Lafora Epilepsy - Basic mechanisms to therapy

拉福拉癫痫 - 治疗的基本机制

• 批准号: 9528683
• 负责人: Matthew S. Gentry
• 金额: $ 186.51万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9528683
• 关键词: Adolescence; Antiepileptic Agents; Antisense Oligonucleotides; Bioenergetics; Biological; Biological Assay; Biological Models; Biological Products; Biology; Brain; Carbohydrates; Cessation of life; Chemistry; Child; Clinic; Clinical Research; Clinical Trials; Collaborations; Communities; Convulsions; Core Facility; Coupled; Cytoplasm; Data; Defect; Dementia; Dendrites; Development; Diagnosis; Diagnostic; Disease; Dreams; Enzymes; Epilepsy; Frequencies; Gene Expression; Generations; Genes; Genetic; Glycogen; Grant; Headache; Hormones; International; Intractable Epilepsy; Knowledge; Lafora Disease; Life; Medicine; Messenger RNA; Methods; Modality; Modeling; Molecular; Molecular Target; Mutation; Myoclonic Epilepsies; Myoclonus; National Institute of Neurological Disorders and Stroke; Neurodegenerative Disorders; Neurons; Neurosciences; Outcome; Pathogenicity; Pathology; Pathway interactions; Patients; Persons; Pharmaceutical Chemistry; Pharmacology; Phase; Phosphoric Monoester Hydrolases; Physicians; Plants; Positioning Attribute; Process; Production; Program Research Project Grants; Pulmonary Inflammation; RNA; Reagent; Refractory; Research; Research Personnel; Scientist; Seizures; Shapes; Starch; Status Epilepticus; Structural Biochemistry; Techniques; Technology; Teenagers; Testing; Therapeutic; Time; Training; Translating; United States National Institutes of Health; Vision; Work; base; brain cell; career; clinical application; cognitive function; genome editing; glycogen metabolism; induced pluripotent stem cell; innovation; insight; interdisciplinary approach; member; mouse model; novel; personalized diagnostics; proteostasis; response; sex; small molecule; small molecule inhibitor; spelling; success; sugar; therapeutic evaluation; ubiquitin-protein ligase

Lafora Disease was originally described over 100 years ago by Dr. Gonzalo Rodriquez-Lafora as a “myoclonus epilepsy with dementia.” A hallmark of the disease identified by Lafora are inclusions in the brain, now known as Lafora bodies (LBs). LD is a rapidly progressing invariably fatal epilepsy. Onset is in adolescence, in apparently healthy teenagers of both sexes, with headaches and insidious decline in cognitive function. Myoclonic seizures, staring spells, and generalized convulsions follow and all escalate over time. Initial response to antiepileptic drugs is lost within three years and a constant myoclonus with atypical absence begins. The young person then develops dementia, often disinhibited, and seizes with increased frequency. The patient becomes bedridden and death comes after a protracted decade of unceasing myoclonus in the form of a particularly massive seizure, status epilepticus, or aspiration pneumonitis. Identification of the genetic basis for LD by members of our group has ushered in a new era in our understanding of the formation of LBs leading to LD. We have made rapid progress, and have now demonstrated that eliminating LBs wholly cures LD in mouse models, opening up the real possibility of a cure. To that end, we propose the establishment of the Lafora Epilepsy Cure Initiative (LECI) Center. We have assembled an international group of pioneers and leaders in the field. We propose to attack the disease from multiple angles, targeting the full spectrum of molecular and cellular causes of LD and believe that we are uniquely positioned to realize the dream of treating and curing LD patients. The overall focus of this Program Project Grant is to: Diagnose, Treat, and eventually Cure LD. Four complimentary projects and three integrated core facilities form the basis of this proposal. Our projects are: Project #1: Personalized diagnosis - defining how glycogen metabolism and proteostasis impact LD. Project #2: Genome editing, mRNA suppression and glycogen chain termination to inhibit glycogen storage as therapy for LD. Project #3: Suppressing glycogen storage with small molecule inhibitors as a therapeutic approach to LD. Project #4: Defining the therapeutic window for the treatment of LD. LD offers a unique window into both normal neuronal glycogen metabolism and epileptic disease when the process is perturbed. While this project aims at defining the basic mechanisms of LD and translating this work into therapeutics and cures, our work is likely to reveal pathogenic mechanisms common to other epilepsies. The collective effort of the LD experts will both define LD therapy options and generate abundant new collateral data that will uncover pathways connecting the bioenergetics of the brain with the generation of seizures and epilepsy. These insights may be particularly informative to the most daunting aspect of epilepsy, namely intractability that afflicts over 30% of patients.

Lafora病最初是在100多年前由Gonzalo Rodriquez-Lafora博士描述为一种 “肌阵挛癫痫伴痴呆”Lafora发现的这种疾病的一个标志是大脑中的内含物， 现在称为Lafora小体（LB）。LD是一种快速进展的致命性癫痫。Onset在 青春期，在明显健康的青少年男女，头痛和认知能力的隐性下降， 功能肌阵挛发作，凝视，全身抽搐，并随着时间的推移而升级。 对抗癫痫药物的初始反应在三年内消失，持续性肌阵挛伴非典型缺失 开始.年轻人然后发展成痴呆症，通常是不受抑制的，并且频率增加。 病人卧床不起，在长达十年的不间断肌阵挛后死亡。 特别是大面积癫痫发作、癫痫持续状态或吸入性肺炎的形式。 我们小组成员对LD遗传基础的鉴定开创了我们研究的新时代。 了解导致LD的LB的形成。我们取得了迅速的进展，现在 在小鼠模型中完全消除LBs治愈了LD，开启了治愈的真实的可能性。 为此，我们建议建立Lafora癫痫治疗倡议（LECI）中心。我们有 聚集了该领域的国际先驱和领导者。我们建议从 多个角度，针对LD的分子和细胞原因的全谱，并相信我们是 独特的定位，以实现治疗和治愈LD患者的梦想。 该计划项目补助金的总体重点是：诊断，治疗，并最终治愈LD。四 配套项目和三个综合核心设施是这个建议的基础。我们的项目包括： 项目#1：个性化诊断-确定糖原代谢和蛋白质稳态如何影响LD。 项目#2：基因组编辑，mRNA抑制和糖原链终止以抑制糖原储存， 治疗LD。 项目#3：用小分子抑制剂抑制糖原储存作为LD的治疗方法。 项目4：确定LD治疗的治疗窗。 LD为正常神经元糖原代谢和癫痫疾病提供了一个独特的窗口， 过程受到干扰。本项目旨在界定LD的基本机制， 我们的工作很可能揭示其他癫痫病常见的致病机制。 LD专家的集体努力将定义LD治疗方案，并产生丰富的新的 间接的数据，将揭示连接大脑的生物能量学与产生的途径， 癫痫和癫痫。这些见解可能对癫痫最令人生畏的方面特别有用， 即困扰超过30%的患者的顽固性。