TorsinA restoration in a mouse model identifies a critical therapeutic window for DYT1 dystonia.
TorsinA restoration in a mouse model identifies a critical therapeutic window for DYT1 dystonia.
复制标题
小鼠模型中的 TorsinA 恢复确定了 DYT1 肌张力障碍的关键治疗窗口。
DOI：
10.1172/jci139606
复制
发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Dauer,WilliamT
中科院分区：
文献类型：
--
作者：
Li,Jay;Levin,DanielS;Kim,AudreyJ;Pappas,SamuelS;Dauer,WilliamT
在遗传性神经发育疾病中，早期大脑发育关键时期特有的致病过程可能会妨碍日后应用基因修饰疗法的有效性。我们在DYT 1肌张力障碍的小鼠模型中探讨了这个问题，DYT 1肌张力障碍是一种由编码torsinA的TOR 1A基因的功能缺失突变引起的神经发育疾病。为了确定正常运动功能和基因替代治疗中torsinA的时间要求，我们开发了一种能够时空控制内源性torsinA等位基因的小鼠系。在胚胎发育过程中抑制torsinA引起肌张力障碍模仿行为和神经病理表型。然而，在成年期抑制torsinA并没有引起明显的异常，这是在发育关键期对torsinA的基本要求。发育中的中枢神经系统表现出扭转A补充的平行“治疗关键期”。虽然恢复torsinA在幼年DYT1小鼠挽救运动表型，有没有从成年torsinA的补充效益。这些数据建立了一个独特的需求torsinA在发育中的神经系统，并证明了关键时期的遗传损伤引起永久性的病理生理学机制脱钩torsinA的功能。这些发现意味着，要有效，扭转蛋白A为基础的治疗策略，必须采用DYT 1肌张力障碍的过程中早期。
In inherited neurodevelopmental diseases, pathogenic processes unique to critical periods during early brain development may preclude the effectiveness of gene modification therapies applied later in life. We explored this question in a mouse model of DYT1 dystonia, a neurodevelopmental disease caused by a loss-of-function mutation in theTOR1Agene encoding torsinA. To define the temporal requirements for torsinA in normal motor function and gene replacement therapy, we developed a mouse line enabling spatiotemporal control of the endogenous torsinA allele. Suppressing torsinA during embryogenesis caused dystonia-mimicking behavioral and neuropathological phenotypes. Suppressing torsinA during adulthood, however, elicited no discernible abnormalities, establishing an essential requirement for torsinA during a developmental critical period. The developing CNS exhibited a parallel “therapeutic critical period” for torsinA repletion. Although restoring torsinA in juvenile DYT1 mice rescued motor phenotypes, there was no benefit from adult torsinA repletion. These data establish a unique requirement for torsinA in the developing nervous system and demonstrate that the critical period genetic insult provokes permanent pathophysiology mechanistically delinked from torsinA function. These findings imply that to be effective, torsinA-based therapeutic strategies must be employed early in the course of DYT1 dystonia.