Impact of SAR152954 on Prenatal Alcohol Exposure-induced Neurobehavioral Deficits

SAR152954 对产前酒精暴露引起的神经行为缺陷的影响

• 批准号: 9386533
• 负责人: Daniel D. Savage
• 金额: $ 30.3万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9386533
• 关键词: Acute; Adolescent; Adverse effects; Agonist; Alcohols; Animal Model; Behavior; Behavioral; Brain Injuries; Chemosensitization; Child; Clinical; Clinical Investigator; Clinical Trials; Cognitive deficits; Coupling; Crossover Design; Data; Dose; Dose-Limiting; Double-Blind Method; Drug Kinetics; Effectiveness; Enrollment; Failure; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Funding; Glutamates; Histamine H3 Receptors; Hour; Intervention; Laws; Lead; Learning; Learning Disabilities; Long-Term Potentiation; Magnetoencephalography; Maximum Tolerated Dose; Measures; Mediating; Memory impairment; Modeling; Neurobiology; Patients; Performance; Pharmaceutical Preparations; Pharmacodynamics; Phase; Placebos; Randomized; Rattus; Research; Research Project Grants; Residual state; Risk; Safety; Saline; Sampling; Schools; Short-Term Memory; Stimulus; Synaptic plasticity; Testing; Tetanus; Therapeutic Agents; Time; Toxic effect; Training; Treatment Efficacy; Visit; Water; base; behavioral health; behavioral plasticity; cognitive disability; conditioned fear; dentate gyrus; design; drug efficacy; evidence base; follow-up; improved; in vivo; memory retention; morris water maze; neurobehavioral; neurophysiology; novel drug class; offspring; phase II trial; pre-clinical; prenatal; programs; response; screening; spatial memory; sustained attention; virtual; way finding

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.

项目概要摘要 学习障碍是胎儿酒精谱系儿童最常见的行为缺陷 紊乱（FASD）。目前，尚无合理的、临床有效的药物治疗方法 针对这些和相关行为缺陷的干预措施。然而，使用成熟的 FASD 大鼠模型， 我们观察到组胺 H3 受体反向激动剂 ABT-239 可改善产前酒精暴露 (PAE) 引起的齿状回长时程增强 (LTP) 和记忆保留缺陷。我们还有 观察到 H3 受体-效应器耦合增加以及 H3 受体介导的谷氨酸抑制增强 PAE 大鼠齿状回的释放。我们的结果表明 PAE 增加 H3 受体介导的抑制 谷氨酸释放，ABT-239 降低了这种增强的抑制影响。这些观察结果提供了 检查 H3 受体反向激动剂治疗学习和记忆功效的临床前原理 FASD 儿童的缺陷。该提案的临床前 UH2 阶段的工作假设是 SAR152954 是另一种组胺 H3 受体反向激动剂，将改善 PAE 诱导的行为和行为 通过逆转 PAE 诱导的谷氨酸活性依赖性增强作用的降低来治疗突触可塑性缺陷 发布。我们将首先检查四种不同剂量的 SAR152954 对 PAE 引起的缺陷的影响： 尝试情境恐惧调节（目标 1A）和使用莫里斯水迷宫保留空间记忆（目标 1B），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 的最佳测试剂量 (OTD)，以逆转 PAE 引起的 记忆缺陷。随后，我们将检查 SAR152954 的 OTD 剂量是否可以逆转 PAE 诱导的 齿状回 LTP（目标 2A）缺陷和谷氨酸水平活动依赖性增强的推定缺陷 位于齿状回（目标 2B）。目标 2 的里程碑目标将是展示这些问题的改善 神经生理学缺陷是推进 H3 受体临床前基本原理的机制基石 临床试验的反向激动剂。假设我们实现了临床前里程碑，我们将提交一年期的 请求资金来制定临床试验计划。我们的临床部门已经制定了计划的暂定草案 调查员小组。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 除了获取药代动力学和安全性数据外，Ib 期主要里程碑目标是 确定药物的最高安全剂量，对综合行为和行为产生显着改善 神经生理反应，使用 hdEEG/脑磁图测量。随后，在一个阶段 IIa临床试验，我们将使用双盲交叉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UH3 达到里程碑后，我们预计将进行后续更广泛的试验，以评估多中心的药物疗效 临床试验。