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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要：癫痫是一种常见的多因素神经系统疾病，影响了大约1％的人群。电压门控钠通道中的突变负责几种单基因癫痫综合征，并且 SCN1a基因中杂合丧失功能突变导致Dravet综合征（DS），这是一种严重的婴儿 - 发作疾病以顽固性癫痫发作，发育延迟和死亡率增加为特征。而 DS表型，如所有单基因发作，在具有相同突变的个体中表达了不同的表达（表明遗传或环境修饰符可能会影响临床严重程度），由此产生的癫痫发作是通常对常规抗癫痫药（AED）有抵抗力，其中一些实际上加剧了癫痫发作紊乱。这是DS中新型的治疗AED靶标是非常可取的。我们和其他人已经确定了从突触中的兴奋性神经递质谷氨酸的次优去除由于星形细胞谷氨酸转运蛋白（GLT-1）的表达降低，作为获得的和先天性癫痫，无论是啮齿动物还是人类。值得注意的是，GLT-1（称为兴奋性氨基酸转运蛋白2，人类中的EAAT2表达时，当抑郁症时，可以通过常见的βlactam抗生素增强（与这些化合物的抗菌特性无关），我们确定用头孢曲松治疗A 具有良好血脑屏障渗透率的β-内酰胺类成员，抑制癫痫发作癫痫模型。与DS相关，我们记录了DS经验儿童的临床观察结果暴露于β乳糖抗生素时，癫痫发作抑制。同时，在DS SCN1A单倍体不足（SCN1A +/-）小鼠模型，我们确定GLT-1蛋白在皮质和海马中抑郁症将GLT-1缺乏症的前景作为DS中合理的新型治疗靶标的前景。根据以下内容，我们提出了一组探索性实验，旨在（1）测试GLT-1的临床实用性头孢曲松（或类似化合物）在DS处理中的增强。（2）测试降低GLT-1是否是 SCN1A +/-内型型，或复发性癫痫发作的产物，（3）表征发育 SCN1A +/-小鼠中GLT-1表达的调节。鉴于DS中的癫痫发作没有对常规AED响应，我们提出的实验将是第一步超越DS，提议实验将提供有关星形胶质细胞谷氨酸转运在SCN1A Miller变体中的作用的洞察力单倍弥补和其他癫痫发作。因为GLT-1上调可能是通过安全和廉价的药物，我们预计拟议研究的有利结果将迅速转化为 DS或相关疾病中的人类试验。