Gene Therapy Decreases Seizures in a Model of Incontinentia pigmenti
Gene Therapy Decreases Seizures in a Model of Incontinentia pigmenti
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DOI：
10.1002/ana.24981
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发表时间：
2017-07-01
影响因子：
11.2
通讯作者：
Schwaninger, Markus
中科院分区：
文献类型：
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作者：
Dogbevia, Godwin K.;Toellner, Kathrin;Schwaninger, Markus
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，如癫痫发作，但目前尚无特异性治疗方法。IP是由使尼莫基因失活的致病变异引起的。通过基因疗法取代尼莫可能会带来治疗效果。方法：在小鼠IP模型中，我们单次静脉注射腺相关病毒（AAV）载体AAV- br1 - cag - Nemo，将Nemo基因传递到脑内皮。监测自发性癫痫发作及血脑屏障（BBB）完整性。结果：内皮靶向基因治疗可改善血脑屏障的完整性。同时，它减少了癫痫发作的发生率，并延缓了它们的发生。经静脉注射AAV-BR1-CAG-NEMO载体的新生小鼠在注射载体11个月后未发生肝细胞癌或其他主要不良反应，表明该载体具有良好的安全性。解释：数据显示血脑屏障是抗癫痫治疗的靶点，更具体地说，为脑内皮靶向基因治疗IP的治疗效果提供了证据。
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.