Screening for new therapies for refractory infantile spasms

描述(申请人提供)：婴儿痉挛(IS)是一种具有明显药物敏感性的癫痫发作，表现为婴儿期的一系列癫痫脑病，在随后的认知结果和出现耐药癫痫方面预后较差。目前的治疗方法(促肾上腺皮质激素(ACTH)、Vigabatrin)并不总是有效的；它们改变长期结果的能力有限，可能与显著的副作用有关。为了确定治疗IS和共病的新方法，我们开发了一种多次打击的IS大鼠模型，该模型展示了人类IS综合征的慢性演变：IS的年龄特异性表达、其他癫痫发作的出现和认知缺陷。这个模型中的痉挛对ACTH是难治性的，对Vigabatrin有瞬时反应，这使得这是一个难治性IS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，结果表明，在痉挛发作后给予卡利沙明和雷帕霉素治疗可以强烈地抑制痉挛，而短暂的雷帕霉素疗程持续地抑制痉挛，对学习和记忆具有疾病修改效果。我们的目标是验证该模型作为临床前筛选工具的作用，以确定具有快速起效、持续效果和疾病修改潜力的难治性SIS的新疗法。我们建议使用这个模型来筛选几种药物的有效性(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一药物注射对行为和电临床痉挛的持续时间。 使用时间和剂量反应实验，以及(B)如果选定的有效药物的脉冲给药停止痉挛，防止出现其他癫痫发作，并改善认知。我们将使用时间和剂量反应实验的随机、盲目设计来测试对痉挛(主要终点)和其他癫痫发作和认知缺陷的急性和持续疗效(次级实验)。方法将包括立体定向药物注射，监测痉挛，其他癫痫类型，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随后通过U01机制申请资金的药物，以完成其临床前药物开发测试，这是IND申请所必需的。如果成功，这项提案将验证这一模式的作用 ACTH难治性是一种临床前筛选工具，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.