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A novel target for the treatment of temporal lobe epilepsy

治疗颞叶癫痫的新靶点

基本信息

批准号：
9087344
负责人：
Andrew P Escayg
金额：
$ 46.58万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9087344
关键词：
Affect Anxiety Behavior Behavioral C57BL/6 Mouse Clinical Control Groups Development Disease Dose Electroencephalography Encephalopathies Epilepsy Etiology Excision Exhibits Febrile Convulsions Frequencies Gene Family Generations Genes Genetic Health Hippocampus (Brain)Hour Human Individual Injection of therapeutic agent Kainic Acid Knockout Mice Laboratories Learning Longevity Measurement Memory Modeling Monitor Morphology Mus Mutation Neuraxis Neurons Operative Surgical Procedures Patient observation Patients Play Procedures Reagent Recurrence Refractory Reporting Resistance Role SCN8A gene Seizures Severities Site Slice Sodium Sodium Channel Syndrome Temporal Lobe Epilepsy Testing adeno-associated viral vector alternative treatment base biophysical properties clinically relevant effective therapy gain of function mutation hippocampal sclerosis improved insight knock-down male mammalian genome mouse model mutant mutant mouse model nervous system disorder neuron loss neuronal excitability neuropsychological novel prevent segregation small hairpin RNA translational study treatment strategy voltage

项目摘要

DESCRIPTION (provided by applicant): Epilepsy is a common neurological disorder that affects 50 million people worldwide. Approximately 30% of epileptic patients have treatment resistant (refractory) seizures, thereby presenting a major clinical challenge and burden. The most common form of refractory epilepsy is mesial temporal lobe epilepsy (MTLE), characterized by spontaneous seizures, neuropsychological deficits, and hippocampal sclerosis. At present, surgical resection of the epilepsy focus is the best treatment strategy for this disorder; however, this procedure is only used in a subset of cases. Consequently, there is an urgent need to develop alternative treatments. Mutations in the voltage-gated sodium channels (VGSCs) SCN1A, SCN2A, and SCN3A are associated with several epilepsy subtypes including Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS+). Gain of function mutations in the VGSC SCN8A have recently identified in individuals with epileptic encephalopathies. However, our laboratory has demonstrated that mice with Scn8a mutations that reduce channel activity or expression are more resistant to induced seizures when compared to their wild-type littermates. In addition, we were able to dramatically ameliorate seizure severity and restore normal lifespans to Scn1a mutants that model DS and GEFS+ by either co-segregation of an Scn8a mutation or hippocampal knockdown of Scn8a expression. Since the hippocampus is the major site of seizure generation and morphological changes in MTLE, we hypothesize that selective reduction of SCN8A expression in the hippocampus will provide an effective strategy for the treatment of MTLE. We will test this hypothesis with three specific aims. In Aim 1, we will establish the effect on spontaneous seizure frequency and severity of reducing hippocampal Scn8a expression in the widely used intra-hippocampal kainic acid mouse model of MTLE. Reduced Scn8a expression will be achieved by hippocampal injection of an adeno-associated viral vector expressing a short hairpin RNA against Scn8a (AAV-3). Seizure activity will be monitored in AAV-3 treated mice using continuous video/EEG analysis and will be compared to control mice injected with a scrambled construct (AAV-GFP). In Aim 2, we will determine if hippocampal reduction of Scn8a expression could also prevent or ameliorate the changes in behavior and hippocampal morphology and that are observed in this model of MTLE. Finally, in Aim 3, we compare the biophysical properties of hippocampal slices from the AAV-3 and AAV-GFP treated mice in order to directly examine neuronal excitability. We will also test if partial pharmacological block of Nav1.6, using novel compounds, can reduce seizure-like bursting activity in hippocampal slices from the MTLE mouse model, and we will explore the contribution of the different VGSCs to the development of MTLE. This clinically relevant proposal will provide important insight into the feasibility of targeting SCN8A as a treatment for MTLE, and more broadly, for other forms of refractory epilepsy.