland Blood Transfusion Service, Royal Infirmary, Edinburgh, Scotland, UK; R.J. Prescott: Medical Statistics Unit, Edinburgh University Medical School, Edinburgh, Scotland, UK. E-mail: christine.farquhar@bbsrc.ac.uk
SP englisch
PO Italien