OBJECTIVE:Incontinentia pigmenti (IP) is a genetic disease leading to severe neurological symptoms, such as epileptic seizures, but no specific treatment is available. IP is caused by pathogenic variants that inactivate the Nemo gene. Replacing Nemo through gene therapy might provide therapeutic benefits. METHODS:In a mouse model of IP, we administered a single intravenous dose of the adeno-associated virus (AAV) vector, AAV-BR1-CAG-NEMO, delivering the Nemo gene to the brain endothelium. Spontaneous epileptic seizures and the integrity of the blood-brain barrier (BBB) were monitored. RESULTS:The endothelium-targeted gene therapy improved the integrity of the BBB. In parallel, it reduced the incidence of seizures and delayed their occurrence. Neonate mice intravenously injected with the AAV-BR1-CAG-NEMO vector developed no hepatocellular carcinoma or other major adverse effects 11 months after vector injection, demonstrating that the vector has a favorable safety profile. INTERPRETATION:The data show that the BBB is a target of antiepileptic treatment and, more specifically, provide evidence for the therapeutic benefit of a brain endothelial-targeted gene therapy in IP. Ann Neurol 2017;82:93-104.

译文

目的:色素失禁(IP)是一种遗传性疾病,可导致严重的神经系统症状,例如癫痫发作,但尚无特效治疗方法。 IP是由使Nemo基因失活的致病变体引起的。通过基因疗法替代Nemo可能会提供治疗益处。
方法:在IP小鼠模型中,我们施用了单次静脉内剂量的腺相关病毒(AAV)载体AAV-BR1-CAG-NEMO,将Nemo基因传递至脑内皮。监测自发性癫痫发作和血脑屏障(BBB)的完整性。
结果:内皮靶向基因治疗改善了血脑屏障的完整性。同时,它减少了癫痫发作的发生并延迟了发作的发生。静脉内注射AAV-BR1-CAG-NEMO载体的新生小鼠在载体注射后11个月未出现肝细胞癌或其他重大不良反应,表明该载体具有良好的安全性。
解释:数据表明,血脑屏障是抗癫痫治疗的目标,更具体地说,它为脑内皮靶向基因疗法在IP中的治疗益处提供了证据。 Ann Neurol 2017; 82:93-104。

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