Lafora Epilepsy - Basic mechanisms to therapy

拉福拉癫痫 - 治疗的基本机制

• 批准号: 9309102
• 负责人: Matthew S. Gentry
• 金额: $ 172.25万
• 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/9309102
• 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; Employee Strikes; 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.

100 多年前，Gonzalo Rodriquez-Lafora 博士最初将拉福拉病描述为一种 “肌阵挛癫痫伴痴呆。”拉福拉发现，这种疾病的一个标志是大脑中存在包涵体， 现在被称为拉福拉体（LB），是一种进展迅速且总是致命的癫痫。 青春期，明显健康的男女青少年都会出现头痛和认知能力隐性下降的症状 随之而来的是肌阵挛发作、凝视发作和全身抽搐，并且随着时间的推移，所有症状都会升级。 对抗癫痫药物的初始反应在三年内消失，并且持续出现不典型失神性肌阵挛 然后，年轻人开始患上痴呆症，通常会失去抑制，并且癫痫发作的频率会增加。 患者长期卧床不起，在经历了长达十年的持续性肌阵挛后死亡。 一种特别严重的癫痫发作、癫痫持续状态或吸入性肺炎。 我们小组成员对 LD 遗传基础的鉴定开创了我们的新时代 对导致 LD 的 LB 形成的理解我们已经取得了快速进展，并且现在已经取得了进展。 消除了小鼠模型中证明的 LB 可以完全治愈 LD 的事实，从而开启了治愈 LD 的真正可能性。 为此，我们建议建立拉福拉癫痫治疗倡议 (LECI) 中心。 我们建议组建一个由该领域的先驱和领导者组成的国际小组来对抗这种疾病。 多角度，针对 LD 的分子和细胞原因的全谱，并相信我们 具有独特的优势，能够实现治疗和治愈 LD 患者的梦想。 该计划项目拨款的总体重点是：诊断、治疗并最终治愈 LD 四。 补充项目和三个综合核心设施构成了该提案的基础： 项目#1：个性化诊断 - 定义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 LD 的治疗。 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 治疗的治疗窗口。 LD 为了解正常神经元糖原代谢和癫痫疾病提供了一个独特的窗口。 虽然这个项目旨在定义 LD 的基本机制并翻译这项工作。 在治疗和治愈方面，我们的工作可能会揭示其他癫痫症常见的致病机制。 LD 专家的集体努力将定义 LD 治疗方案并产生大量新的 附带数据将揭示大脑的生物能量学与生成的联系 这些见解可能对癫痫最令人畏惧的方面特别有用， 即困扰超过 30% 患者的棘手问题。