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通路，其中对DNA的过度氧化损伤导致聚（ADP-核糖）聚合酶（PARP）过度激活，然后刺激大型聚（ADP-核糖）聚合物的形成，从而诱导凋亡诱导因子（AIF）从外部miRochrane Membrocochrane诱导凋亡因子（AIF）释放。在细胞质中，AIF形成具有巨噬细胞迁移抑制因子（MIF）的复合物，该复合物将MIF降解DNA并产生细胞死亡的细胞核中。对文献的综述揭示了23个出版物，这些出版物支持parthanatos在年轻的雄性小鼠和受到瞬时和永久性脑动脉闭塞（MCAO）的大鼠中，基于使用9种不同的PARP抑制剂（19项研究）或13个不同实验室的9个不同的PARP1 NULL小鼠（6个研究）。几项研究表明，MCAO后4-6小时的治疗窗口。在年轻的雌性大鼠中，来自2个实验室的2项研究基于使用2种不同的PARP抑制剂来支持parthanatos的作用，而来自一个实验室的2项研究不支持在年轻的雌性PARP1 NULL小鼠中的作用。除了parthanatos介导的神经元细胞死亡外，文献表明，PARP抑制剂可以通过干扰小胶质细胞中的NFKB转录来降低神经炎症，从而抑制MMP-9释放，并限制了血脑屏障损伤和降低血液屏障损害和出血性转化。总体而言，大多数文献都强烈支持科学前提，即PARP抑制剂是神经保护剂，即使在MCAO之后再灌注时进行了神经保护。但是，没有对MCAO的研究测试了已知具有衰老免疫系统和性激素保护降低的老年动物的PARP抑制剂。由于人们认为老年动物与人类中风种群更具翻译相关，因此在进行临床中风试验之前，应在两性的老年动物中对PARP抑制剂进行测试。我们建议根据MCAO在老年男性和雌性小鼠的大脑渗透及其在人类肿瘤学试验中的既定安全性，在MCAO中进行PARP抑制剂Veliparib进行再灌注。我们计划的主要结果是在中风后一个月以上显示持续的赤字的触手可及的敏捷任务中的一个月表现。次要结果包括其他四项感觉运动任务中的短期缺陷，一个月的恐惧条件认知，一个月时的脑萎缩以及病变量的急性MRI确定，CBF和与组织pH图的DTI不匹配DTI。该团队由PI领导，具有30年的经验，在进行MCAO，神经科学家的临床前研究经验，他们在兴奋性和中风的模型中阐明了Parthanatos信号，这是一名中风临床医生，这是一名中风临床医生，在中风后在小鼠中进行神经行为的专业知识，在Streoke术后进行了25年的MR Scientist，在MR上进行了25年的经验，从事了新的模态和其他模态的经验，并具有新的模态，并具有新的模态，并具有新的模态，并具有新的模态，并具有新的模态，并具有新的模态，并具有新的模态，并且是一名新模态，并且是一名新模态，并且是一名脑中的MRIGING，并具有新的模态。啮齿动物中多模式MR成像的专业知识。该团队在实验性中风上合作有悠久的历史，并且通过作为六种候选药物的测试地点，可用于缺血性中风的再灌注疗法，以高度致力于SPAN任务的科学严谨性。