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Pathogenesis of epilepsy in a SCN8A human mutation mouse model

SCN8A 人类突变小鼠模型中癫痫的发病机制

基本信息

批准号：
10334438
负责人：
MANOJ K PATEL
金额：
$ 35.33万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10334438
关键词：
15 year old Age Age-Months Anticonvulsants Antiepileptic Agents Ataxia Attenuated Axon Behavior Birth Brain region Cessation of life Child Clinical Code Data Dependence Development Disease Early Infantile Epileptic Encephalopathy Epilepsy Equilibrium Exhibits Genes Hour Human Human Genetics Intellectual functioning disability Intractable Epilepsy Knock-in Mouse Lead Length Life Membrane Missense Mutation Modeling Motor Mus Mutant Strains Mice Mutation Neurons Parvalbumins Pathogenesis Pathologic Patients Pharmaceutical Preparations Phenotype Phenytoin Physiological Physiology Play Potassium Potassium Channel Property Protein Isoforms Recurrence Reporting Role SCN8A encephalopathy SCN8A gene Seizures Sodium Channel Somatosensory Cortex Somatostatin Sudden Death Testing Time Viral Wheelchairs antagonist clinical efficacy de novo mutation epileptic encephalopathies excitatory neuron experience gain of function gain of function mutation human model inhibitor inhibitory neuron innovation insight mouse model neuronal excitability new therapeutic target novel novel therapeutics prevent response small hairpin RNA sudden unexpected death in epilepsy targeted treatment

项目摘要

De novo mutations of SCN8A, the gene that encodes for the sodium (Na) channel isoform Nav1.6, are known to cause early infantile epileptic encephalopathy 13 (EIEE13). To date, more than 150 SCN8A mutations have been identified. Patients experience a variety of seizure types and motor features that can lead to wheelchair dependence. Intellectual disability varies from mild to severe and becomes progressively worst with seizure onset. Sudden unexpected death in epilepsy (SUDEP) occurs in approximately 10% of patients and increases significantly if seizures are not controlled. Unfortunately, a majority of patients have drug refractory epilepsy or a mixed response to anti-epileptic drugs (AEDs). Very little is known about the pathogenesis of SCN8A epileptic encephalopathy or treatment options for patients. In this proposal we will use a highly novel and innovative knock-in mouse model, developed by the Meisler lab, carrying the human SCN8A encephalopathy mutation p.Asn1768Asp (N1768D). The mutation was identified in a child who presented with refractory epilepsy at the age of 6 months, intellectual disability, ataxia and SUDEP at 15 years of age. The mouse model exhibits many of the pathological phenotypes seen in patients, including spontaneous seizures and sudden death. In homozygous mutant mice (D/D), seizures begin at 3 weeks of age and progress to death within 24 hours. Heterozygous mutant mice (D/+) have later seizure onset starting at 8 weeks of age and progression to death within one to two months. The availability of this mouse model provides a unique opportunity to fully investigate the pathogenesis of this devastating human epileptic encephalopathy and to also test new and selective therapies. In this proposal we will investigate when alterations in Na channel physiology and membrane excitability begin to appear in our model of epileptic encephalopathy, testing both excitatory and inhibitory neurons within brain regions known to be involved in seizure activity. In Aim 1 we will determine the pathogenesis of these alterations at specific time points before and after seizure onset using mutant mice. In Aim 2, we will silence Nav1.6 using virally delivered, dox-inducible, Nav1.6 shRNA, targeting either excitatory or inhibitory neurons and determine the effects on Na channel activity, neuronal excitability and seizure activity in mutant mice. We will determine if we can delay the onset of seizures by targeting at a time point before the onset of seizures and also if we can modulate seizure activity in mice with spontaneous seizures. In Aim 3, we will test whether our Nav1.6 subtype selective compound (MV1505) can reduce seizure activity in heterozygous (D/+) mice and delay SUDEP. We will also evaluate two clinically used anticonvulsants (phenytoin and lacosamide). These studies will significantly impact our current understanding of the physiological consequences of increased Nav1.6 activity in SCN8A epileptic encephalopathy. They will also provide important insight into the selective targeting of Nav1.6 for therapy.

