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.

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