Prion Disease Therapeutics

传染性海绵状脑病(TSE或Prion病)是一种致命的、无法治疗的神经退行性疾病，如瘙痒病、克雅氏病(CJD)、牛海绵状脑病和慢性衰弱病(CWD)。TSE的发病机制涉及到一种名为PrPres的异常蛋白质在受感染的宿主中积累。我们和其他人之前已经确定了各种线形或支化的硫酸盐聚合物，它们可以有效地抑制PrPres在实验动物中的积累，减缓或防止瘙痒病的进展。然而，这些大的带电聚合物在外周给药后很难通过血脑屏障进入大脑。因此，我们一直在寻找这类较小的分子，这些分子可能是有效的PrPres抑制剂，同时对受感染的人具有更好的生物利用度或较低的毒性。为此，我们测试了几种硫酸盐化的环糊精，发现其中一些是在感染瘙痒病的组织培养细胞中积累PrP-res的优秀抑制剂。

The transmissible spongiform encephalopathies (TSEs or prion diseases)are fatal untreatable neurodegenerative diseases such as scrapie, Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy and chronic wasting disease (CWD). TSE pathogenesis involves the accumulation of an abnormal protein, called PrPres, in infected hosts. We and others previously identified a variety of linear or branched sulfated polymers that are effective in inhibiting PrPres accumulation and slowing or prevent the progression of scrapie in experimental animals. However, these large charged polymers have difficulty crossing the blood-brain barrier to enter the brain after peripheral administration. We have therefore sought smaller molecules of this sort that might be effective PrPres inhibitors while having better bioavailability or lower toxicity in infected individuals. Toward this goal, we tested several sulfated cyclodextrins and found that some were excellent inhibitors of PrP-res accumulation in scrapie-infected tissue culture cells.