Infantile Spasms: Molecular Underpinnings of a Novel Combination Therapy

婴儿痉挛症：新型联合疗法的分子基础

基本信息

批准号：
10341168
负责人：
John William Swann
金额：
$ 34.67万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-15 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10341168
关键词：
4-Aminobutyrate aminotransferase Animal Model Animals Anticonvulsants Behavioral Biological Markers Birth Brain Brain Injuries Cerebrospinal Fluid Child Childhood Chronic Clinical Clinical Research Combined Modality Therapy Corticotropin Development Disabled Persons Disease Electroencephalography Enzymes Epilepsy Event FDA approved FRAP1 gene Gastaut syndrome Gene Mutation Glutamates Glycine Growth Hypoxia Hypsarrhythmia Impairment Incidence Infant Infantile spasms Infection Infusion procedures Insulin-Like Growth Factor I Insulin-Like-Growth Factor I Receptor Intellectual functioning disability Interneurons Intractable Epilepsy Knockout Mice Laboratories Life Live Birth Modeling Molecular Neocortex Nerve Neurodevelopmental Disorder Neurologic Neuropeptides PI3 gene Partial Epilepsies Parvalbumins Pathway interactions Patients Pattern Peripheral Pharmaceutical Preparations Pharmacology Phenotype Play Proline Proteins Proto-Oncogene Proteins c-akt Rattus Reporting Role Signal Pathway Signal Transduction Sodium Channel Spasm Symptomatic West Syndrome Synapses Synaptic Transmission Testing Therapeutic Time United States Vigabatrin Visual Fields Work antagonist conditional knockout dosage early childhood epileptic encephalopathies experimental study gamma-Aminobutyric Acid in vivo neurodevelopment new combination therapies novel novel therapeutics postnatal presynaptic presynaptic neurons side effect suicide substrates synaptotagmin II synergism virtual animals

项目摘要

Infantile spasms is a severe childhood seizure disorder. The incidence is 1 in every 2000 -3000 live births. The spasms are only a few seconds in duration but occur in clusters of up to 100 in a few minutes. The EEG correlates of the disorder are unique. Coincident with each behavioral spasm is a brief ictal event and the interictal EEG is dominated by a chaotic pattern called hypsarrhythmia. The majority of children are intellectually disabled later in life and most of them develop other forms of drug resistant epilepsy. ACTH and vigabatrin can abolish spasms and hypsarrhythmia in 30-80% of patients - depending on the study. However, both drugs can have significant side effects and usually do not prevent the development of the intellectual disabilities and severe epilepsy seen later. Thus better treatments are needed and the hope is that with the advent of relevant animal models, the discovery of underlying mechanisms will lead to new therapies. Our laboratory has developed a model of infantile spasms that recreates the critical features of the disorder. Like infants, the majority of these animals respond to both ACTH and vigabatrin. However, our work has also pointed to a potential new therapy for this disorder. We have found that the expression of Insulin-like Growth Factor -1 (IGF-1) is suppressed in the neocortex of animals with spasms as is signaling through the PI3K-AKT- mTOR growth pathway. At the same time, the expression of parvalbumin and synaptotagmin 2, biomarkers for an important class of inhibitory interneurons and their presynaptic nerve terminals, are also reduced. This has led us to hypothesize that reduced signaling through the PI3K-AKT-mTOR pathway impairs inhibitory interneuron growth which results in an imbalance in synaptic excitation and inhibition and epileptic spasms. Remarkably, treatment with (1-3)IGF-1, a tripeptide derivative of IGF-1, rescues the inhibitory interneurons and abolishes spasms and hypsarrhythmia in over 60% of animals. Moreover, (1-3)IGF-1 dramatically augments the anticonvulsant effects of vigabatrin, reducing the dosage needed to abolish spasms and potentially eliminates its retinotoxicity. This synergy is likely produced by (1-3)IGF-1’s increase in the number of GABAergic nerve terminals and vigabatrin-induced increase in GABA levels in the same synapses. However, very little is known about (1-3)IGF-1 and experiments proposed here focus on understanding its mechanism of action. We plan to test 2 hypotheses. The first is that (1-3)IGF-1 acts through the IGF-1 receptor to activate the PI3K-AKT-mTOR growth pathway. The second is that (1-3)IGF-1 stimulates the growth of parvalbumin interneurons and thereby adds new GABAergic nerve terminals to the neocortex. Lastly, we will attempt to show that (1-3)IGF-1 acts via the IGF-1 receptor when it augments the anticonvulsant effects of vigabatrin. Our results will advance an understanding of the actions of a novel, naturally occurring neuropeptide that likely plays an important roles in neurodevelopment and neurodevelopmental disorders. Moreover, the combination therapy of (1-3)IGF-1 and vigabatrin has significant potential as a better way to treat infantile spasms.

婴儿痉挛症是一种严重的儿童癫痫症，发病率为每 2000 -3000 名活产婴儿中就有 1 人罹患。痉挛持续时间只有几秒钟，但几分钟内就会出现多达 100 次痉挛。该疾病的相关因素是独特的，与每次行为痉挛同时发生的是短暂的发作事件。发作间期脑电图以一种称为高度节律失常的混乱模式为主。他们在以后的生活中出现智力障碍，并且大多数人会患上其他形式的抗促肾上腺皮质激素（ACTH）和癫痫。氨己烯酸可以消除 30-80% 患者的痉挛和心律失常——具体取决于研究。两者都会产生显着的副作用，并且通常不会妨碍智力的发展因此，需要更好的治疗方法，希望能得到更好的治疗。相关动物模型的出现，潜在机制的发现将带来新的疗法。实验室开发了一种婴儿痉挛症模型，可以重现该疾病的关键特征。在婴儿中，大多数动物对促肾上腺皮质激素和氨己烯酸都有反应。我们发现胰岛素样生长的表达指出了这种疾病的潜在新疗法。痉挛动物的新皮质中的因子 -1 (IGF-1) 受到抑制，就像通过 PI3K-AKT- 发出的信号一样 mTOR生长途径同时，小清蛋白和突触结合蛋白2的表达，生物标志物。一类重要的抑制性中间神经元及其突触前神经末梢也减少了。使我们发现通过 PI3K-AKT-mTOR 途径的信号传导减少会损害抑制中间神经元生长导致突触兴奋和抑制失衡以及癫痫痉挛。值得注意的是，用 (1-3)IGF-1（IGF-1 的三肽衍生物）治疗可挽救抑制性中间神经元并消除超过 60% 的动物的痉挛和高度心律失常。此外，(1-3)IGF-1 显着增强作用。氨己烯酸的抗惊厥作用，减少消除痉挛所需的剂量，并可能消除其视网膜毒性可能是通过 (1-3)IGF-1 数量的增加产生的。 GABA 能神经末梢和氨己烯酸诱导相同突触中 GABA 水平的增加。人们对 (1-3)IGF-1 知之甚少，这里提出的实验重点是了解其机制我们计划测试 2 个假设：(1-3)IGF-1 通过 IGF-1 受体发挥作用。 PI3K-AKT-mTOR 生长途径第二个是 (1-3)IGF-1 刺激小清蛋白的生长。中间神经元，从而向新皮质添加新的 GABA 神经末梢。表明 (1-3)IGF-1 通过 IGF-1 受体发挥作用，增强氨己烯酸的抗惊厥作用。我们的结果将促进对一种新颖的、天然存在的神经肽的作用的理解，该神经肽可能此外，这种组合在神经发育和神经发育障碍中发挥着重要作用。 (1-3)IGF-1 和氨己烯酸治疗具有作为治疗婴儿痉挛症更好方法的巨大潜力。