A Novel Targeted Therapy for Subarachnoid Hemorrhage

蛛网膜下腔出血的新型靶向治疗

基本信息

批准号：
10385590
负责人：
Kalidip Choudhury
金额：
$ 25.64万
依托单位：
LOXAGEN INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10385590
关键词：
12-HETE ALOX15 gene Age Alcoholism Aneurysmal Subarachnoid Hemorrhages Animals Arachidonate 15-Lipoxygenase Arachidonic Acids Behavioral Blood Blood - brain barrier anatomy Brain Brain Edema Brain Injuries Brain Pathology Calcium Channel Blockers Canis familiaris Cause of Death Cell Death Cerebral Aneurysm Cerebral Ischemia Cerebrovascular Spasm Dose Enzymes Extravasation Family Female Goals Hemorrhage High Pressure Liquid Chromatography Human Hydroxyeicosatetraenoic Acids Hypertension Injections Interleukin-6 Investigation Ischemic Stroke Knockout Mice Lead Legal patent Lipoxygenase Lipoxygenase Inhibitors Mass Spectrum Analysis Measures Mediating Mus Neurologic Deficit Neurological outcome Neurons Nimodipine Operative Surgical Procedures Outcome Parents Pathway interactions Patients Pharmaceutical Preparations Pharmacological Treatment Phase Phase I Clinical Trials Play Population Publishing Recording of previous events Risk Risk Factors Rodent Role Rupture Small Business Innovation Research Grant Smoking Stains Stroke Subarachnoid Hemorrhage Subarachnoid Space Survivors Testing Therapeutic Time Toxic effect United States Work aged behavioral outcome disability efficacy testing functional outcomes improved in vivo inflammatory marker inhibitor knockout gene macrophage male mortality mouse model neuron loss neuroprotection new therapeutic target novel novel therapeutics overexpression pharmacokinetics and pharmacodynamics prevent public health relevance sham surgery standard of care

12-HETE ALOX15 gene Age Alcoholism Aneurysmal Subarachnoid Hemorrhages Animals Arachidonate 15-Lipoxygenase Arachidonic Acids Behavioral Blood Blood - brain barrier anatomy Brain Brain Edema Brain Injuries Brain Pathology Calcium Channel Blockers Canis familiaris Cause of Death Cell Death Cerebral Aneurysm Cerebral Ischemia Cerebrovascular Spasm Dose Enzymes Extravasation Family Female Goals Hemorrhage High Pressure Liquid Chromatography Human Hydroxyeicosatetraenoic Acids Hypertension Injections Interleukin-6 Investigation Ischemic Stroke Knockout Mice Lead Legal patent Lipoxygenase Lipoxygenase Inhibitors Mass Spectrum Analysis Measures Mediating Mus Neurologic Deficit Neurological outcome Neurons Nimodipine Operative Surgical Procedures Outcome Parents Pathway interactions Patients Pharmaceutical Preparations Pharmacological Treatment Phase Phase I Clinical Trials Play Population Publishing Recording of previous events Risk Risk Factors Rodent Role Rupture Small Business Innovation Research Grant Smoking Stains Stroke Subarachnoid Hemorrhage Subarachnoid Space Survivors Testing Therapeutic Time Toxic effect United States Work aged behavioral outcome disability efficacy testing functional outcomes improved in vivo inflammatory marker inhibitor knockout gene macrophage male mortality mouse model neuron loss neuroprotection new therapeutic target novel novel therapeutics overexpression pharmacokinetics and pharmacodynamics prevent public health relevance sham surgery standard of care

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项目摘要

Summary The goal of this project is to develop a therapeutic capable of treating subarachnoid hemorrhage (SAH), a severe form of stroke characterized by bleeding into the subarachnoid space. Around 30,000 cases of spontaneous SAH occur in the US population every year. They are typically caused by a ruptured cerebral aneurysm, whose risk factors include, high blood pressure, smoking, family history and alcoholism. Aneurysmal SAH is associated with high mortality: 50% of patients die within 30 days, and of the survivors many retain neurological deficits. We have recently shown that the lipoxygenase ALOX15 is increased in macrophages adjacent to the subarachnoid blood in a mouse model of SAH, contributing to early brain injury. SAH induced brain edema was ALOX15 dependent and ALOX15 gene knockout reduced neuronal cell death and improved behavioral outcome. Loxagen’s lead compound, BPN-27332, selectively inhibits ALOX15 with high potency (IC50 = 80 nM) and can reduce neuronal cell death and improve neurological outcome after SAH. In this project, we will pursue the following aims: Aim 1: Synthesize sufficient amounts of BPN-27332 to support in vivo studies. Aim 2: Determine the most effective dose, confirm target engagement by lowering ALOX15 product and determine the optimal time window for treatment. These results will allow us to apply for a Phase II SBIR where we will expand our investigations and develop BPN-27332 as novel therapeutic to treat the brain injury resulting from subarachnoid hemorrhage.

概括该项目的目的是开发能够治疗亚蛛网膜下腔出血的治疗性（SAH），一种严重的中风形式，其特征是蛛网膜下腔出血。大约每年在美国人口中发生30,000例赞助SAH。他们通常是由脑动脉瘤破裂引起的，其危险因素包括高血压，吸烟，家族史和酗酒。动脉瘤SAH与高死亡率有关：50％患者在30天内死亡，并且在许多人表面上保留了神经系统缺陷。我们有最近表明，在与 SAH小鼠模型中的蛛网膜下腔血液，导致早期脑损伤。 SAH引起的脑水肿为ALOX15依赖性，ALOX15基因敲除降低神经元细胞死亡并改善行为结果。 Loxagen的铅化合物BPN-27332有选择地抑制具有高效力的ALOX15（IC50 = 80 nm），可以减少神经元细胞死亡并改善 SAH后的神经系统结果。在这个项目中，我们将追求以下目标：目标1：合成足够数量的BPN-27332来支持体内研究。目标2：确定最有效的剂量，通过降低Alox15产品来确认目标参与并确定最佳治疗时间窗口。这些结果将使我们能够申请II期SBIR 我们将在其中扩展调查并开发BPN-27332作为治疗的新疗法蛛网膜下腔出血引起的脑损伤。