Mechanistically-oriented therapy for a progressive myoclonus epilepsy

进行性肌阵挛癫痫的机械导向治疗

• 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
• 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

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.

项目概要 进行性肌阵挛癫痫 7 型 (EPM7) 是由 KCNC1 基因中的复发性致病性变异引起的， 它编码电压门控钾 (K+) 通道亚基 Kv3.1。 EPM 是一类具有破坏性的 以前正常的儿童或年轻人出现震颤、癫痫发作和共济失调的病症， 轮椅依赖性以及癫痫和肌阵挛不断恶化。进一步的研究是 需要阐明 Kv3 通道在正常大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展， 预防措施，或治疗。这些见解可能会被证明可以推广到其他形式的 EPM，而 EPM 仍然是一个 一类无法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 功能丧失导致的选择性 整个大脑离散位置表达 Kv3.1 的快速尖峰神经元功能障碍。有针对性 使用强效、特异性 Kv3 激活剂对 Kv3 通道进行药理学调节将恢复细胞和突触 Kv3.1 表达神经元的异常，导致癫痫发作的易感性降低并改善 EPM7 实验模型中的小脑功能障碍。 拟议的实验将确定特定 KCNC1 变体、生理学和临床之间的关系 表型（伴有/不伴有癫痫的轻度智力障碍；EPM7；或严重的早发性肌阵挛性癫痫 脑病）在一大群患有 KCNC1 相关神经系统疾病的人类患者中由 申请人。为了将 KCNC1 变异与离子通道功能障碍联系起来，我们将比较 KCNC1 变异的生物物理特性 正常 Kv3 K+ 通道到包含变异 Kv3.1 亚基的通道，以及新型 Kv3- 的能力 使病理通道活性正常化的特定药物（目标 1）。变体KCNC1的影响 将使用 Kv3.1 表达神经元的内在兴奋性、突触和电路功能来研究 申请人生成的EPM7新小鼠模型（Kcnc1-R320H/+小鼠），概括了核心临床 在人类中看到的表型）（目标 2）。然后，我们将尝试通过给药来改善疾病病理学 体内靶向治疗（目标 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相关神经系统疾病的发病机制的开发和实施 对人类患者进行新颖的靶向治疗。