Novel therapeutic strategies targeting malleability of wild-type and mutant prions

朊病毒疾病总是致命的神经退行性疾病， 感染性和遗传性形式，并且是由野生型或突变型转化引起的。 将细胞朊病毒蛋白（PrPC）转化为自我繁殖、错误折叠的构象异构体 （统称为PrPSc）。目前没有临床有效的治疗任何形式的 朊病毒病 最近，化学筛选已经确定了不同类别的口服药物， 降低野生型PrPSc的形成率，从而增加无病生存率。 朊病毒感染的动物然而，在每一个病例中，药物治疗都不能治愈朊病毒感染， 最终使被治疗的动物不堪重负。在几乎所有情况下，替代PrPSc 在治疗过程中出现的构象，导致朊病毒菌株适应，在某些情况下，药物 阻力有趣的是，来自药物治疗动物的朊病毒可以恢复其原始菌株 在未处理宿主中连续传代期间的特征和药物敏感性。另外我们 初步的研究表明，同时给予朊病毒感染的小鼠两种不同的药物未能产生协同作用，这是由于出现了一种非正统的新的 对两种药物组合具有抗性但对两种药物单独敏感的菌株。采取 总之，这些观察结果表明，野生型朊病毒具有高度的可塑性，即能够 在不同PrPSc构象之间来回转换，以响应选择性 抗朊病毒药物治疗引起的压力。负责的分子机制 野生型朊病毒的延展性目前是未知的。同样未知的是， 特别是引起遗传性朊病毒疾病的病毒， 朊病毒该提案的总体目标是评估新的治疗策略， 合理地靶向朊病毒的可塑性，并研究辅因子分子在药物诱导的 朊病毒株适应具体而言，我们将：（1）评价交替口服药物的疗效 方案在野生型朊病毒感染模型;（2）确定辅因子选择是否发挥作用， 在野生型朊病毒获得耐药性的机制中的作用;和（3）测试 口服药物方案在遗传性朊病毒疾病新基因敲入小鼠模型中的功效。

Prion diseases are invariably fatal neurodegenerative disorders that occur in sporadic, infectious, and inherited forms, and are caused by the conversion of either wild-type or mutant versions of the cellular prion protein (PrPC) into self-propagating, misfolded conformers (collectively termed PrPSc). There is currently no clinically effective treatment for any form of prion disease. Recently, chemical screens have identified different classes of oral drugs that can significantly decrease the rate of wild-type PrPSc formation, and thereby increase disease-free survival in prion-infected animals. However, in each case, drug treatment did not cure prion infection, which eventually overwhelmed the treated animals. In almost all cases, an alternative PrPSc conformation emerged during therapy, causing prion strain adaptation and, in some cases, drug resistance. Interestingly, prions from drug-treated animals can recover their original strain characteristics and drug susceptibility during serial passage in untreated hosts. In addition, our preliminary work shows that simultaneous co-administration of two different drugs to prion-infected mice failed to create a synergistic effect due to the emergence of an unorthodox new strain that is resistant to the two-drug combination yet susceptible to both drugs alone. Taken together, these observations show that wild-type prions are highly malleable, i.e. able to switch back and forth between different PrPSc conformations in response to changes in selective pressure caused by anti-prion drug therapy. The molecular mechanism responsible for the malleability of wild-type prions is currently unknown. It is also unknown whether mutant prions, which specifically cause the inherited forms of prion disease, are as malleable as wild-type prions. The overall objectives of this proposal are to evaluate novel therapeutic strategies that rationally target prion malleability, and to study the role of cofactor molecules in drug-induced prion strain adaptation. Specifically, we will: (1) evaluate the efficacy of alternating oral drug regimens in a wild-type prion infection model; (2) determine whether cofactor selection plays a role in the mechanism by which wild-type prions acquire drug resistance; and (3) test the efficacy of oral drug regimens in new knock-in mouse models of inherited prion diseases.