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. 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, ∆E302/3 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 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 activation. These preclinical results identify ritonavir as a drug candidate for dystonia with disease-modifying potential.

肌张力障碍是一组慢性运动障碍性疾病，缺乏高效的口服药物或疾病缓解疗法。最有效的治疗需要侵入性程序，例如深部脑刺激。在这项研究中，我们使用了一种基于单基因肌张力障碍 DYT1 (DYT-TOR1A) 的高通量检测方法来筛选批准用于人类的化合物库，即 NCATS 药物库（NPC；2816 种化合物），以及鉴定能够纠正致病蛋白变体 ∆E302/3 hTorsinA 错误定位的药物。HIV 蛋白酶抑制剂利托那韦是发现使 hTorsinA 错误定位正常化的 18 种化合物之一。使用 DYT1 敲入小鼠模型来测试对脑部病变的疗效，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。利托那韦急性纠正成熟大脑中的纹状体胆碱能中间神经元生理学，并在离散的早期发育窗口期间交付时产生弥散张量磁共振成像信号的持续纠正。从机制上讲，我们发现，在整个 HIV 蛋白酶抑制剂家族中，功效与综合应激反应激活相关。这些临床前结果将利托那韦确定为具有改善疾病潜力的肌张力障碍的候选药物。