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.

项目摘要 进行性肌阵挛癫痫7型（EPM 7）是由于基因KCNC 1中的复发性致病变异， 其编码电压门控钾（K+）通道亚基Kv3.1。这是一种毁灭性的 由先前正常的儿童或年轻成人发生震颤、癫痫发作和共济失调定义的疾病， 对轮椅的依赖以及癫痫和肌阵挛的持续恶化。进一步的研究 需要澄清Kv 3通道在正常脑功能中的功能作用，以及KCNC 1 导致EPM 7和其他形式的神经系统疾病，以促进新疗法的进展， 预防措施或治疗。这种见解可能被证明可以推广到其他形式的广告，这仍然是一个问题。 一类无法治愈的疾病。 这个为期5年的协作应用程序采用全面的方法和新生成的工具来测试 假设EPM 7的临床表型是由于Kv3.1功能的丧失，导致选择性 Kv3.1表达的快速尖峰神经元在整个大脑的离散位置的功能障碍。针对性 用有效的、特异性的Kv 3激活剂对Kv 3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， EPM 7实验模型中的小脑功能障碍。 拟议的实验将确定特定KCNC 1变异体、生理学和临床表现之间的关系。 表型（轻度智力残疾伴/不伴癫痫; EPM 7;或重度早发性肌阵挛性癫痫 在一个大型的KCNC 1相关神经系统疾病患者队列中， 申请人。为了将KCNC 1变体与离子通道功能障碍联系起来，我们将比较KCNC 1变体的生物物理特性。 正常的Kv 3 K+通道与含有变异Kv3.1亚基的通道的能力，以及一种新的Kv 3- 使病理性通道活性正常化的特异性药理学试剂（目的1）。变种KCNC 1的影响 对Kv3.1表达神经元的内在兴奋性和突触及电路功能的影响将使用 由申请人产生的新的EPM 7小鼠模型（Kcnc 1-R320 H/+小鼠，其概括了核心临床试验， 在人类中观察到的表型）（目的2）。然后，我们将尝试通过给药来改善疾病病理 体内靶向治疗（目标3）。 这些结果将为Kv3.1在细胞、突触和电路功能中的作用提供新的信息，并定义Kv3.1在细胞、突触和电路功能中的作用。 KCNC 1相关神经系统疾病的发病机制的发展和实施 在人类患者身上的新型靶向治疗。