Preclinical Animal Models for Dravet Syndrome: Seizure Phenotypes, Comorbidities and Drug Screening.
Preclinical Animal Models for Dravet Syndrome: Seizure Phenotypes, Comorbidities and Drug Screening.
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Dravet综合征的临床前动物模型：癫痫发作表型，合并症和药物筛查。
DOI：
10.3389/fphar.2018.00573
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发表时间：
2018
影响因子：
5.6
通讯作者：
Baraban SC
中科院分区：
文献类型：
--
作者：
Griffin A;Hamling KR;Hong S;Anvar M;Lee LP;Baraban SC
癫痫是一种常见的慢性神经系统疾病，影响着美国近300万人和全球5000万人。尽管有二十多种FDA批准的抗癫痫药物（AED），但仍有三分之一的患者未能获得充分的癫痫控制。具体来说，儿童遗传性癫痫通常是最严重的，使人衰弱的和耐药性形式的癫痫。癫痫综合征共享一个共同的症状，无端癫痫发作。虽然一些癫痫/癫痫形式是后天性损伤的结果，如头部创伤，热性癫痫发作或病毒感染，但其他癫痫具有遗传基础。癫痫相关基因的发现提示了各种潜在的病理学，并为每种遗传性癫痫的新的“个性化”治疗方案的开发打开了大门。其中，Dravet综合征（DS）在临床前和早期临床开发新疗法方面受到了极大的关注。尽管有这些进展，但没有FDA批准的DS治疗方法。超过80%的诊断为DS的患者在电压门控钠通道基因SCN 1A内携带从头突变，这些患者患有耐药性和危及生命的癫痫发作。在这里，我们将审查DS的临床前动物模型，其特点是SCN 1A失活（包括斑马鱼和小鼠），重点是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地方失败，因此我们了解这些模型如何对已知的AED做出反应同样重要。因此，我们还将审查现有的文献和最近的药物筛选工作，使用这些模型的重点是分析方案和预测药理学概况。这些临床前模型的验证是我们努力为这些患者有效发现新疗法的关键一步。行为和电生理学的药物筛选试验在斑马鱼将详细讨论，包括具体的例子，从我们的实验室使用斑马鱼scn 1突变体和近3000药物筛选总结日期。随着DS的发现和开发阶段从实验室迅速转移到临床，人们希望这种临床前策略为如何处理任何遗传性癫痫提供一个平台。
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 de novo mutation within the voltage-gated sodium channel gene SCN1A and these patients suffer with drug resistant and life-threatening seizures. Here we will review the preclinical animal models for DS featuring inactivation of SCN1A (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 scn1 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.
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影响因子：
3.6
作者：
Higurashi N;Uchida T;Lossin C;Misumi Y;Okada Y;Akamatsu W;Imaizumi Y;Zhang B;Nabeshima K;Mori MX;Katsurabayashi S;Shirasaka Y;Okano H;Hirose S
通讯作者：
Hirose S
影响因子：
14.5
作者：
Griffin, Aliesha;Hamling, Kyla R.;Baraban, Scott C.
通讯作者：
Baraban, Scott C.
影响因子：
5.6
作者：
Galanopoulou, Aristea S.;Buckmaster, Paul S.;Simonato, Michele
通讯作者：
Simonato, Michele
影响因子：
5.3
作者：
Hedrich, Ulrike B. S.;Liautard, Camille;Lerche, Holger
通讯作者：
Lerche, Holger
影响因子：
3.7
作者：
Auerbach DS;Jones J;Clawson BC;Offord J;Lenk GM;Ogiwara I;Yamakawa K;Meisler MH;Parent JM;Isom LL
通讯作者：
Isom LL