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.

West 综合征是儿童早期最常见的灾难性癫痫。 在出生后的第一年内，患有这种疾病的婴儿会出现非常短暂的癫痫发作（出生后仅几秒钟） 持续时间）——因此产生了婴儿痉挛症的替代名称，癫痫痉挛通常发生在。 几分钟内就会出现多达 100 个痉挛，并伴有高度混乱的脑电图模式，称为“脑电图”。 事实上，节律失常被认为会导致大多数儿童出现严重的智力障碍。 痉挛发作时经常观察到神经发育停滞或退化。 合并症也会发生变化，包括多动症。在治疗方面，ACTH 和氨己烯酸是 FDA 的药物。 经批准可阻止痉挛，对约 50% 的儿童有效。然而，这两种药物都会产生严重的后果。 更重要的是，虽然这些药物可以消除一些儿童的水疗问题，但最常见的是。 神经行为合并症持续存在并且是终生的，因此需要的治疗不仅能阻止疾病的发生。 痉挛还可预防近期出现的智力障碍和其他神经行为缺陷。 多中心临床试验报告了更乐观的结果，他们表明及时诊断和治疗。 快速消除痉挛可以改善神经行为结果，例如，结果是。 如果在诊断后 1 周内开始治疗，效果会比 2 个月内开始更好。 他们得出了一份得到儿童神经病学协会和美国癫痫协会认可的立场声明 及时治疗癫痫痉挛对于防止发育和智力恶化至关重要 在本申请中，我们建议建立婴儿痉挛症的 TTX 动物模型。 发现预防神经行为合并症的新疗法该模型已经具有良好的外部效果。 此外，这里报告的初步结果表明，患有痉挛的动物具有学习和能力。 我们提出了 4 个具体目标。 将充分表征这些动物的学习和记忆缺陷以及多动表型。 其次，我们将确定氨己烯酸和神经活性药物的新型联合疗法的最佳剂量 肽 (1-3)IGF-1 与氨己烯酸协同作用，增强 GABA 能突触传递并迅速增强 消除大多数动物的痉挛 在第三个和第四个目标中，我们将建立预测。 通过用联合疗法治疗大鼠并显示早期消除痉挛来验证模型的有效性 心律失常可以改善神经行为合并症，但如果成功的话，延迟治疗不会。 这些研究将建立 TTX 模型作为发现毒性更小、更有效的药物急需的工具 新疗法将显着改善患有这种毁灭性癫痫发作的儿童的长期结果 紊乱。