SCN8A encephalopathy: disease mechanisms and treatment

SCN8A 脑病：疾病机制和治疗

基本信息

批准号：
10586642
负责人：
Andrew P Escayg
金额：
$ 55.38万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10586642
关键词：
Address Antiepileptic Agents Basic Science Behavior Behavioral Behavioral Assay Biological Assay Biological Markers Biophysics Brain Brain region Cells Central Nervous System Clinical Complex Development Developmental Delay Disorders Disease Electrophysiology (science)Epilepsy Etiology Face Frequencies Functional disorder Future Gene Family Generations Genes Heterozygote Hippocampus Human In Vitro Individual Intellectual functioning disability Interneurons Intractable Epilepsy Knock-in Knock-in Mouse Lead Modeling Mus Mutation Parvalbumins Pathogenicity Pathologic Pathology Patients Pharmaceutical Preparations Phenotype Physiology Play Predisposition Preparation Recurrence Resistance Risk Role SCN8A encephalopathy SCN8A gene Seizures Severities Slice Sodium Channel Somatostatin Testing Thalamic structure Therapeutic Translational Research Variant Vasoactive Intestinal Peptide autism spectrum disorder behavioral phenotyping cell type childhood epilepsy clinical heterogeneity clinical phenotype disease mechanisms study drug candidate effective therapy epileptic encephalopathies excitatory neuron experimental study gain of function genetic approach genetic inhibitor improved in vivo inhibitory neuron loss of function mammalian genome mouse model mutant nervous system disorder novel therapeutic intervention personalized medicine pharmacologic preclinical study premature respiratory response selective expression social deficits sudden unexpected death in epilepsy therapeutic development therapy development treatment optimization treatment strategy voltage

项目摘要

PROJECT SUMMARY The mammalian genome contains four voltage-gated sodium channels that are expressed at high levels in the central nervous system: SCN1A, SCN2A, SCN3A and SCN8A. This gene family plays an important role in the etiology of human epilepsy and mutations in each gene are associated with different types of epilepsy. However, the relationship between altered SCN8A function and epilepsy appears more complex. While we have shown that mice with loss-of-function Scn8a mutations are more resistant to induced seizures, many de novo gain-of- function SCN8A mutations have been identified in patients with a range of clinical features including catastrophic childhood epilepsy, autism, intellectual disability and developmental delay. Individuals with SCN8A mutations also face an increased risk for sudden unexpected death in epilepsy (SUDEP). The mechanisms by which SCN8A mutations lead to the observed range of clinically challenging features remain poorly understood, and current therapies are often woefully inadequate. Our central hypothesis is that the development of the most effective therapy for SCN8A disorders requires a mechanistic understanding of the precise cell types and brain regions underlying SCN8A pathologies. Our proposal builds on our recent studies in which we decoupled the cell types, circuits, and regions underlying seizure generation versus seizure resistance due to Scn8a haploinsufficiency. We will expand on these findings by studying three different SCN8A variants: R850Q – one of the most severe and recurrent SCN8A mutations, R1620L – a mutation associated with relatively mild epilepsy, yet intellectual disability and social dysfunction, and N1768D – a mutation associated with epileptic encephalopathy. We will study the R850Q mutation in Aim 1 by using a conditional knock-in (CKI) mouse line to enable cell- and region-selective expression of this variant, which until now was not possible to study due to the severe phenotype and premature lethality when globally expressed in mice. The CKI R850Q line will be used to establish the contribution of different cell types to the seizure, behavioral, and biophysical phenotypes associated with SCN8A dysfunction. In Aim 2, we will implement two parallel approaches to guide the identification of more efficacious SCN8A therapies using pharmacological and cell-specific manipulations in both the R1620L and N1768D lines, thereby spanning the range of SCN8A clinical presentations. Given the lack of optimized treatment strategies for patients with SCN8A mutations, we will conduct the first systematic comparison of selected antiepileptic and candidate drugs for their ability to decrease spontaneous seizures and SUDEP risk, and normalize behavior. We will also use a chemogenetic approach to further interrogate cell type-specific contributions to disease mechanisms and establish the therapeutic potential of selectively modulating the excitability of excitatory neurons, as well as parvalbumin, somatostatin, and vasoactive intestinal peptide- expressing interneurons. The proposed experiments provide a path towards personalized medicine for SCN8A patients and a blueprint for treatment development in other neurological disorders.

项目摘要哺乳动物基因组包含四个电压门控钠通道，在高水平中表达中枢神经系统：SCN1A，SCN2A，SCN3A和SCN8A。这个基因家族在每个基因中人类癫痫和突变的病因与不同类型的癫痫有关。然而，改变的SCN8A功能与癫痫之间的关系似乎更为复杂。虽然我们已经显示功能丧失SCN8A突变的小鼠对诱发性癫痫发作更具抵抗力，许多从头获得在具有一系列临床特征（包括灾难性）的患者中已经确定了功能SCN8A突变儿童癫痫，自闭症，肠道残疾和发育延迟。患有SCN8A突变的个体还面临着突然出现癫痫死亡（SUDEP）死亡的风险。所在的机制 SCN8A突变导致观察到的临床挑战特征的范围仍然很众所周知，并且当前的疗法通常不足。我们的中心假设是最大的发展 SCN8A疾病的有效疗法需要对精确细胞类型的机械理解和SCN8A病理的脑部区域。我们的建议建立在我们最近的研究基础上将癫痫发作产生与癫痫发作抗性的细胞类型，电路和区域解耦 SCN8A单倍体不足。我们将通过研究三种不同的SCN8A变体来扩展这些发现：R850Q - 最严重和经常性的SCN8A突变之一，R1620L - 相对较中的突变癫痫病，智力残疾和社会功能障碍以及N1768D - 与癫痫相关的突变脑病。我们将通过使用条件敲门（CKI）小鼠线来研究AIM 1中的R850Q突变启用该变体的细胞和区域选择性表达，到目前为止，由于全球表达小鼠时，严重的表型和早产性。 CKI R850Q系列将用于建立不同细胞类型对相关的癫痫发作，行为和生物物理表型的贡献具有SCN8A功能障碍。在AIM 2中，我们将实施两种平行方法来指导更多在R1620L和 N1768D线，从而涵盖SCN8A临床表现的范围。鉴于缺乏优化的治疗 SCN8A突变患者的策略，我们将进行选定的首次系统比较抗癫痫药和候选药物降低赞助和SUDEP风险的能力以及标准化行为。我们还将使用一种化学论方法来进一步询问细胞类型特异性对疾病机制的贡献，并确定选择性调节的治疗潜力兴奋性神经元以及白蛋白，生长抑素和血管活性肠胡椒的兴奋性表达中间神经元。拟议的实验为SCN8A提供了个性化医学的途径患者和其他神经系统疾病治疗发展的蓝图。