Lafora Epilepsy - Basic mechanisms to therapy

拉福拉病最初由Gonzalo Rodriquez-Lafora博士在100多年前描述为一种 “肌阵挛癫痫伴痴呆症。”拉福拉确认的这种疾病的一个特征是大脑中的包裹体， 现在称为Lafora Body(LBS)。LD是一种进展迅速、总是致命的癫痫。发病时间到了 青春期，明显健康的青少年，无论男女，都有头痛和潜伏的认知能力下降 功能。随之而来的是肌阵挛发作、凝视发作和全身性抽搐，随着时间的推移，所有这些都会升级。 对抗癫痫药物的初始反应在三年内消失，持续的肌阵挛伴不典型的缺失 开始。然后，年轻人患上痴呆症，通常是无节制的，癫痫发作的频率增加。 病人卧床不起，在长达十年的无休止的肌阵挛后死亡 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的遗传基础的鉴定开启了我们的 对LBS形成导致学习障碍的理解。我们已经取得了快速的进步，现在已经 证明了完全消除LBS可以在小鼠模型中治愈LD，从而打开了治愈的真正可能性。 为此，我们提议建立拉福拉癫痫治疗倡议(莱西)中心。我们有 召集了一个由该领域的先驱和领导者组成的国际小组。我们建议从以下几个方面来防治这种疾病 多角度，针对LD的分子和细胞原因的全光谱，并相信我们是 在实现治疗和治愈LD患者的梦想方面具有独特的地位。 该计划项目赠款的总体重点是：诊断、治疗并最终治愈LD。四 免费项目和三个综合核心设施构成了这一提议的基础。我们的项目包括： 项目1：个性化诊断--确定糖原代谢和蛋白平衡如何影响LD。 项目2：基因组编辑、信使核糖核酸抑制和糖原链终止以抑制糖原储存 学习障碍的治疗。 项目3：使用小分子抑制剂抑制糖原储存，作为治疗LD的方法。 项目4：确定LD治疗的治疗窗口。 LD为了解正常的神经元糖原代谢和癫痫疾病提供了一个独特的窗口 这一过程受到了干扰。虽然这个项目的目的是定义LD的基本机制并翻译这部作品 在治疗和治疗方面，我们的工作可能会揭示其他癫痫的共同致病机制。 LD专家的集体努力将既定义LD治疗方案，又产生大量新的 附带数据，将揭示将大脑的生物能量学与 癫痫发作和癫痫。这些见解可能对癫痫最令人望而生畏的方面特别有帮助， 即困扰30%以上患者的顽固性。

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.