Repurposing of KCa3.1 Inhibitor Senicapoc for Stroke: A Pre-clinical Study

KCa3.1 抑制剂 Senicapoc 治疗中风的再利用：临床前研究

• 批准号: 10463846
• 负责人: JONATHAN R WEINSTEIN
• 金额: $ 39.15万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10463846
• 关键词: 3-Dimensional; Ablation; Acute; Animals; Asthma; Attenuated; Biological Markers; Brain; Brain Injuries; Calcium-Activated Potassium Channel; Cause of Death; Cells; Central Nervous System Diseases; Cerebral Edema; Cerebrovascular Circulation; Clinical; Clinical Data; Clinical Trials; Cognitive; Cyclic GMP; Data; Dose; Drug Kinetics; Effector Cell; Evaluation; Flow Cytometry; Foundations; Functional disorder; Funding; Future; Genetic; Goals; High Pressure Liquid Chromatography; Human; Immune; Immunoassay; In Vitro; Infarction; Inflammatory; Injury; Institutes; Intellectual Property; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Macrophage Activation; Magnetic Resonance Imaging; Mass Spectrum Analysis; Measures; Mediating; Microglia; Microscopy; Middle Cerebral Artery Occlusion; Mitochondria; Modeling; Morbidity - disease rate; Motor; Mus; Neuroimmune; Outcome; Patients; Penetrance; Perfusion; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phase III Clinical Trials; Phenotype; Plasma; Play; Positron; Positron-Emission Tomography; Proteins; Quantitative Microscopy; Rattus; Recovery; Reperfusion Therapy; Reporting; Research; Research Personnel; Rodent; Role; Safety; Secure; Sensory; Sickle Cell Anemia; Stroke; Technology; Therapeutic; Therapeutic Intervention; Time; Traction; United States National Institutes of Health; Wild Type Mouse; appropriate dose; cell type; chemokine; clinical development; comorbidity; cytokine; drug repurposing; efficacy evaluation; emission spectroscopy; hypertensive; improved; in vivo; industry partner; inhibitor; injury recovery; ischemic injury; liquid chromatography mass spectroscopy; macrophage; neurobehavioral; neurobehavioral test; neurocognitive test; neuroimaging; neuroimmunology; neuroinflammation; neurological recovery; novel therapeutics; pharmacodynamic biomarker; post stroke; pre-clinical; preclinical study; radioligand; response; sex; stroke model; stroke therapy; tractography; translational health science; white matter; young adult

The concept of drug repurposing refers to the evaluation and use of existing drugs, as well as failed, abandoned, or not yet pursued clinical development candidates, for new clinical indications. This idea has gained increasing traction in recent years including for CNS disorders such as stroke. Microglia (MG), the resident immune cells of the CNS, and infiltrating macrophages (MP) are critical in ischemic brain injury. Modulating the MG/MP phenotype is a promising avenue for developing novel therapeutics for stroke. KCa3.1 is a calcium activated potassium channel that is highly expressed in reactive MG/MP. Prior studies using either genetic deletion or pharmacologic ablation of KCa3.1 have demonstrated that it contributes to neuroinflammation and exacerbation of post-stroke injury. Senicapoc is a KCa3.1-specific inhibitor that has been used in human clinical trials for non- neurological indications. The drug has a proven safety record and there is substantial pharmacokinetic (PK), pharmacodynamic (PD) and cell type specific expression data completed and available on this agent. The goals of the R61 phase of this proposal are: (1) Quantify senicapoc's PK profile specifically in the setting of stroke (mouse transient middle cerebral artery occlusion/reperfusion model) and identify an optimal dosing and temporal administration paradigm for ischemic brain injury, (2) Determine the efficacy of senicapoc in reducing stroke-induced brain injury in young adult wild-type mice using cutting-edge neuroimaging technology as well as sensory-motor, neurobehavioral and cognitive longitudinal assessments and (3) Determine senicapoc's PD profile and quantify the drug's CNS target engagement using state-of-the-art neuroimmunology biomarkers. PK assessments will include quantifying total and free levels of senicapoc in brain and plasma using HPLC/mass spectroscopy. In addition we will quantify levels of pro-inflammatory cytokines and chemokines using immunoassays. Efficacy assessments will include multiparametric 14 T MRI to quantify infarct volume (DWI/T2), cerebral edema (T2/FLAIR) and white matter integrity (DTI/tractography). Sensory-motor, neurobehavioral and cognitive measures will include both observational and dynamic assessments. For PD studies, we will examine the effect of senicapoc on stroke-induced changes in the neuroimmune response in vivo using MG/MP-targeted TSPO-radioligand and positron emission spectroscopy (PET) as well as ex vivo studies using flow cytometry and immunofluorescent microscopy. For the R33 phase of the project, we will determine if senicapoc's efficacy and PD profiles in stroke are altered: (i) in mice by age and/or sex and (ii) in spontaneously hypertensive, co- morbid rats. Overall, these studies will provide a comprehensive assessment of the ability of senicapoc to influence stroke-induced changes in the CNS and provide a scientific foundation for future clinical trials assessing both drug (senicapoc) and target (KCa3.1).

