Hawkins Nicole A, Anderson Lyndsey L, Gertler Tracy S, Laux Linda, George Alfred L, Kearney Jennifer A
Department of Pharmacology Northwestern University Feinberg School of Medicine Chicago Illinois.
Department of Pediatrics Northwestern University Feinberg School of Medicine Division of Neurology Ann & Robert H. Lurie Children's Hospital of Chicago Chicago Illinois.
Ann Clin Transl Neurol. 2017 Apr 26;4(5):326-339. doi: 10.1002/acn3.413. eCollection 2017 May.
Epilepsy is a common neurological disorder that affects 1% of the population. Approximately, 30% of individuals with epilepsy are refractory to treatment, highlighting the need for novel therapies. Conventional anticonvulsant screening relies predominantly on induced seizure models. However, these models may not be etiologically relevant for genetic epilepsies. Mutations in are a common cause of Dravet Syndrome, a severe epileptic encephalopathy. Dravet syndrome typically begins in infancy with seizures provoked by fever and then progresses to include afebrile pleomorphic seizure types. Affected children respond poorly to available anticonvulsants. heterozygous knockout mice recapitulate features of Dravet syndrome and provide a potential screening platform to investigate novel therapeutics. In this study, we conducted a screening of conventional anticonvulsants in mice to establish assays that most closely correlate with human response data.
On the basis of clinical response data from a large, single center, retrospective survey of Dravet syndrome case records, we selected nine drugs for screening in mice to determine which phenotypic measures correlate best with human therapeutic response. We evaluated several screening paradigms and incorporated pharmacokinetic monitoring to establish drug exposure levels.
mice exhibited responses to anticonvulsant treatment similar to those observed clinically. Sodium channel blockers were not effective or exacerbated seizures in mice. Overall, clobazam was the most effective anticonvulsant in mice, consistent with its effect in Dravet syndrome.
Genetic models of spontaneous epilepsy provide alternative screening platforms and may augment the AED development process. In this study, we established an effective screening platform that pharmacologically validated mice for preclinical screening of potential Dravet syndrome therapeutics.
癫痫是一种常见的神经系统疾病，影响着1%的人口。大约30%的癫痫患者对治疗无效，这凸显了对新型疗法的需求。传统的抗惊厥药物筛选主要依赖于诱导性癫痫模型。然而，这些模型可能与遗传性癫痫的病因无关。[相关基因]突变是严重癫痫性脑病——德雷维特综合征的常见病因。德雷维特综合征通常始于婴儿期，由发热引发癫痫发作，随后发展为包括无热多形性癫痫发作类型。受影响的儿童对现有的抗惊厥药物反应不佳。[相关基因]杂合敲除小鼠重现了德雷维特综合征的特征，并提供了一个潜在的筛选平台来研究新型疗法。在本研究中，我们在[相关基因]小鼠中对传统抗惊厥药物进行了筛选，以建立与人类反应数据最密切相关的检测方法。
基于对德雷维特综合征病例记录的大型单中心回顾性调查的临床反应数据，我们选择了九种药物在[相关基因]小鼠中进行筛选，以确定哪些表型指标与人类治疗反应最相关。我们评估了几种筛选模式，并纳入药代动力学监测以确定药物暴露水平。
[相关基因]小鼠对抗惊厥治疗的反应与临床观察到的反应相似。钠通道阻滞剂在[相关基因]小鼠中无效或会加重癫痫发作。总体而言，氯巴占是[相关基因]小鼠中最有效的抗惊厥药物，这与其在德雷维特综合征中的作用一致。
自发性癫痫的遗传模型提供了替代筛选平台，并可能增强抗癫痫药物的开发过程。在本研究中，我们建立了一个有效的筛选平台，从药理学角度验证了[相关基因]小鼠可用于潜在德雷维特综合征治疗药物的临床前筛选。
