Mechanistically-oriented therapy for a progressive myoclonus epilepsy

进行性肌阵挛癫痫的机械导向治疗

基本信息

批准号：
10444009
负责人：
ETHAN M GOLDBERG
金额：
$ 49.96万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10444009
关键词：
Acute Animal Model Ataxia Biophysics Brain Calcium Caring Case Study Cells Cerebellar Diseases Cerebellum Cerebral cortex Cessation of life Child Chronic Clinical Cognitive Collaborations Data Defect Dependence Deterioration Development Disease Electrophysiology (science)Epilepsy Exhibits Experimental Animal Model Experimental Models Fire - disasters Frequencies Functional disorder Funding Gene Targeting Genes Genetic Genetic Variation Goals Hindlimb Home Human Image In Vitro Individual Institution Intellectual functioning disability Interneurons Ion Channel Knock-in Mouse Link Location Measures Medical Genetics Modeling Mus Myoclonus Neocortex Neurologic Dysfunctions Neurons Parvalbumins Pathogenicity Pathologic Pathology Pathway interactions Patients Performance Pharmacology Pharmacotherapy Phenocopy Physiological Physiology Potassium Potassium Channel Pre-Clinical Model Predisposition Preventive measure Progressive Myoclonic Epilepsies Property Purkinje Cells Pyramidal Cells Reagent Recurrence Research Role Seizures Severities Slice Synapses Synaptic Transmission System Testing Translating Tremor United States National Institutes of Health Variant Voltage-Gated Potassium Channel Walking Wheelchairs Work biophysical properties clinical phenotype cohort comorbidity de novo mutation early onset epileptic encephalopathies experimental study gene function genetic disorder diagnosis granule cell in vivo indexing induced pluripotent stem cell insight loss of function mouse model neocortical nervous system disorder neural circuit neurogenetics neuronal circuitry novel novel therapeutic intervention novel therapeutics patch clamp pre-clinical precision medicine targeted treatment therapy development tool voltage voltage clamp young adult

项目摘要

PROJECT SUMMARY Progressive myoclonus epilepsy type 7 (EPM7) is due to a recurrent pathogenic variant in the gene KCNC1, which encodes the voltage-gated potassium (K+) channel subunit Kv3.1. EPM is a class of devastating conditions defined by onset of tremor, seizures, and ataxia in a previously normal child or young adult, with relentless deterioration to wheelchair dependency as well as epilepsy and myoclonus. Further research is required to clarify the functional role of Kv3 channels in normal brain function and how genetic variation in KCNC1 leads to EPM7 and other forms of neurological disease, so as to facilitate progress towards novel therapies, preventative measures, or cure. Such insights may prove generalizable to other forms of EPM, which remains a class of untreatable and incurable disorders. This 5-year collaborative application employs a comprehensive approach and newly-generated tools to test the hypothesis that the clinical phenotype of EPM7 is due to loss of Kv3.1 function, leading to the selective dysfunction of Kv3.1-expressing fast-spiking neurons in discrete locations throughout the brain. Targeted pharmacologic modulation of Kv3 channels with a potent, specific Kv3 activator will recover cellular and synaptic abnormalities of Kv3.1-expressing neurons, leading to decreased susceptibility to seizure and improvement in cerebellar dysfunction in an experimental model of EPM7. Proposed experiments will determine the relationship between specific KCNC1 variants, physiology, and clinical phenotype (mild intellectual disability with/without epilepsy; EPM7; or severe early-onset myoclonic epileptic encephalopathy) in a large cohort of human patients with KCNC1-related neurological disorders compiled by the applicant. To link KCNC1 variants to ion channel dysfunction, we will compare the biophysical properties of normal Kv3 K+ channels to channels containing variant Kv3.1 subunits, as well as the ability of a novel Kv3- specific pharmacological agent to normalize pathological channel activity (Aim 1). The impact of variant KCNC1 on the intrinsic excitability and synaptic and circuit function of Kv3.1-expressing neurons will be pursued using a new mouse model of EPM7 generated by the applicant (Kcnc1-R320H/+ mice, which recapitulate the core clinical phenotype seen in humans) (Aim 2). Then, we will attempt to ameliorate disease pathology via administration of targeted therapeutics in vivo (Aim 3). Results will provide novel information as to the role of Kv3.1 in cellular, synaptic, and circuit function and define the pathogenic mechanisms of KCNC1-related neurological disorders towards development and implementation of novel, targeted therapies in human patients.

项目摘要进行性肌阵癫痫7型（EPM7）是由于基因KCNC1中复发性的致病变异引起的编码电压门控钾（K+）通道亚基Kv3.1。 EPM是一类毁灭性的以前正常的儿童或年轻人中的震颤，癫痫发作和共济失调定义的条件，对轮椅依赖以及癫痫和肌阵挛的不断恶化。进一步的研究是需要阐明KV3通道在正常脑功能中的功能作用以及KCNC1的遗传变异如何导致EPM7和其他形式的神经系统疾病，从而促进新疗法的进步，预防措施或治愈。这种见解可能证明可以推广到其他形式的EPM，这仍然是一类不可治疗和无法治愈的疾病。这个为期5年的协作应用程序采用了一种全面的方法和新生成的工具来测试假设EPM7的临床表型是由于Kv3.1功能的丧失，导致选择性在整个大脑的离散位置中表达kv3.1的快速神经元的功能障碍。目标具有有效的特异性KV3激活剂的KV3通道的药理调制将恢复细胞和突触表达KV3.1的神经元的异常，导致癫痫发作和改善的敏感性降低 EPM7实验模型中的小脑功能障碍。提出的实验将确定特定的KCNC1变体，生理学和临床之间的关系表型（轻度智障患有/没有癫痫的智障； EPM7；或严重的早期发作的肌持续性癫痫脑病）在大量的人类患者患有KCNC1相关神经系统疾病的人群中申请人。要将KCNC1变体与离子通道功能障碍联系起来，我们将比较正常的Kv3 K+通道，通向包含变体KV3.1亚基的通道以及新型KV3-的能力特定的药理剂以使病理通道活性归一化（AIM 1）。变体KCNC1的影响将使用表达Kv3.1神经元的固有兴奋性以及突触和电路功能。申请人生成的EPM7的新鼠标模型（KCNC1-R320H/+小鼠，概括核心临床在人类中看到的表型）（目标2）。然后，我们将尝试通过给药改善疾病病理体内靶向疗法（AIM 3）。结果将提供有关Kv3.1在细胞，突触和电路功能中的作用的新信息，并定义 KCNC1相关的神经系统疾病的致病机制针对发展和实施人类患者的新型靶向疗法。