Infantile Spasms: Tools for Therapies

婴儿痉挛症：治疗工具

基本信息

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
项目类别：
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

项目摘要

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）：婴儿痉挛症是幼儿时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低下。目前，尽管 ACTH 可以抑制 40-60% 受影响儿童的痉挛，但尚无改善长期预后的治疗方法。由于缺乏相关的动物模型，新疗法的开发受到严重阻碍。这里提出的研究基于重现这种临床综合征的动物模型的创建。在该模型中，幼鼠的新皮质被局部注入钠通道拮抗剂河豚毒素（TTX），从而导致神经元活动的区域性阻断。两周内，许多大鼠表现出频繁的痉挛，包括轴向肌肉组织的短暂弯曲或伸展，这与婴儿痉挛非常相似。与儿童一样，这些事件通常成群发生，脑电图异常与儿童中所见的异常几乎相同。在痉挛期间，通常会出现普遍的高压慢波，随后是一段时期的明显电压衰减（电衰减），并叠加较高频率的活动。使用快速数字采样，我们最近还发现了从痉挛发作开始的高频振荡（80-200 Hz）。在发作间期，观察到高度节律失常模式，由高振幅慢波与频繁的多灶尖峰混合组成。在此提出的研究中，患有这种综合征的动物的长期视频/脑电图记录将用于充分描述这种癫痫症的自然病程。我们将确定：1) 痉挛首次出现的时间；2) 痉挛持续的时间；3) 不同动物之间以及特定动物不同时间的癫痫发作频率和聚集情况的差异。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测量和最省时、最具成本效益的方案。我们的长期目标是基于对这种毁灭性癫痫症的生物学基础的日益了解，利用这种动物模型来筛选新疗法。公共卫生相关性：婴儿痉挛症是幼儿时期最严重的癫痫之一，目前尚无令人满意的治疗方法。我们计划使用新开发的这种疾病的动物模型来全面描述这些动物的痉挛特征，并测试促肾上腺皮质激素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方案，用于测试针对这种破坏性神经系统疾病的新一代合理药物疗法。免责声明：请注意，以下评论是由审稿人在研究部分会议之前准备的，并且以基本上未经编辑的形式提供。虽然审稿人有机会根据小组的讨论更新或修改他们的书面评估，但不能保证个人批评在会议讨论后得到更新。因此，评论可能无法完全反映小组讨论结束时个别审稿人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审稿人在会议上实际认为关键的内容的最终决定。