Mechanistically-oriented therapy for a progressive myoclonus epilepsy

项目总结 进行性肌阵挛癫痫7型(EPM7)是由于KCNC1基因的一个反复发生的致病变异引起的， 其编码电压门控钾(K+)通道亚单位KV3.1。EPM是一类毁灭性的 以前正常的儿童或年轻人出现震颤、癫痫和共济失调的情况， 不断恶化为轮椅依赖以及癫痫和肌阵挛。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 导致EPM7和其他形式的神经疾病，以促进新疗法的进展， 预防措施，或治疗。这样的见解可能被证明可以推广到其他形式的EPM，它仍然是一种 一类无法治疗和无法治愈的疾病。 这款为期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EPM7的临床表型是由于KV3.1功能丧失，导致选择性 KV3.1表达的快速放电神经元在整个大脑的离散位置的功能障碍。目标明确 用有效的、特异的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，导致癫痫易感性降低，并改善 EPM7实验性模型的小脑功能障碍。 拟议的实验将确定特定的KCNC1变异、生理学和临床之间的关系 表型(轻度智力残疾伴/不伴癫痫；EPM7；或重度早发性肌阵挛癫痫 脑病)在一大群患有KCNC1相关神经疾病的人类患者中 申请人。为了将KCNC1变体与离子通道功能障碍联系起来，我们将比较KCNC1变体的生物物理特性 正常的Kv3K+通道到含有变异Kv3.1亚基的通道，以及一种新的Kv3- 使病理通道活动正常化的特定药物(目标1)。KCNc1基因变异的影响 关于表达KV3.1的神经元的内在兴奋性和突触和回路功能，将使用 申请人建立的新的EPM7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的病理 体内靶向治疗(目标3)。 这些结果将提供关于KV3.1在细胞、突触和电路功能中的作用的新信息，并定义 KCNC1相关性神经疾病的发病机制及其发展与实施 新的靶向治疗方法在人类患者中的应用。

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.