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

致力于开发 SCN1A 源性癫痫的有效治疗方法

基本信息

批准号：
9272959
负责人：
Andrew P Escayg
金额：
$ 19.35万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9272959
关键词：
Acetylcholine Address Adult Adverse effects Affect Alzheimer&apos s Disease Antiepileptic Agents Anxiety Behavioral Biological Cells Childhood Chinese People Cholinergic Receptors Clinical Clinical Management Cognitive Combined Modality Therapy Comorbidity Data Development Disease Drug usage Encephalopathies Epilepsy Equilibrium Etiology Event Exhibits Family Febrile Convulsions Fever Folk Medicine Foundations Frequencies Functional disorder Generations Genes Genetic Goals Hippocampus (Brain)Hyperactive behavior Implant Inborn Genetic Diseases Incidence Induced Hyperthermia Inflammation Intervention Knockout Mice Lead Learning Life Lycopodium plant Memory Modeling Mus Muscarinics Mutant Strains Mice Mutation Neurologic Neurons Outcome Study Patients Pharmaceutical Preparations Play Population Property Recurrence Refractory Research Personnel Resistance Role Safety Seizures Sesquiterpenes Severities Social Interaction Sodium Channel Syndrome Testing Work base clinically relevant cognitive function comparative efficacy effective therapy gamma-Aminobutyric Acid huperzine A improved inhibitor/antagonist loss of function mutation lycopodium alkaloid mortality mouse model mutant nervous system disorder neuropsychiatry novel therapeutics osmotic minipump prevent voltage

项目摘要

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.

项目总结电压门控钠通道SCN1A(编码Nav1.1)的从头功能丧失突变是德雷特综合征(DS)的主要原因，这是一种灾难性的早期脑病，与长期和复发性热性癫痫(FSS)、难治性无热性癫痫、认知和行为障碍以及死亡率为15%-20%。SCN1A突变也会导致遗传性癫痫伴热性惊厥(GEFS+)，以及以早期FSS和多种成人癫痫的发展为特征的遗传性疾病子类型。目前的抗癫痫药物往往不能提供足够的保护，防止严重的癫痫发作和发生在SCN1A突变患者中的神经精神共病。此外，几乎三分之一的人癫痫患者没有实现足够的癫痫发作控制，突出了发展多模式的迫切需要可有效缓解与难治性疾病相关的广泛临床特征的治疗方法癫痫，同时将不良副作用降至最低。在这个探索性的R21提案中，我们将检验假设石杉碱甲(Hup A)是一种天然的倍半萜石杉碱类生物碱，对糖尿病有明显的治疗作用。 DS的治疗。这一假设是基于Hup A的生物学特性，它证明了它的临床应用安全性、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 SCN1A基因敲除小鼠(DS模型)评估Hup A提高癫痫阈值和预防自发性癫痫发作(目标1)和改善认知和行为缺陷(目标2)。这一具有临床相关性的建议可能为开发一种新的治疗方法奠定基础。 SCN1A型癫痫。此外，由于SCN1A突变导致神经元抑制减少，这是许多常见形式癫痫的共同机制，这项研究的结果可能有对于难治性癫痫的治疗具有重要而广泛的意义。