Astrocytic Glutamate Transporter 1 (GLT-1) enhancement for the treatment of seizures in Dravet Syndrome

星形细胞谷氨酸转运蛋白 1 (GLT-1) 增强治疗 Dravet 综合征癫痫发作

• 批准号: 10288936
• 负责人: Alexander Rotenberg
• 金额: $ 48.68万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10288936
• 关键词: Adult; Affect; Age; Antiepileptic Agents; Astrocytes; Astrocytosis; Biological; Biology; Blood - brain barrier anatomy; Budgets; Ceftriaxone; Child; Clinical; Congenital Epilepsy; Depressed mood; Development; Developmental Delay Disorders; Disease; Disease model; Down-Regulation; Drug Targeting; Electroencephalography; Epilepsy; Excision; Excitatory Amino Acid Transporter 2; Exposure to; Frequencies; Genes; Genetic; Glutamate Transporter; Glutamates; Hippocampus (Brain); Human; Individual; Infant; Laboratories; Lead; Maps; Measures; Modeling; Monitor; Monobactams; Mus; Mutation; Neocortex; Neurotransmitters; Onset of illness; Penetrance; Pentylenetetrazole; Pharmaceutical Preparations; Phenotype; Population; Property; Proteins; Protocols documentation; Public Health; Rattus; Recurrence; Regulation; Reproducibility; Resistance; Rodent; Role; Running; Seizures; Severities; Sodium Channel; Structure; Synapses; Syndrome; Testing; Translating; Up-Regulation; Variant; Western Blotting; Wild Type Mouse; acquired epilepsy; antimicrobial; base; beta-Lactams; childhood epilepsy; cohort; design; dravet syndrome; endophenotype; experience; experimental study; insight; loss of function mutation; member; mortality; mouse model; nervous system disorder; new therapeutic target; novel; novel therapeutics; senescence; sex; targeted treatment; voltage; young adult

Project Summary: Epilepsy is a common, multifactorial neurological disorder affecting approximately 1% of the population. Mutations in voltage-gated sodium channels are responsible for several monogenic epilepsy syndromes, and heterozygous loss-of-function mutations in the SCN1A gene result in Dravet syndrome (DS), a severe infant- onset disease characterized by intractable seizures, developmental delays and increased mortality. While the DS phenotype, as in all monogenic epilepsies, expresses variably among individuals with the same mutation (suggesting that genetic or environmental modifiers may influence clinical severity), the resultant seizures are often resistant to conventional antiepileptic drugs (AEDs), some of which in fact exacerbate seizures in this disorder. Thus, a novel therapeutic AED target in DS is highly desirable. We and others have identified suboptimal removal of the excitatory neurotransmitter glutamate from synapses due to reduced expression of astrocytic glutamate transporter (GLT-1) as a contributor to acquired and congenital epilepsy, both in rodents and humans. Notably, GLT-1 (termed excitatory amino acid transporter 2, EAAT2 in humans) expression, when depressed, can be enhanced by common beta lactam antibiotics (unrelated to these compounds' antimicrobial properties), and we identified that treatment with ceftriaxone, a member of the β-lactam class with good blood-brain barrier penetrance, suppresses seizures in a rat acquired epilepsy model. Relevant to DS, we documented a clinical observation where children with DS experience seizure suppression when exposed to beta lactam antibiotics. In parallel, in a DS SCN1A haploinsufficiency (Scn1a+/-) mouse model, we identified that GLT-1 protein is depressed in cortex and hippocampus, which raises prospects for GLT-1 deficiency as a plausible novel therapeutic target in DS. Accordingly, we propose a set of exploratory experiments aimed to (1) test the clinical utility of GLT-1 enhancement by ceftriaxone (or analogous compound) in DS treatment. (2) test whether GLT-1 reduction is an Scn1a+/- endophenotype, or the product of recurrent seizures, and (3) characterize the developmental regulation of GLT-1 expression in the Scn1a+/- mouse. Given that seizures in DS do not respond to conventional AEDs, our proposed experiments will be the first step toward a novel adjunctive antiepileptic treatment in this devasting syndrome. Beyond DS, the proposed experiments will provide insight into the role of astrocytic glutamate transport in milder variants of SCN1A haploinsufficiency, and in other epilepsies. As GLT-1 upregulation may be accomplished by safe and inexpensive drugs, we anticipate that favorable results from the proposed studies will translate rapidly to human trials in DS or in related disorders.

项目概要： 癫痫是一种常见的多因素神经系统疾病，影响约 1% 的人口。 电压门控钠通道的突变导致多种单基因癫痫综合征，并且 SCN1A 基因杂合性功能丧失突变导致 Dravet 综合征 (DS)，这是一种严重的婴儿 以顽固性癫痫发作、发育迟缓和死亡率增加为特征的发病性疾病。虽然 与所有单基因癫痫一样，DS 表型在具有相同突变的个体中表达不同 （表明遗传或环境修饰因素可能会影响临床严重程度），由此产生的癫痫发作是 通常对传统抗癫痫药物 (AED) 具有抗药性，其中一些药物实际上会加剧癫痫发作 紊乱。因此，迫切需要一种新的 DS 治疗 AED 靶点。 我们和其他人已经发现从突触中去除兴奋性神经递质谷氨酸的效果不理想 由于星形胶质细胞谷氨酸转运蛋白（GLT-1）的表达减少，作为获得性和 先天性癫痫，包括啮齿类动物和人类。值得注意的是，GLT-1（称为兴奋性氨基酸转运蛋白 2， 当人类的 EAAT2 表达受到抑制时，常见的 β 内酰胺抗生素可以增强 EAAT2 的表达 （与这些化合物的抗菌特性无关），我们发现用头孢曲松（一种 β-内酰胺类成员，具有良好的血脑屏障渗透性，可抑制大鼠的癫痫发作 癫痫模型。与 DS 相关，我们记录了一项临床观察，其中患有 DS 的儿童经历过 接触β内酰胺抗生素时可抑制癫痫发作。同时，在 DS SCN1A 单倍体不足中 (Scn1a+/-) 小鼠模型中，我们发现皮层和海马中的 GLT-1 蛋白被抑制，这 提出了 GLT-1 缺陷作为 DS 的新治疗靶点的前景。 因此，我们提出了一组探索性实验，旨在 (1) 测试 GLT-1 的临床效用 DS 治疗中头孢曲松（或类似化合物）的增强作用。 (2)测试GLT-1还原是否是 Scn1a+/- 内表型，或反复发作​​的产物，以及 (3) 表征发育 Scn1a+/- 小鼠中 GLT-1 表达的调节。 鉴于 DS 癫痫发作对传统 AED 没有反应，我们提出的实验将是第一步 针对这种破坏性综合征的新型辅助抗癫痫治疗。除了 DS 之外，建议 实验将深入了解星形胶质细胞谷氨酸转运在 SCN1A 轻度变体中的作用 单倍体不足以及其他癫痫。由于 GLT-1 的上调可以通过安全和 廉价药物，我们预计拟议研究的有利结果将迅速转化为 DS 或相关疾病的人体试验。