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.

项目摘要电压门控钠通道SCN1A（编码NAV1.1）中的从头丧失功能突变是 Dravet综合征（DS）的主要原因，这是一种灾难性的早期生活脑病，与长期和长期相关的脑病复发性发作癫痫发作（FSS），抗治疗的AFEBRILE癫痫，认知和行为缺陷以及A 15-20％的死亡率。 SCN1a突变还导致遗传性癫痫发作癫痫发作加上（GEFS+），一个遗传性疾病的特征是早期FSS和广泛的成人癫痫的发展亚型。当前的抗癫痫药物通常无法提供适当的保护，以防止严重的癫痫发作和 SCN1A突变患者发生的神经精神合并症。此外，几乎三分之一癫痫患者无法实现足够的癫痫发作控制，强调迫切需要发展多模式可以有效减轻与难治相关的广泛临床特征的治疗癫痫病，同时最大程度地减少不需要的副作用。在此探索性R21提案中，我们将检验该假设那个huperzine a（hup a），一种天然存在的倍苯二酚番茄生物碱，将有效 DS的处理。该假设基于HUP A的生物学特性，其临床证明安全性，耐受性，提高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敲除小鼠（DS的模型）评估HUP A的潜力增加癫痫发作阈值和防止自发癫痫发作（目标1）并改善认知和行为缺陷（AIM 2）。该临床上相关的建议可以为开发一种新的治疗疗法奠定基础 SCN1A衍生的癫痫。此外，由于SCN1A突变导致神经元抑制减少，这就是许多常见形式的癫痫的共同机制，这项研究的结果可能具有对难治性癫痫的治疗的重要重要意义。