Screening for new therapies for refractory infantile spasms

筛选难治性婴儿痉挛症的新疗法

基本信息

批准号：
8551764
负责人：
Aristea S Galanopoulou
金额：
$ 20.14万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8551764
关键词：
Acute Adverse effects Age Algorithms Antiepileptic Agents Antiepileptogenic Behavioral Benchmarking Blinded Brain Pathology Chronic Clinical Research Cognition Cognitive Cognitive deficits Comorbidity Corticotropin Data Development Disease Dose Drug Kinetics Drug resistance Effectiveness Encephalopathies Epilepsy Evolution Funding Health Human Impaired cognition Infant Infantile spasms Inflammatory Infusion procedures Injection of therapeutic agent Intractable Epilepsy Investigational New Drug Application Lead Learning Medical Care Costs Memory Methods Modeling Modification Monitor Neurodevelopmental Deficit Outcome Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Phenytoin Physiologic pulse Population Preclinical Drug Development Protocols documentation Quality of life Randomized Rattus Recombinant Interleukins Reflex action Refractory Research SDZ RAD Seizures Signal Pathway Sirolimus Spasm Steroids Symptomatic West Syndrome Syndrome Technology Testing Time Vigabatrin analog base design drug testing improved in vivo infancy mTOR Inhibitor novel therapeutics outcome forecast pre-clinical preclinical efficacy preclinical safety prevent pup receptor research study response role model screening therapy development time use tool

项目摘要

DESCRIPTION (provided by applicant): Infantile spasms (IS) are epileptic seizures with distinct pharmacosensitivity that manifest in a spectrum of epileptic encephalopathies of infancy with poor prognosis in terms of subsequent cognitive outcomes and emergence of drug-resistant epilepsy. The current therapies (adrenocorticotropic hormone (ACTH), vigabatrin) are not always effective; their ability to alter long-term outcomes is limited and may be associated with significant side effects. To identify new therapies for IS and comorbidities, we have developed a rat multiple-hit model of IS which demonstrates the chronic evolution of the human IS syndrome: age-specific expression of IS, emergence of other seizures and cognitive deficits. Spasms in this model are refractory to ACTH and transiently responsive to vigabatrin, rendering this a model of refractory IS. We have previously demonstrated the feasibility of preclinical drug testing in our model by showing that carisbamate and rapamycin therapy, given after the onset of spasms, can acutely suppress spasms, and a brief course of rapamycin persistently suppresses spasms with disease modifying effects on learning and memory. Our objective is to validate the role of this model as a preclinical screening tool for the identification of new therapies for medically-refractory SIS with rapid onset, sustained effect, and disease-modifying potential. We propose to use this model to screen the efficacy of several agents (administered after the onset of spasms, as is the case in human babies) and determine: (a) their acute efficacy and duration of effect of a single drug injection on behavioral and electroclinical spasms using time and dose response experiments, and (b) if a pulse administration of selected effective drugs stops spasms, prevents the emergence of other seizures and improves cognition. We will use a randomized, blinded design of time and dose-response experiments to test for acute and sustained efficacy on spasms (primary endpoints) and other seizures and cognitive deficits (secondary experiments). Methods will include stereotactic drug infusions, monitoring for spasms, other seizure types, neurodevelopmental reflexes and cognitive abilities. Drugs that successfully pass this screening algorithm, will be used in subsequent application for funding through a U01 mechanism to complete their preclinical drug development testing, necessary for IND application. If successful, this proposal will validate the role of this model of ACTH-refractory IS as a preclinical screening tool for the identification of new, rapid-onset therapies and test their antiepileptogenic and disease-modifying potential.

描述（由申请人提供）：婴儿痉挛（IS）是癫痫发作，具有明显的药物敏感性，在婴儿期的一系列癫痫性脑病中表现出来，预后不佳，而后续的认知结果和药物耐药性癫痫的出现。当前的疗法（肾上腺皮质激素（ACTH），Vigabatrin）并不总是有效的；他们改变长期结局的能力是有限的，可能与重大副作用有关。为了鉴定IS和合并症的新疗法，我们开发了一种大鼠多击模型IS，该模型证明了人类IS综合征的慢性演变：IS的年龄特异性表达，其他癫痫发作和认知缺陷的出现。该模型中的痉挛对ACTH具有难治性，并且对Vigabatrin迅速响应，这使该模型是难治性的模型。以前，我们以前已经证明了临床前药物测试在我们的模型中的可行性，这表明在痉挛发作后进行的carisbamate和雷帕霉素疗法可以急剧抑制痉挛，而短暂的雷帕霉素则持续抑制痉挛，从而抑制了疾病对学习和记忆的疾病影响。我们的目标是验证该模型作为临床前筛查工具的作用，以鉴定具有快速发作，持续效应和疾病改良潜力的医学上难治性SIS的新疗法。我们建议使用该模型来筛选几种药物的功效（痉挛发作后施用，就像人类婴儿一样），并确定：（a）它们的急性疗效和单个药物注射对行为和电力痉挛的效果持续时间使用时间和剂量反应实验，（b）如果选定有效药物的脉冲施用会阻止痉挛，则可以防止其他癫痫发作的出现并改善认知。我们将使用随机的，盲目的时间和剂量反应实验来测试痉挛（主要终点）以及其他癫痫发作和认知缺陷（次级实验）的急性和持续功效。方法将包括立体定向药物输注，监测痉挛，其他癫痫发作类型，神经发育反射和认知能力。成功通过此筛查算法的药物将通过U01机制用于随后的资金应用，以完成其临床前药物开发测试，这是IND应用所必需的。如果成功，该建议将验证该模型的作用 ACTH-REFRACTORY是鉴定新的快速发作疗法的临床前筛查工具，并测试其抗癫痫发作和疾病调整潜力。