Modeling West Syndrome to Prevent Neurobehavioral Disabilities

模拟韦斯特综合症以预防神经行为障碍

• 批准号: 10471061
• 负责人: John William Swann
• 金额: $ 40.13万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10471061
• 关键词: Modeling; West; Syndrome; Prevent; Neurobehavioral

West syndrome is the most common of the catastrophic epilepsies of early childhood. Onset is most often within the first year of life and babies with this disorder have very brief seizures (only a few seconds in duration) – thus the coining of the alternate name infantile spasms. The epileptic spasms commonly occur in clusters of up to 100 in a few minutes. The spasms, along with the highly chaotic EEG patterns called hypsarrhythmia, are thought to contribute to the severe intellectual disabilities seen in most children. Indeed neurodevelopmental arrest or regression is frequently observed upon spasm onset. Other neurobehavioral comorbidities evolve as well including hyperactivity. In terms of treatments, ACTH and vigabatrin are FDA approved to stop the spasms and are effective in ~ 50% of children. However, both drugs can produce serious side effects. More importantly, while these drugs can eliminate spasms in some children, most often the neurobehavioral comorbidities persist and are life-long. Thus treatments are needed that will not only stop the spasms but also prevent the intellectual disabilities and other neurobehavioral deficits. Recent large multicenter clinical trials have reported more optimistic outcomes. They suggest that prompt diagnosis and rapid elimination of spasms can result in improved neurobehavioral outcomes. For instance, outcomes are better if treatment is initiated within 1 week of diagnosis rather than 2 months. These results and others like them have led to a position statement endorsed by the Child Neurology Society and American Epilepsy Society that prompt treatment of epileptic spasms is essential in order to prevent worse developmental and intellectual outcomes. In this application, we propose to establish the TTX animal model of infantile spasms for the discovery of new treatments to prevent neurobehavioral comorbidities. The model already has good external validity. In addition, preliminary results reported here indicate that animals with spasms have learning and memory deficits and an accompanying hyperactivity phenotype. We propose 4 specific aims. In the first, we will fully characterize the learning and memory deficits and hyperactivity phenotype in these animals. In the second, we will establish the best dosing for a novel combination therapy of vigabatrin and the neuroactive peptide (1-3)IGF-1 that synergies with vigabatrin to enhance GABAergic synaptic transmission and rapidly eliminates spasms in a large majority of animals. In the third and fourth aims, we will establish the predictive validity of the model by treating rats with the combination therapy and showing that early elimination of spasms and hypsarrhythmia will ameliorate neurobehavioral comorbidities but delayed treatment will not. If successful, these studies will establish the TTX model as a much-needed tool for discovering less toxic and more effective new therapies, which will significantly improve long-term outcomes for children with this devastating seizure disorder.

西综合征是幼儿期灾难性癫痫中最常见的。发作通常是 在生命的第一年内，患有这种疾病的婴儿有很短的癫痫发作（只有几秒钟 持续时间） - 因此，替代名称婴儿痉挛的结合。癫痫痉挛通常发生在 几分钟内最多可达100。痉挛以及高度混乱的脑电图模式称为 人们认为催眠性心律失常会导致大多数儿童看到的严重智力残疾。的确 痉挛发作经常观察到神经发育停滞或消退。其他神经行为 合并症也进化，包括多动症。在治疗方面，ACTH和Vigabatrin是FDA 批准停止痉挛，并在约50％的儿童中有效。但是，两种药物都可以严重 副作用。更重要的是，尽管这些药物可以消除某些儿童的痉挛，但通常 神经行为合并症持续存在，是终身的。需要这种治疗，不仅会阻止 痉挛，但也可以防止智力残疾和其他神经行为定义。最近大 多中心临床试验报告了更乐观的结果。他们建议及时诊断和 痉挛的快速演变可以改善神经行为结局。例如，结果是 如果在诊断后的1周内开始治疗，而不是2个月，则更好。这些结果和其他结果喜欢 他们导致了儿童神经病学协会和美国癫痫学会认可的职位声明 为了防止更严重的发展和智力，对癫痫痉挛的迅速治疗至关重要 结果。在此应用中，我们建议建立基础设施痉挛的TTX动物模型 发现新疗法以防止神经行为合并症。该模型已经具有良好的外部 有效性。此外，这里报告的初步结果表明，痉挛的动物有学习和 记忆定义和累积的多动症表型。我们提出了4个具体目标。首先，我们 将充分表征学习和记忆的定义和多动症表型。在 其次，我们将建立最佳的剂量，用于新型的Vigabatrin和神经活性的组合疗法 肽（1-3）IGF-1与Vigabatrin协同以增强Gabaergic合成传播并迅速 消除了绝大多数动物的痉挛。在第三和第四目标中，我们将建立预测性 模型通过结合疗法治疗大鼠的有效性并表明早期消除痉挛 催眠术会改善神经行为合并症，但延迟治疗不会。如果成功， 这些研究将建立TTX模型作为一种急需的工具，以发现毒性较小，更有效 新疗法将大大改善这种毁灭性癫痫发作的儿童的长期结局 紊乱。