Drug resistance confounding prion therapeutics
Drug resistance confounding prion therapeutics
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DOI：
10.1073/pnas.1317164110
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发表时间：
2013-10-29
影响因子：
11.1
通讯作者：
Giles, Kurt
中科院分区：
文献类型：
--
作者：
Berry, David B.;Lu, Duo;Giles, Kurt
没有一种药物可以阻止甚至减缓任何神经退行性疾病。越来越多的证据表明，朊病毒导致许多神经退行性疾病，可以说，羊瘙痒症和克雅氏病朊病毒代表了最好的治疗目标。我们在这里报告说，之前发现的2-氨基噻唑IND 24和IND 81使感染瘙痒症的野生型小鼠的生存时间增加了一倍。然而，感染了落基山实验室（RML）朊病毒（一种瘙痒病衍生株）并接受IND 24治疗的小鼠最终表现出神经功能障碍并死亡。我们在小鼠和培养细胞中连续传代他们的脑匀浆。我们发现，从IND 24处理的小鼠中分离的朊病毒株（命名为RML[IND 24]）在处理的小鼠中的单次传代期间出现。尽管RML朊病毒感染N2 a和CAD 5细胞系，但RML[IND 24]朊病毒仅能感染CAD 5细胞。当在CAD 5细胞中传代时，朊病毒对高浓度的IND 24保持抗性。然而，未处理小鼠中RML[IND 24]朊病毒的一次传代恢复了CAD 5细胞中对IND 24的易感性。尽管IND 24治疗延长了繁殖不同朊病毒株的小鼠的寿命，包括RML，另一种瘙痒症衍生的朊病毒株ME 7和慢性消耗性疾病，但它在减缓转基因小鼠中克雅氏病朊病毒的繁殖方面无效。我们的研究表明，朊病毒株在暴露于IND 24后可获得抗性，该抗性在不存在IND 24的小鼠中传代后丧失。这些数据表明，单一疗法可以选择耐药性，因此可能需要用抗朊病毒化合物的混合物进行间歇性治疗来减缓或停止神经变性。
There is not a single pharmaceutical that halts or even slows any neurodegenerative disease. Mounting evidence shows that prions cause many neurodegenerative diseases, and arguably, scrapie and Creutzfeldt-Jakob disease prions represent the best therapeutic targets. We report here that the previously identified 2-aminothiazoles IND24 and IND81 doubled the survival times of scrapie-infected, wild-type mice. However, mice infected with Rocky Mountain Laboratory (RML) prions, a scrapie-derived strain, and treated with IND24 eventually exhibited neurological dysfunction and died. We serially passaged their brain homogenates in mice and cultured cells. We found that the prion strain isolated from IND24-treated mice, designated RML[IND24], emerged during a single passage in treated mice. Although RML prions infect both the N2a and CAD5 cell lines, RML[IND24] prions could only infect CAD5 cells. When passaged in CAD5 cells, the prions remained resistant to high concentrations of IND24. However, one passage of RML[IND24] prions in untreated mice restored susceptibility to IND24 in CAD5 cells. Although IND24 treatment extended the lives of mice propagating different prion strains, including RML, another scrapie-derived prion strain ME7, and chronic wasting disease, it was ineffective in slowing propagation of Creutzfeldt-Jakob disease prions in transgenic mice. Our studies demonstrate that prion strains can acquire resistance upon exposure to IND24 that is lost upon passage in mice in the absence of IND24. These data suggest that monotherapy can select for resistance, thus intermittent therapy with mixtures of antiprion compounds may be required to slow or stop neurodegeneration.