Towards the development of an effective treatment for SCN1A-derived epilepsy

项目摘要 电压门控钠通道SCN 1A（编码Nav1.1）中的从头功能丧失突变是 Dravet综合征（DS）的主要原因，这是一种灾难性的早期脑病， 复发性热性惊厥（FS）、难治性无热性癫痫、认知和行为缺陷，以及 15-20%的死亡率。SCN 1A突变还导致遗传性癫痫伴热性惊厥+（GEFS+）， 一种以早期FS和广泛成人癫痫发展为特征的遗传性疾病 亚型目前的抗癫痫药物往往不能提供足够的保护，以防止严重的癫痫发作， 发生在SCN 1A突变患者中的神经精神共病。此外，几乎三分之一的 癫痫患者没有实现充分的癫痫发作控制，突出了迫切需要开发多模式 可有效缓解与难治性前列腺癌相关的广泛临床特征的治疗 癫痫，同时尽量减少不必要的副作用。在这个探索性的R21提案中，我们将测试假设 石杉碱甲（石杉碱甲），一种天然存在的倍半萜石松属生物碱，将有效地在 治疗DS。这一假设是基于石杉碱甲的生物学特性，其已证实的临床 安全性、耐受性、改善认知功能的能力以及我们的初步数据。我们将使用杂合子 Scn 1a基因敲除小鼠（DS模型），以评价Hup A增加癫痫发作阈值的潜力， 预防自发性癫痫发作（目的1）和改善认知和行为缺陷（目的2）。 这一临床相关的建议可以为开发一种新的治疗方法奠定基础， SCN 1A源性癫痫。此外，由于SCN 1A突变导致神经元抑制减少， 许多常见形式的癫痫的共同机制，这项研究的结果可能有 对难治性癫痫的治疗具有重要而广泛的意义。

PROJECT SUMMARY De novo loss-of-function mutations in the voltage-gated sodium channel SCN1A (encoding Nav1.1) are the main cause of Dravet syndrome (DS), a catastrophic early-life encephalopathy associated with prolonged and recurrent febrile seizures (FSs), treatment-resistant afebrile epilepsy, cognitive and behavioral deficits, and a 15-20% mortality rate. SCN1A mutations also lead to genetic epilepsy with febrile seizures plus (GEFS+), an inherited disorder characterized by early-life FSs and the development of a wide range of adult epilepsy subtypes. Current anti-epilepsy drugs often fail to provide adequate protection against the severe seizures and neuropsychiatric comorbidities that occur in patients with SCN1A mutations. Furthermore, almost a third of all epilepsy patients do not achieve adequate seizure control, highlighting the urgent need to develop multimodal treatments that can effectively mitigate the broad spectrum of clinical features associated with refractory epilepsies, while minimizing unwanted side effects. In this exploratory R21 proposal, we will test the hypothesis that Huperzine A (Hup A), a naturally occurring sesquiterpene Lycopodium alkaloid, will be efficacious in the treatment of DS. This hypothesis is based on the biological properties of Hup A, its demonstrated clinical safety, tolerability, ability to improve cognitive function, and our preliminary data. We will use heterozygous Scn1a knockout mice (a model of DS) to evaluate the potential of Hup A to increase seizure thresholds and prevent spontaneous seizure generation (Aim 1) and to ameliorate cognitive and behavioral deficits (Aim 2). This clinically relevant proposal could lay the foundation for the development of a novel therapy to treat SCN1A-derived epilepsies. Furthermore, since SCN1A mutations lead to reduced neuronal inhibition, which is a shared mechanism underlying many common forms of epilepsy, the outcome of this study may have important, broad implications for the treatment of refractory epilepsies.