编码钠(Na)通道亚型Nav1.6的基因SCN8A的从头突变是已知会导致早期婴儿癫痫脑病13(EIEE13)。到目前为止，已有150多台SCN8A 已经确定了突变。患者会经历各种类型的癫痫发作和运动特征，这可能会导致对轮椅的依赖。智力残疾从轻微到严重不等，并逐渐恶化。伴随着癫痫发作。约10%的患者会发生癫痫猝死(SUDEP) 如果癫痫发作得不到控制，这种情况会显著增加。不幸的是，大多数患者都有药物难治性癫痫或对抗癫痫药物(AEDs)的混合反应。关于SCN8A癫痫性脑病的发病机制或治疗方案知之甚少病人。在这项提案中，我们将使用一种非常新颖和创新的敲入鼠标模型，由 Meisler实验室，携带人类SCN8A脑病突变P.Asn1768Asp(N1768D)。突变在一名6个月大的儿童身上发现了难治性癫痫，智力残疾，共济失调和SUDEP在15岁时。小鼠模型表现出许多在患者，包括自发性癫痫发作和猝死。在纯合子突变小鼠(D/D)中，癫痫发作开始在3周大时，并在24小时内进展到死亡。杂合突变小鼠(D/+)后来癫痫发作发病开始于8周大，并在一到两个月内进展到死亡。这款产品的可用性小鼠模型提供了一个独特的机会来全面研究这种毁灭性的人类疾病的发病机制癫痫脑病，并测试新的和选择性的治疗方法。在这项建议中，我们将研究钠通道生理和膜的变化兴奋性开始出现在我们的癫痫脑病模型中，测试兴奋性和抑制性。已知的参与癫痫发作活动的大脑区域内的神经元。在目标1中，我们将确定利用突变小鼠研究癫痫发作前后特定时间点的这些改变的发病机制。在……里面目标2，我们将使用病毒传递的、DOX诱导的、Nav1.6 shRNA来沉默Nav1.6，靶向于任何一种兴奋性或抑制性神经元，并测定对钠通道活动、神经元兴奋性和癫痫活动的影响在突变的小鼠身上。我们将确定是否可以通过在癫痫发作之前的某个时间点进行定位来推迟癫痫发作的发生以及我们是否能调节自发性癫痫小鼠的癫痫发作活动。在目标3中，我们将测试我们的Nav1.6亚型选择性化合物(MV1505)是否可以减少杂合子癫痫发作活动 (D/+)小鼠，延迟SUDEP。我们还将评估两种临床使用的抗惊厥药物(苯妥英和乳糖胺)。这些研究将极大地影响我们目前对生理学的理解在SCN8A癫痫脑病中Nav1.6活性增加的后果。他们还将提供对选择性靶向Nav1.6进行治疗的重要洞察。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The novel sodium channel modulator GS-458967 (GS967) is an effective treatment in a mouse model of SCN8A encephalopathy.

DOI：
10.1111/epi.14196
发表时间：
2018-06
期刊：
Epilepsia
影响因子：
5.6
作者：
Baker EM;Thompson CH;Hawkins NA;Wagnon JL;Wengert ER;Patel MK;George AL Jr;Meisler MH;Kearney JA
通讯作者：
Kearney JA

EpiPro, a Novel, Synthetic, Activity-Regulated Promoter That Targets Hyperactive Neurons in Epilepsy for Gene Therapy Applications.

DOI：
10.3390/ijms241914467
发表时间：
2023-09-23
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Burke CT;Vitko I;Straub J;Nylund EO;Gawda A;Blair K;Sullivan KA;Ergun L;Ottolini M;Patel MK;Perez-Reyes E
通讯作者：
Perez-Reyes E

Somatostatin-Positive Interneurons Contribute to Seizures in SCN8A Epileptic Encephalopathy.

生长抑素阳性中间神经元导致 SCN8A 癫痫性脑病的癫痫发作。

DOI：
10.1523/jneurosci.0718-21.2021
发表时间：
2021
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Wengert,EricR;Miralles,RaquelM;Wedgwood,KyleCA;Wagley,PravinK;Strohm,SamanthaM;Panchal,PayalS;Idrissi,AbrarMajidi;Wenker,IanC;Thompson,JeremyA;Gaykema,RonaldP;Patel,ManojK
通讯作者：
Patel,ManojK

Postictal Death Is Associated with Tonic Phase Apnea in a Mouse Model of Sudden Unexpected Death in Epilepsy.

DOI：
10.1002/ana.26053
发表时间：
2021-05
期刊：
Annals of neurology
影响因子：
11.2
作者：
Wenker IC;Teran FA;Wengert ER;Wagley PK;Panchal PS;Blizzard EA;Saraf P;Wagnon JL;Goodkin HP;Meisler MH;Richerson GB;Patel MK
通讯作者：
Patel MK

Adrenergic Mechanisms of Audiogenic Seizure-Induced Death in a Mouse Model of SCN8A Encephalopathy.