A Novel Targeted Therapy for Subarachnoid Hemorrhage

蛛网膜下腔出血的新型靶向治疗

• 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
• 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

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.

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