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Preclinical stroke trial with the PARP inhibitor veliparib

PARP 抑制剂 veliparib 的临床前卒中试验

基本信息

批准号：
10218283
负责人：
RAYMOND Charles KOEHLER
金额：
$ 46.21万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10218283
关键词：
Acute Animal Model Animals Blinded Blood - brain barrier anatomy Blood coagulation Blood flow Brain Brain imaging Cell Death Cell Death Signaling Process Cell Nucleus Cessation of life Clinical Trials Coagulation Process Cognition Cognitive Collaborations Complex Core-Binding Factor Cytolysis Cytosol DNA Data Disease Dose Enzyme Inhibitor Drugs Evaluation Excision Experimental Models Female Filament Gelatinase B Generations Genetic Transcription Gonadal Steroid Hormones Grant Hemorrhage Histologic Human Immune system Inflammation Inflammatory Inflammatory Response Injury Ischemic Stroke Knockout Mice Lesion Literature Logistics Magnetic Resonance Imaging Maps Measurement Mediating Microglia Middle Cerebral Artery Occlusion Migration Inhibitory Factor Mission Modality Modeling Mus Neurologic Deficit Neurological outcome Neurons Neuroprotective Agents Nuclear Translocation Outer Mitochondrial Membrane Patients Penetration Performance Perfusion Persons Pharmaceutical Preparations Phase Placebos Poly Adenosine Diphosphate Ribose Poly(ADP-ribose) Polymerases Polymers Population Process Protocols documentation Publications Randomized Rattus Recording of previous events Records Recovery Reperfusion Injury Reperfusion Therapy Reporting Research Personnel Review Literature Rodent Role Safety Scientist Sensorimotor functions Signal Pathway Signal Transduction Site Stroke Techniques Teleconferences Testing Therapeutic Thrombectomy Time Tissues Translations U-Series Cooperative Agreements United States National Institutes of Health Update aged apoptosis inducing factor base cancer clinical trial cerebral artery cerebral atrophy cognitive function cohort conditioned fear dexterity drug candidate drug testing efficacy evaluation efficacy testing endovascular thrombectomy excitotoxicity experience grasp improved improved outcome inhibitor/antagonist interest male meetings member mouse model multi-site trial multidisciplinary multimodality neurobehavior neuroinflammation neuron loss oncology trial oxidative damage post stroke pre-clinical pre-clinical assessment preclinical study primary outcome reproductive response restoration secondary outcome senescence sex stroke clinical trials stroke model stroke patient stroke trials success

项目摘要

Parthanatos is a cell death signaling pathway in which excessive oxidative damage to DNA leads to over- activation of poly(ADP-ribose) polymerase (PARP), which then stimulates the formation of large poly(ADP- ribose) polymers that induce the release of apoptosis-inducing factor (AIF) from the outer mitochondrial membrane. In the cytosol, AIF forms a complex with macrophage migration inhibitory factor (MIF) that translocates into the nucleus where the MIF degrades DNA and produces cell death. A review of the literature reveals 23 publications that support a role for parthanatos in young male mice and rats subjected to transient and permanent middle cerebral artery occlusion (MCAO) based on the use of 9 different PARP inhibitors (19 studies) or PARP1 null mice (6 studies) from 13 different labs. Several studies indicate a therapeutic window of 4-6 h after MCAO. In young female rats, 2 studies from 2 labs support a role for parthanatos based on the use of 2 different PARP inhibitors, whereas 2 studies from one lab do not support a role in young female PARP1 null mice. In addition to parthanatos-mediated neuronal cell death, a body of literature indicates that PARP inhibitors can reduce neuroinflammation by interfering with NFkB transcription in microglia, suppressing MMP- 9 release, and limiting blood-brain barrier damage and hemorrhagic transformation. Overall, most of the literature strongly supports the scientific premise that a PARP inhibitor is neuroprotective, even when it is given at reperfusion after MCAO. However, no studies of MCAO have tested PARP inhibitors in aged animals known to have a senescent immunologic system and diminished protection by sex hormones. Because aged animals are thought to be more translationally relevant for the human stroke population, a PARP inhibitor should be tested in aged animals of both sexes before moving into clinical stroke trials. We propose testing the PARP inhibitor veliparib at reperfusion after MCAO in aged male and female mice based on its good brain penetration and its established safety in human oncology trials. Our planned primary outcome is one-month performance on a reaching-to-grasp dexterity task known to display sustained deficits for over a month after stroke. Secondary outcomes include short-term deficits in four other sensorimotor tasks, fear conditioning cognition at one month, brain atrophy at one month, and acute MRI determinations of lesion volume, CBF, and mismatch of DTI with tissue pH maps. The team is led by a PI with 30 years of experience in performing preclinical studies of MCAO, neuroscientists who elucidated parthanatos signaling in models of excitotoxicity and stroke, a stroke clinician with expertise in neurobehavior testing in mice after stroke, an MR scientist with 25 years of experience in developing new modalities of brain imaging for use in stroke and other disorders, and a MR scientist with expertise in multimodal MR imaging in rodents. The team has a long history of collaborating together on experimental stroke and is highly dedicated to the scientific rigor of the SPAN mission by serving as a test site for six candidate drugs for adjunct use with reperfusion therapies in ischemic stroke.

