The HIV protease inhibitor, ritonavir, corrects diverse brain phenotypes across development in mouse model of DYT-TOR1A dystonia.
The HIV protease inhibitor, ritonavir, corrects diverse brain phenotypes across development in mouse model of DYT-TOR1A dystonia.
复制标题
DOI：
10.1126/scitranslmed.abd3904
复制
发表时间：
2021-08-18
影响因子：
17.1
通讯作者：
Calakos N
中科院分区：
文献类型：
--
作者：
Caffall ZF;Wilkes BJ;Hernández-Martinez R;Rittiner JE;Fox JT;Wan KK;Shipman MK;Titus SA;Zhang YQ;Patnaik S;Hall MD;Boxer MB;Shen M;Li Z;Vaillancourt DE;Calakos N
肌张力障碍是一组慢性运动障碍，缺乏有效的口服药物或疾病改善疗法。最有效的治疗方法需要侵入性手术，如深部脑刺激（DBS）。在这项研究中，我们使用了一种基于单基因形式肌张力障碍DYT1 （DYT-TOR1A）的高通量测定方法，筛选了批准用于人类的化合物库NCATS药物收集（NPC； 2816种化合物），并鉴定了能够纠正致病蛋白变体ΔE302/3 hTorsinA错误定位的药物。HIV蛋白酶抑制剂利托那韦（ritonavir）是18种能使hTorsinA错位正常化的化合物之一。通过DYT1敲入小鼠模型来测试对脑部病理的疗效，我们发现利托那韦在整个发育过程中恢复了多种脑部异常。利托那韦在成熟大脑的纹状体胆碱能中间神经元生理学中具有急性纠正作用，并在离散的早期发育窗口期给药时产生持续的弥散张量磁共振成像（MRI）信号纠正。在机制上，我们发现在整个HIV蛋白酶抑制剂家族中，疗效与综合应激反应（ISR）激活相关。这些临床前结果确定利托那韦是一种具有改善疾病潜力的肌张力障碍候选药物。利托那韦通过DYT1肌张力障碍体外药物筛选鉴定，可纠正DYT1小鼠大脑中的神经元放电反应和白质缺陷。
Dystonias are a group of chronic movement-disabling disorders for which highly effective oral medications or disease-modifying therapies are lacking. The most effective treatments require invasive procedures such as deep brain stimulation (DBS). In this study, we used a high-throughput assay based on a monogenic form of dystonia, DYT1 (DYT-TOR1A), to screen a library of compounds approved for use in humans, the NCATS Pharmaceutical Collection (NPC; 2816 compounds) and identify drugs able to correct mislocalization of the disease-causing protein variant, ΔE302/3 hTorsinA. The HIV protease inhibitor, ritonavir, was among 18 compounds found to normalize hTorsinA mislocalization. Using a DYT1 knock-in mouse model to test efficacy on brain pathologies, we found that ritonavir restored multiple brain abnormalities across development. Ritonavir acutely corrected striatal cholinergic interneuron physiology in the mature brain and yielded sustained correction of diffusion tensor magnetic resonance imaging (MRI) signals when delivered during a discrete early developmental window. Mechanistically, we found that across the family of HIV protease inhibitors, efficacy correlated with integrated stress response (ISR) activation. These preclinical results identify ritonavir as a drug candidate for dystonia with disease-modifying potential. Ritonavir, identified by a DYT1 dystonia in vitro drug screen, corrects neuronal firing response and white matter deficits in the DYT1 mouse brain.
登录
查看更多内容
影响因子：
5.3
作者：
Bruhat, A;Jousse, C;Fafournoux, P
通讯作者：
Fafournoux, P
影响因子：
2.5
作者：
Belleau, ML;Warren, RA
通讯作者：
Warren, RA
影响因子：
81.5
作者：
Balint, Bettina;Mencacci, Niccolo E.;Bhatia, Kailash P.
通讯作者：
Bhatia, Kailash P.
影响因子：
5.3
作者：
Bennett, BD;Callaway, JC;Wilson, CJ
通讯作者：
Wilson, CJ
影响因子：
9.9
作者：
Brueggemann, Norbert;Kuehn, Andrea;Klein, Christine
通讯作者：
Klein, Christine