SCN8A encephalopathy: disease mechanisms and treatment

SCN8A 脑病：疾病机制和治疗

• 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
• 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

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，其在细胞膜中以高水平表达。 中枢神经系统：SCN 1A、SCN 2A、SCN 3A和SCN 8A。该基因家族在人类免疫系统中起着重要作用。 人类癫痫的病因和每个基因的突变与不同类型的癫痫有关。然而，在这方面， SCN 8A功能改变与癫痫之间的关系似乎更为复杂。虽然我们已经表明 具有Scn 8a功能丧失突变的小鼠对诱导的癫痫发作更有抵抗力，许多从头获得突变的小鼠对诱导的癫痫发作更有抵抗力。 已在具有一系列临床特征的患者中鉴定出功能性SCN 8A突变，包括灾难性的 儿童癫痫、自闭症、智力残疾和发育迟缓。携带SCN 8A突变的个体 癫痫患者也面临着突发意外死亡（SUDEP）的风险增加。的机制 SCN 8A突变导致观察到的一系列临床挑战性特征仍然知之甚少， 目前的治疗方法往往严重不足。我们的中心假设是， SCN 8A疾病的有效治疗需要对精确的细胞类型的机制理解 和SCN 8A病理基础的大脑区域。我们的建议建立在我们最近的研究基础上， 解耦的细胞类型，电路，和潜在的癫痫发作产生与癫痫发作阻力，由于 scn 8a单倍不足。我们将通过研究三种不同的SCN 8A变体来扩展这些发现：R850 Q - 最严重和复发的SCN 8A突变之一，R1620 L-一种与相对轻微的 癫痫，但智力残疾和社会功能障碍，和N1768 D-与癫痫相关的突变 脑病我们将通过使用条件性敲入（CKI）小鼠系来研究Aim 1中的R850 Q突变， 使这种变体的细胞和区域选择性表达成为可能，这直到现在还不可能研究， 严重的表型和过早致死。CKI R850 Q生产线将用于 确定不同细胞类型对癫痫发作、行为和相关生物物理表型的贡献 SCN 8A功能障碍在目标2中，我们将实施两种并行的方法来指导识别更多 在R1620 L和R1620 B中使用药理学和细胞特异性操作的有效SCN 8A疗法 N1768 D线，从而跨越了SCN 8A临床表现的范围。由于缺乏最佳治疗方法 SCN 8A突变患者的策略，我们将进行第一次系统性比较， 抗癫痫药和候选药物，其降低自发性癫痫发作和SUDEP风险的能力，以及 规范行为我们还将使用化学遗传学方法进一步询问细胞类型特异性 疾病机制的贡献，并建立选择性调节 兴奋性神经元的兴奋性以及小清蛋白、生长抑素和血管活性肠肽- 表达中间神经元。所提出的实验为SCN 8A的个性化药物提供了一条途径 患者和其他神经系统疾病的治疗发展蓝图。