药物再利用的概念是指对现有药物以及失败、废弃、 或尚未进行临床开发的候选者，用于新的临床适应症。这个想法得到了越来越多的关注 近年来牵引包括中风等中枢神经系统疾病。小胶质细胞 (MG)，常驻免疫细胞 中枢神经系统和浸润巨噬细胞 (MP) 在缺血性脑损伤中至关重要。调制 MG/MP 表型是开发中风新疗法的一个有前途的途径。 KCa3.1 是一种钙激活剂 钾通道在反应性 MG/MP 中高度表达。先前的研究使用基因删除或 KCa3.1 的药物消融已证明它会导致神经炎症和恶化 中风后损伤。 Senicapoc 是一种 KCa3.1 特异性抑制剂，已用于人体临床试验，用于治疗非 神经系统指征。该药物具有经过验证的安全记录，并且有显着的药代动力学（PK）， 该药物的药效学 (PD) 和细胞类型特异性表达数据已完成并可用。目标 该提案 R61 阶段的主要内容是： (1) 量化 senicapoc 的 PK 特征，特别是在中风的情况下 （小鼠短暂大脑中动脉闭塞/再灌注模型）并确定最佳剂量和 缺血性脑损伤的时间给药范例，（2）确定 senicapoc 在减少 使用尖端神经影像技术以及 感觉运动、神经行为和认知纵向评估以及 (3) 确定 senicapoc 的 PD 使用最先进的神经免疫学生物标志物来分析和量化药物的中枢神经系统靶点参与。 PK 评估将包括使用 HPLC/质谱定量脑和血浆中千尼卡波克的总水平和游离水平 光谱学。此外，我们将使用以下方法量化促炎细胞因子和趋化因子的水平 免疫测定。疗效评估将包括量化梗塞体积 (DWI/T2) 的多参数 14 T MRI， 脑水肿（T2/FLAIR）和白质完整性（DTI/纤维束成像）。感觉运动、神经行为和 认知测量将包括观察评估和动态评估。对于 PD 研究，我们将检查 使用 MG/MP 靶向研究 senicapoc 对中风引起的体内神经免疫反应变化的影响 TSPO-放射性配体和正电子发射光谱 (PET) 以及使用流式细胞术的离体研究 和免疫荧光显微镜。对于该项目的 R33 阶段，我们将确定 senicapoc 的功效是否 中风中的 PD 特征发生改变：(i) 小鼠中因年龄和/或性别而改变；(ii) 自发性高血压、共存性高血压 病态的老鼠。总体而言，这些研究将对 senicapoc 的能力进行全面评估 影响中风引起的中枢神经系统变化，为未来的临床试验评估提供科学基础 药物（senicapoc）和靶标（KCa3.1）。

项目成果

Repurposing the KCa3.1 Blocker Senicapoc for Ischemic Stroke.

重新利用 KCa3.1 阻滞剂 Senicapoc 治疗缺血性中风。

• 发表时间: 2023-04-24
• 影响因子: 6.9
• 作者: Lee, Ruth D;Chen, Yi;Nguyen, Hai M;Singh, Latika;Dietrich, Connor J;Pyles, Benjamin R;Cui, Yanjun;Weinstein, Jonathan R;Wulff, Heike
• 通讯作者: Wulff, Heike