Screening for new therapies for refractory infantile spasms

描述（由申请方提供）：婴儿痉挛（IS）是一种具有明显药物敏感性的癫痫发作，表现为一系列婴儿期癫痫性脑病，在随后的认知结局和耐药性癫痫的出现方面预后不良。目前的治疗（促肾上腺皮质激素（ACTH），氨己烯酸）并不总是有效的;他们改变长期结果的能力是有限的，可能与显着的副作用。为了确定IS和合并症的新疗法，我们开发了一种IS的大鼠多次打击模型，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不敏感，对氨己烯酸有短暂反应，使其成为难治性IS的模型。我们之前已经证明了在我们的模型中进行临床前药物测试的可行性，表明在痉挛发作后给予卡立氨酯和雷帕霉素治疗可以急性抑制痉挛，并且雷帕霉素的短暂疗程持续抑制痉挛，对学习和记忆具有疾病修饰作用。我们的目标是验证该模型作为临床前筛选工具的作用，用于鉴定具有快速起效、持续作用和疾病修饰潜力的医学难治性SIS的新疗法。我们建议使用这个模型来筛选几种药物的疗效（在痉挛发作后给药，就像人类婴儿的情况一样），并确定：（a）它们的急性疗效和单次药物注射对行为和电临床痉挛的作用持续时间 使用时间和剂量反应实验，和（B）如果脉冲施用所选择的有效药物，则停止痉挛，防止其他癫痫发作的出现并改善认知。我们将使用随机、设盲设计的时间和剂量-反应实验来测试对痉挛（主要终点）和其他癫痫发作和认知缺陷（次要实验）的急性和持续疗效。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。成功通过该筛选算法的药物将用于后续的资金申请，通过U 01机制完成IND申请所需的临床前药物开发测试。如果成功，这一建议将证实这一模式的作用， ACTH难治性IS作为临床前筛选工具，用于识别新的快速起效的治疗方法，并测试其抗癫痫和改善疾病的潜力。

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.