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

• 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
• 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

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病。发病率为每2000 - 3000例活产中有1例。 痉挛的持续时间只有几秒钟，但在几分钟内会发生多达100次的集群。脑电图 这种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， 发作间期的脑电图主要是一种称为心律失常的混乱模式。大多数孩子都是 他们中的大多数人在以后的生活中患有智力残疾，并且他们中的大多数人发展为其他形式的耐药性癫痫。ACTH和 氨己烯酸可以消除30-80%的患者的痉挛和心律失常-这取决于研究。然而，在这方面， 这两种药物都有明显的副作用，通常不会阻止智力发育。 残疾和严重的癫痫症后见。因此，需要更好的治疗方法，希望随着 随着相关动物模型的出现，潜在机制的发现将导致新的治疗方法。我们 一个实验室开发了一种婴儿痉挛症模型，重现了这种疾病的关键特征。像 在婴儿中，这些动物中的大多数对ACTH和氨己烯酸都有反应。然而，我们的工作也 指出了治疗这种疾病的潜在新疗法。我们发现胰岛素样生长因子的表达 因子-1（IGF-1）在痉挛动物的新皮层中受到抑制，这是通过PI 3 K-AKT-1信号传导的。 mTOR生长途径。与此同时，小清蛋白和突触结合蛋白2的表达， 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。这 这使我们假设通过PI 3 K-AKT-mTOR途径的信号传导减少损害了抑制性 中间神经元生长，其导致突触兴奋和抑制的不平衡以及癫痫性痉挛。 值得注意的是，用（1-3）IGF-1（IGF-1的三肽衍生物）治疗，挽救了抑制性中间神经元， 消除了超过60%的动物的痉挛和心律失常。此外，（1-3）IGF-1显著增加 氨己烯酸的抗惊厥作用，减少消除痉挛所需的剂量， 消除了它的视网膜毒性。这种协同作用可能是由（1-3）IGF-1增加了 GABA能神经末梢和氨己烯酸诱导的相同突触中GABA水平的增加。然而，在这方面， 关于（1-3）IGF-1知之甚少，这里提出的实验集中于了解其作用机制。 行动上我们计划测试2个假设。第一个是（1-3）IGF-1通过IGF-1受体激活 PI 3 K-AKT-mTOR生长途径。第二是（1-3）IGF-1刺激小清蛋白的生长 这是因为它可以激活中间神经元，从而向新皮层添加新的GABA能神经末梢。最后，我们将尝试 显示（1-3）当IGF-1增强氨己烯酸的抗惊厥作用时，IGF-1通过IGF-1受体起作用。 我们的研究结果将促进对一种新的、天然存在的神经肽的作用的理解， 在神经发育和神经发育障碍中起重要作用。此外，组合 （1-3）IGF-1和氨己烯酸的疗法作为治疗婴儿痉挛症的更好方法具有显著的潜力。