Infantile Spasms: Tools for Therapies

婴儿痉挛症：治疗工具

• 批准号: 7788439
• 负责人: John William Swann
• 金额: $ 23.03万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7788439
• 关键词: Adverse effects; Affect; Age; Animal Model; Animal Testing; Animals; Anticonvulsants; Biological; Child; Clinical; Corticotropin; Critiques; Development; Disease; Dose; Drug usage; Effectiveness; Epilepsy; Evaluation; Event; Frequencies; Future; Generations; Goals; High Frequency Oscillation; Human; Impaired cognition; Impairment; Incidence; Individual; Infant; Infantile spasms; Laboratories; Learning; Life; Live Birth; Memory; Memory impairment; Mental Retardation; Modeling; Neocortex; Neurologic; Neurons; Outcome; Outcome Measure; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Protocols documentation; Rattus; Recording of previous events; Research; Sampling; Seizures; Sodium Channel; Spasm; Study Section; Syndrome; Testing; Tetrodotoxin; Time; United States; Update; Variant; Writing; attenuation; base; behavior test; cost effective; digital; dosage; drug efficacy; early childhood; improved; infancy; meetings; nervous system disorder; public health relevance; response; tool; voltage

DESCRIPTION (provided by applicant): Infantile Spasms is one of the catastrophic epilepsies of early childhood. The disorder commonly leads to life- long epilepsy and mental retardation. At this time, there is no treatment for this disorder that improves long- term outcome, although ACTH can suppress the spasms in 40-60% of affected children. The development of new therapies has been severely hampered by the lack of a relevant animal model. Studies proposed here are based on the creation of an animal model that reproduces this clinical syndrome. In this model, the neocortex of infant rats is locally infused with the sodium channel antagonist, tetrodotoxin (TTX), which results in a regionalized blockade of neuronal activity. Within 2 weeks, many of these rats display frequent spasms that consist of brief flexions or extensions of axial musculature, which closely resemble infantile spasms. As in children, these events often occur in clusters EEG abnormalities are virtually identical to those seen in children. During a spasm, there is typically a generalized high voltage slow wave, followed by a period of marked voltage attenuation (electrodecrement) with superimposed higher frequency activity. Using rapid digital sampling we also have recently discovered high frequency oscillations (80-200 Hz) beginning at spasm onset. During the interictal period a hypsarrhythmic pattern is observed, consisting of high amplitude slow waves intermixed with frequent multifocal spikes. In the studies proposed here long term video/EEG recordings from animals with this syndrome will be used to fully characterize the natural course of this seizure disorder. We will determine: 1) when the spasms first appear 2) how long they persist and 3) variations in seizures frequency and clustering from animal to animal and from time to time in a given animal. We will also test rats for impairments in learning and memory and assess the ability of ACTH to suppress spasms. Our short-term goal is to develop reliable outcome measures of drug efficacy and the most time efficient and cost effective protocols for future drug trials. Our long-range goal is to use this animal model to screen new therapies based on a growing understanding of the biological basis of this devastating seizure disorder. PUBLIC HEALTH RELEVANCE: Infantile Spasms is one of the most severe epilepsies of early childhood for which there is no satisfactory treatment. Using a newly developed animal model of this disorder we plan to fully characterize the spasms in these animals and test the effectiveness of ACTH in suppressing these seizures. Our goal is to develop research and analytical protocols that can be used to test new generations of rational drug therapies for this devastating neurological disorder. Disclaimer: Please note that the following critiques were prepared by the reviewers prior to the Study Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation, based upon the group's discussion, there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore, the critiques may not fully reflect the final opinions of the individual reviewers at the close of group discussion or the final majority opinion of the group. Thus the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.

描述（由申请人提供）：婴儿痉挛症是儿童早期的灾难性癫痫之一。这种疾病通常会导致终身癫痫和智力迟钝。在这个时候，没有治疗这种疾病，改善长期的结果，虽然ACTH可以抑制痉挛在40-60%的受影响的儿童。由于缺乏相关的动物模型，新疗法的开发受到严重阻碍。这里提出的研究是基于建立一个动物模型，重现这种临床综合征。在该模型中，幼鼠的新皮层局部注入钠通道拮抗剂河豚毒素（TTX），导致神经元活动的区域性阻断。在2周内，这些大鼠中的许多表现出频繁的痉挛，包括轴向肌肉组织的短暂屈曲或伸展，其非常类似于婴儿痉挛。在儿童中，这些事件通常发生在集群脑电图异常几乎是相同的，在儿童中看到。在痉挛期间，通常有一个广义的高电压慢波，随后是一段时间的明显电压衰减（电减量）与叠加的高频活动。使用快速数字采样，我们最近还发现了在痉挛发作时开始的高频振荡（80-200 Hz）。在发作间期观察到高血压模式，由高振幅慢波与频繁的多灶性棘波混合组成。在本文提出的研究中，将使用患有该综合征的动物的长期视频/EEG记录来充分表征该癫痫发作疾病的自然过程。我们将确定：1）痉挛何时首次出现; 2）痉挛持续多长时间; 3）癫痫发作频率的变化以及动物之间和特定动物中的聚集性。我们还将测试大鼠的学习和记忆障碍，并评估ACTH抑制痉挛的能力。我们的短期目标是为未来的药物试验开发可靠的药物疗效结果指标和最具时间效率和成本效益的方案。我们的长期目标是使用这种动物模型，根据对这种毁灭性癫痫发作疾病的生物学基础的不断了解来筛选新的治疗方法。 公共卫生相关性：婴儿痉挛症是儿童早期最严重的癫痫之一，目前尚无令人满意的治疗方法。使用一种新开发的这种疾病的动物模型，我们计划充分描述这些动物的痉挛，并测试ACTH抑制这些癫痫发作的有效性。我们的目标是开发研究和分析协议，可用于测试新一代的合理药物治疗这种毁灭性的神经系统疾病。 免责声明：请注意，以下评论由审查员在研究部分会议之前准备，并以基本上未经编辑的形式提供。 虽然审查人员有机会根据小组讨论情况更新或修订其书面评价，但不能保证在会议讨论之后更新了个人评论。 因此，这些评论可能并不完全反映小组讨论结束时单个评审员的最终意见或小组的最终多数意见。因此，讨论的简历和摘要是评审员在会议上实际认为关键的最后一句话。