Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany.
Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine and Center for Systems Neuroscience, Hannover, Germany.
Ann Neurol. 2017 Jul;82(1):93-104. doi: 10.1002/ana.24981.
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.
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.
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.
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.
色素失禁症（IP）是一种导致严重神经症状（如癫痫发作）的遗传疾病，但目前尚无特效治疗方法。IP 是由导致 Nemo 基因失活的致病性变异引起的。通过基因治疗替代 Nemo 可能会带来治疗益处。
在 IP 的小鼠模型中，我们单次静脉给予腺相关病毒（AAV）载体 AAV-BR1-CAG-NEMO，将 Nemo 基因递送至脑内皮细胞。监测自发性癫痫发作和血脑屏障（BBB）的完整性。
内皮细胞靶向基因治疗改善了 BBB 的完整性。同时，它降低了癫痫发作的发生率并延迟了发作的发生。新生小鼠静脉注射 AAV-BR1-CAG-NEMO 载体后，在载体注射 11 个月后未发生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。
数据表明 BBB 是抗癫痫治疗的靶点，更具体地说，为 IP 中脑内皮靶向基因治疗的治疗益处提供了证据。神经病学年鉴 2017；82:93-104。
