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.

项目概要哺乳动物基因组包含四个电压门控钠通道，它们在中枢神经系统：SCN1A、SCN2A、SCN3A 和 SCN8A 该基因家族在神经系统中发挥重要作用。人类癫痫的病因学和每个基因的突变都与不同类型的癫痫有关。尽管我们已经证明，SCN8A 功能改变与癫痫之间的关系似乎更为复杂。具有 Scn8a 功能丧失突变的小鼠对诱发癫痫发作的抵抗力更强，许多小鼠从头开始获得了功能 SCN8A 突变已在具有一系列临床特征的患者中被发现，包括灾难性的患有 SCN8A 突变的儿童癫痫、自闭症、智力障碍和发育迟缓的个体。还面临癫痫猝死（SUDEP）风险增加的机制。 SCN8A 突变导致观察到的一系列临床挑战性特征仍知之甚少，并且目前的疗法往往严重不足，我们的中心假设是，最先进的疗法的发展。 SCN8A 疾病的有效治疗需要对精确细胞类型的机制了解我们的建议建立在我们最近的研究基础上。将癫痫发作产生的细胞类型、回路和区域与癫痫发作抵抗性解耦我们将通过研究三种不同的 SCN8A 变体来扩展这些发现：R850Q。 – 最严重和复发的 SCN8A 突变之一，R1620L – 与相对轻微的突变相关的突变癫痫，但智力障碍和社交功能障碍，以及 N1768D——一种与癫痫相关的突变我们将通过使用条件敲入 (CKI) 小鼠系来研究 Aim 1 中的 R850Q 突变。使该变体能够进行细胞和区域选择性表达，由于 CKI R850Q 系将用于在小鼠中全面表达时出现严重表型和过早致死。确定不同细胞类型对相关癫痫发作、行为和生物物理表型的贡献在目标 2 中，我们将实施两种并行方法来指导识别更多 SCN8A 功能障碍。在 R1620L 和 R1620L 中使用药理学和细胞特异性操作的有效 SCN8A 疗法 N1768D 系，涵盖了 SCN8A 临床表现的范围，因此缺乏优化的治疗。针对 SCN8A 突变患者的治疗策略，我们将对选定的患者进行首次系统比较抗癫痫药和候选药物能够降低自发性癫痫发作和 SUDEP 风险，以及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。对疾病机制的贡献并建立选择性调节的治疗潜力兴奋性神经元的兴奋性，以及小白蛋白、生长抑素和血管活性肠肽- 所提出的实验为 SCN8A 的个性化医疗提供了一条途径。患者和其他神经系统疾病的治疗开发蓝图。