Impact of SAR152954 on Prenatal Alcohol Exposure-induced Neurobehavioral Deficits

项目总结摘要 学习障碍是胎儿酒精谱儿童最常见的行为缺陷 精神障碍(FASD)。目前，还没有建立合理的、临床有效的药物治疗方法。 对这些和相关行为缺陷的干预。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可以改善产前酒精暴露 (PAE)导致齿状回长时程增强(LTP)和记忆保持的缺陷。我们还有 观察到H3受体-效应偶联增强和H3受体介导的谷氨酸抑制作用增强 在PAE大鼠齿状回释放。我们的结果表明，PAE增加了H3受体介导的抑制 减少谷氨酸释放，ABT-239可降低这种增强的抑制作用。这些观察结果提供了 检测H3受体反向激动剂治疗学习记忆疗效的临床前理论基础 FASD儿童的缺陷。这项提议的临床前UH2阶段的工作假设是 另一种组胺H3受体反向激动剂SAR152954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增强减少而导致的突触可塑性缺陷 放手。我们将首先研究四种不同剂量的SAR152954对PAE诱导的缺陷的影响。 使用Morris水迷宫(Aim)的情景恐惧条件作用试验(Aim 1A)与空间记忆的保持 1b)，这两种行为对PAE引起的齿状回功能损伤非常敏感。里程碑 目标1的目标是确定SAR152954逆转PAE诱导的最佳测试剂量(OTD 记忆缺陷。随后，我们将研究SAR152954的OTD剂量是否逆转PAE诱导的 齿状回LTP缺陷(目标2A)和谷氨酸水平的活性依赖增强缺陷 在齿状回(目标2B)。目标2的里程碑目标将是演示这些改进 神经生理学缺陷是促进H3受体进展的临床前理论的机制基石 反向激动剂用于临床试验。假设我们达到了临床前的里程碑，我们将提交一年的 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临时计划草案 调查组。首先，建议在患有FASD的青少年中使用三种药物剂量进行Ib期试验。在……里面 除了获得药代动力学和安全性数据外，Ib阶段的主要里程碑目标将是 确定最高安全剂量的制剂，在综合行为和 神经生理学反应，用hdEEG/脑磁图测量。随后，在一个阶段中 Iia临床试验，我们将采用双盲交叉试验来评估最佳药物剂量的疗效。 采用与Ib期试验相同的药效学评估的设计。假设这些UH3 随着里程碑的实现，我们预计随后将进行更广泛的试验，以评估多地点的药物疗效 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.