Griffin Aliesha, Hamling Kyla R, Hong SoonGweon, Anvar Mana, Lee Luke P, Baraban Scott C
Epilepsy Research Laboratory Department of Neurological Surgery and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States.
Department of Bioengineering, University of California, Berkeley, Berkeley, CA, United States.
Front Pharmacol. 2018 Jun 4;9:573. doi: 10.3389/fphar.2018.00573. eCollection 2018.
Epilepsy is a common chronic neurological disease affecting almost 3 million people in the United States and 50 million people worldwide. Despite availability of more than two dozen FDA-approved anti-epileptic drugs (AEDs), one-third of patients fail to receive adequate seizure control. Specifically, pediatric genetic epilepsies are often the most severe, debilitating and pharmaco-resistant forms of epilepsy. Epileptic syndromes share a common symptom of unprovoked seizures. While some epilepsies/forms of epilepsy are the result of acquired insults such as head trauma, febrile seizure, or viral infection, others have a genetic basis. The discovery of epilepsy associated genes suggests varied underlying pathologies and opens the door for development of new "personalized" treatment options for each genetic epilepsy. Among these, Dravet syndrome (DS) has received substantial attention for both the pre-clinical and early clinical development of novel therapeutics. Despite these advances, there is no FDA-approved treatment for DS. Over 80% of patients diagnosed with DS carry a mutation within the voltage-gated sodium channel gene and these patients suffer with drug resistant and life-threatening seizures. Here we will review the preclinical animal models for DS featuring inactivation of (including zebrafish and mice) with an emphasis on seizure phenotypes and behavioral comorbidities. Because many drugs fail somewhere between initial preclinical discovery and clinical trials, it is equally important that we understand how these models respond to known AEDs. As such, we will also review the available literature and recent drug screening efforts using these models with a focus on assay protocols and predictive pharmacological profiles. Validation of these preclinical models is a critical step in our efforts to efficiently discover new therapies for these patients. The behavioral and electrophysiological drug screening assays in zebrafish will be discussed in detail including specific examples from our laboratory using a zebrafish mutant and a summary of the nearly 3000 drugs screened to date. As the discovery and development phase rapidly moves from the lab-to-the-clinic for DS, it is hoped that this preclinical strategy offers a platform for how to approach any genetic epilepsy.
癫痫是一种常见的慢性神经系统疾病，在美国影响着近300万人，在全球影响着5000万人。尽管有二十多种经美国食品药品监督管理局（FDA）批准的抗癫痫药物（AEDs），但仍有三分之一的患者未能得到充分的癫痫发作控制。具体而言，儿童遗传性癫痫往往是最严重、最使人衰弱且对药物耐药的癫痫形式。癫痫综合征有一个共同的症状，即无诱因发作。虽然有些癫痫/癫痫形式是由后天损伤引起的，如头部外伤、热性惊厥或病毒感染，但其他癫痫则有遗传基础。与癫痫相关基因的发现表明存在多种潜在病理机制，并为开发针对每种遗传性癫痫的新“个性化”治疗方案打开了大门。其中，Dravet综合征（DS）在新型疗法的临床前和早期临床开发方面受到了广泛关注。尽管取得了这些进展，但目前尚无FDA批准的用于治疗DS的药物。超过80%被诊断为DS的患者在电压门控钠通道基因中携带突变，这些患者患有耐药性且危及生命的癫痫发作。在这里，我们将综述以（包括斑马鱼和小鼠）失活为特征的DS临床前动物模型，重点关注癫痫发作表型和行为共病。由于许多药物在最初的临床前发现和临床试验之间的某个阶段失败，因此了解这些模型对已知AEDs的反应同样重要。因此，我们还将综述使用这些模型的现有文献和近期药物筛选工作，重点关注检测方案和预测性药理学特征。验证这些临床前模型是我们为这些患者有效发现新疗法所做努力中的关键一步。将详细讨论斑马鱼中的行为和电生理药物筛选试验，包括我们实验室使用斑马鱼突变体的具体例子以及迄今为止筛选的近3000种药物的总结。随着DS的发现和开发阶段迅速从实验室转向临床，希望这种临床前策略能为如何应对任何遗传性癫痫提供一个平台。
