Impact of SAR152954 on Prenatal Alcohol Exposure-induced Neurobehavioral Deficits

项目摘要 学习障碍是在患有胎儿酒精谱系的儿童中观察到的最常见的行为缺陷 疾病（FASD）。目前，还没有建立合理的临床有效的药物 干预这些和相关的行为缺陷。然而，使用一种成熟的FASD大鼠模型， 我们已经观察到组胺H3受体反向激动剂ABT-239改善了产前酒精暴露， （PAE）诱导的齿状回长时程增强（LTP）和记忆保持缺陷。我们还 观察到H3受体-效应器偶联增加和H3受体介导的谷氨酸抑制作用增强 在PAE大鼠的齿状回释放。我们的研究结果表明，PAE增加H3受体介导的抑制 ABT-239降低了这种增强的抑制作用。这些观察提供 用于检查H3受体反向激动剂治疗学习和记忆的功效的临床前原理 FASD儿童的缺陷。本提案临床前UH 2阶段的工作假设是， 另一种组胺H3受体反向激动剂SAR 152954将改善PAE诱导的行为和 通过逆转PAE诱导的谷氨酸活性依赖性增强的降低来改善突触可塑性缺陷 release.我们将首先检查四种不同剂量的SAR 152954对一种药物中PAE诱导缺陷的影响- 试验情境恐惧条件反射（Aim 1A）和使用Morris水迷宫的空间记忆保持（Aim 这两种行为对PAE引起的齿状回功能损伤非常敏感。里程碑 目的1的目的是确定逆转PAE诱导的SAR 152954的最佳试验剂量（OTD）。 记忆缺陷随后，我们将检查SAR 152954的OTD剂量是否逆转PAE诱导的 齿状回LTP（Aim 2A）缺陷和谷氨酸水平活动依赖性增强的推定缺陷 齿状回（Aim 2B）。目标2的里程碑目标将是证明这些方面的改进 神经生理学缺陷作为推进H3受体的临床前原理的机制基石 反向激动剂的临床试验。假设我们实现了临床前里程碑，我们将提交一份为期一年的 申请资金以制定临床试验计划。我们的临床医生已经制定了一份初步的计划草案， 调查员团队首先，在患有FASD的青少年中使用三种药物剂量进行Ib期试验。在 除了获得药代动力学和安全性特征数据外，Ib期的主要里程碑目标将是 确定最高安全剂量的代理产生显着改善组合的行为和 神经生理反应，如使用hdEEG/脑磁图测量的。随后，在一个阶段 在临床试验中，我们将采用双盲交叉的方法来评估最佳药物剂量的治疗效果 设计采用与Ib期试验相同的药效学评估。假设这些UH 3 里程碑的实现，我们预计随后，更广泛的试验，以评估药物的疗效，在一个多地点 临床试验

PROJECT SUMMARY ABSTRACT Learning disabilities are the most common behavioral deficit observed in children with Fetal Alcohol Spectrum Disorder (FASD). Currently, there are no established rationally-based clinically-effective pharmacotherapeutic interventions for these and related behavioral deficits. However, using a well-established rat model of FASD, we have observed that the histamine H3 receptor inverse agonist ABT-239 ameliorates prenatal alcohol exposure (PAE)-induced deficits in dentate gyrus long-term potentiation (LTP) and retention of memory. We have also observed increased H3 receptor-effector coupling and a heightened H3 receptor-mediated inhibition of glutamate release in the dentate gyrus of PAE rats. Our results suggest that PAE increases H3 receptor-mediated inhibition of glutamate release and that ABT-239 reduces this heightened inhibitory influence. These observations provide preclinical rationale for examining the efficacy of H3 receptor inverse agonists on treating learning and memory deficits in children with FASD. The working hypothesis for the preclinical UH2 phase of this proposal is that SAR152954, another histamine H3 receptor inverse agonist, will ameliorate PAE-induced behavioral and synaptic plasticity deficits by reversing PAE-induced decreases in activity-dependent potentiation of glutamate release. We will first examine the effects of four different doses of SAR152954 on PAE-induced deficits in one- trial contextual fear conditioning (Aim 1A) and the retention of spatial memory using the Morris Water Maze (Aim 1B), two behaviors quite sensitive to PAE-induced functional damage of the dentate gyrus. The milestone objective of Aim 1 will be to identify the optimal test dose (OTD) of SAR152954 that reverses PAE-induced memory deficits. Subsequently, we will examine whether the OTD dose of SAR152954 reverses PAE-induced deficits in dentate gyrus LTP (Aim 2A) and putative deficits in activity-dependent potentiation of glutamate levels in dentate gyrus (Aim 2B). The milestone objective of Aim 2 will be to demonstrate the amelioration of these neurophysiological deficits as the mechanistic cornerstone of a preclinical rationale for advancing H3 receptor inverse agonists to clinical trial. Assuming we achieve the preclinical milestones, we will submit a one-year request for funding to develop a clinical trial plan. A tentative draft of plans has been developed by our clinical investigator team. First, a Phase Ib trial is proposed using three drug doses in adolescents with FASD. In addition to acquiring pharmacokinetic and safety profile data, the primary Phase Ib milestone objective will be to identify the highest safe dose of the agent producing significant improvements in combined behavioral and neurophysiologic responses, as measured using hdEEG/magnetoencephalography. Subsequently, in a Phase IIa clinical trial, we would assess the therapeutic efficacy of the optimal drug dose using a double-blind crossover design that employs the same pharmacodynamic assessments used in the Phase Ib trial. Assuming these UH3 milestones are achieved, we anticipate a subsequent, more extensive trial to assess drug efficacy in a multisite clinical trial.