Parthanatos 是一种细胞死亡信号传导途径，其中 DNA 过度氧化损伤导致聚（ADP-核糖）聚合酶（PARP）过度激活，然后刺激大聚（ADP-核糖）聚合物的形成，诱导线粒体外膜释放凋亡诱导因子（AIF）。在细胞质中，AIF 与巨噬细胞迁移抑制因子 (MIF) 形成复合物，巨噬细胞迁移抑制因子 (MIF) 易位到细胞核中，MIF 降解 DNA 并导致细胞死亡。文献综述显示，基于使用来自 13 个不同实验室的 9 种不同的 PARP 抑制剂（19 项研究）或 PARP1 无效小鼠（6 项研究），23 篇出版物支持 parthanatos 在遭受短暂性和永久性大脑中动脉闭塞 (MCAO) 的年轻雄性小鼠和大鼠中的作用。多项研究表明 MCAO 后 4-6 小时为治疗窗口。在年轻雌性大鼠中，来自 2 个实验室的 2 项研究支持基于使用 2 种不同 PARP 抑制剂的 parthanatos 的作用，而来自一个实验室的 2 项研究不支持在年轻雌性 PARP1 缺失小鼠中的作用。除了 parthanatos 介导的神经元细胞死亡之外，大量文献表明 PARP 抑制剂还可以通过干扰小胶质细胞中 NFkB 转录、抑制 MMP-9 释放以及限制血脑屏障损伤和出血性转化来减少神经炎症。总体而言，大多数文献强烈支持这样的科学前提：PARP 抑制剂具有神经保护作用，即使在 MCAO 后再灌注时给予也是如此。然而，尚无 MCAO 研究在已知免疫系统衰老且性激素保护减弱的老年动物中测试 PARP 抑制剂。由于老年动物被认为与人类中风人群的转化相关性更高，因此在进入临床中风试验之前，应在两种性别的老年动物中测试 PARP 抑制剂。基于 PARP 抑制剂 veliparib 良好的脑渗透性及其在人类肿瘤学试验中已确定的安全性，我们建议在老年雄性和雌性小鼠的 MCAO 后再灌注时测试 PARP 抑制剂 veliparib。我们计划的主要结果是在一个月内执行一项可抓握的灵活性任务的表现，已知该任务在中风后一个多月内会表现出持续的缺陷。次要结局包括其他四项感觉运动任务的短期缺陷、一个月时的恐惧条件性认知、一个月时的脑萎缩、以及急性 MRI 确定的病变体积、CBF 以及 DTI 与组织 pH 值图的不匹配。该团队由一位在 MCAO 临床前研究方面拥有 30 年经验的 PI 领导，一位在兴奋性毒性和中风模型中阐明了parthanatos 信号传导的神经科学家，一位在中风后小鼠神经行为测试方面具有专业知识的中风临床医生，一位在开发用于中风和其他疾病的新脑成像模式方面拥有 25 年经验的 MR 科学家，以及一位具有 25 年经验的 MR 科学家。啮齿动物多模态 MR 成像方面的专业知识。该团队在实验性中风方面有着悠久的合作历史，并高度致力于 SPAN 使命的科学严谨性，作为六种候选药物的测试场所，用于辅助缺血性中风再灌注治疗。