Kv2.1-Targeted First in Class Neuroprotective Therapeutic for Acute Ischemic Stroke

Kv2.1 靶向急性缺血性中风的一流神经保护疗法

• 批准号: 10598185
• 负责人: Julie H Coleman
• 金额: $ 23.2万
• 依托单位: CELDARA MEDICAL, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598185
• 关键词: Acceleration; Acute; Adverse effects; Alteplase; Alzheimer' s Disease; American; Animal Model; Animals; Brain Infarction; Cell Death; Cell Death Induction; Chronic; Climacteric; Clinical; Cytoplasm; Data; Development; Dose; Eligibility Determination; FDA approved; Fibrinolytic Agents; Freezing; Frequencies; Funding; Goals; Guidelines; Health; Industry; Infarction; Intervention; Investments; Ischemia; Ischemic Penumbra; Ischemic Stroke; Kv2.1 channel; Laboratories; Lead; Maximum Tolerated Dose; Measures; Mechanics; Middle Cerebral Artery Occlusion; Modeling; National Institute of Neurological Disorders and Stroke; Nerve Degeneration; Neurologic; Neurological status; Neurons; Neuroprotective Agents; Outcome; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Phase; Potassium; Potassium Channel Blockers; Pre-Clinical Model; Production; Program Development; Radiology Specialty; Rattus; Reproducibility; Rodent; Rodent Model; Salvage Therapy; Signal Pathway; Signal Transduction; Solubility; Stroke; Therapeutic; Thrombectomy; Time; Toxic effect; Translating; Traumatic Brain Injury; Validation; Work; aged; cerebrovascular; clinically relevant; delayed rectifier potassium channel; disability; disability-adjusted life years; economic cost; economic impact; efficacy study; follow-up; improved; improved outcome; in vitro activity; ischemic injury; mouse model; multidisciplinary; nervous system disorder; neuron apoptosis; neuron loss; neuroprotection; novel; patient population; phase 1 study; pre-clinical; pre-clinical assessment; preservation; prevent; programs; response; side effect; stroke model; stroke patient; stroke therapy

Project Summary Acute ischemic stroke (AIS) impacts 795,000 Americans per year, leaving 90% of patients with chronic disability. Prevalent cases of AIS in the US were estimated at 6.7M in 2017, translating to 6M Americans living with permanent stroke-related disability. AIS is characterized by cerebrovascular blockage that results in the formation of a central infarct with a surrounding ischemic penumbra; the goal for neuroprotection is based on the fundamental concept of penumbral preservation (a.k.a. penumbral freezing). Currently, the only approved therapy for patients suffering from AIS is the thrombolytic agent alteplase (tPA), approved in 1996 and burdened by expansive side effects, a host of contraindications restricting eligible patient populations, and a limited therapeutic time window. Importantly, the use of mechanical thrombectomy has drastically increased in the past decade, bringing along improved clinical outcomes. It has been strongly argued that thrombectomy outcomes can be further improved by neuroprotective therapies that salvage neuronal loss in the penumbra. Our team has identified a signaling pathway that is ubiquitously activated following ischemic injury, enabling the completion of neuronal programmed cell death. Our lead neuroprotective, CM-EA1, specifically disrupts this neuronal cell death pathway. CM-EA1 is being developed to treat patients suffering from AIS, to prevent neuronal loss in the ischemic penumbra, translating to decreased disability-adjusted life years (DALYs) for patient suffering from AIS. In this application, we will demonstrate efficacy via a rigorous rat transient middle cerebral artery occlusion (tMCAO) dose-escalation study. Following these key efficacy studies, we will advance CM-EA1 to aged rodent models and large gyrencephalic animals in a Phase II development program. Our multidisciplinary team brings together a unique combination of academic, clinical and commercial expertise that will permit the development of a life-changing drug for AIS patients.

项目概要 急性缺血性中风 (AIS) 每年影响 795,000 名美国人，其中 90% 的患者患有慢性残疾。 2017 年，美国 AIS 流行病例估计为 670 万例，也就是说有 600 万美国人患有此病 与中风相关的永久性残疾。 AIS 的特点是脑血管阻塞，导致 形成中央梗塞，周围有缺血半暗带；神经保护的目标基于 半影保存（又名半影冻结）的基本概念。目前，唯一获批的 AIS 患者的治疗方法是溶栓剂阿替普酶 (tPA)，于 1996 年获得批准并负担 由于广泛的副作用、限制符合条件的患者群体的一系列禁忌症以及有限的 治疗时间窗。重要的是，机械血栓切除术的使用在过去急剧增加 十年来，带来了更好的临床结果。人们强烈认为血栓切除术的结果 可以通过挽救半暗带神经元损失的神经保护疗法进一步改善。我们的团队有 确定了缺血性损伤后普遍激活的信号通路，从而能够完成 神经元程序性细胞死亡。我们的主要神经保护剂 CM-EA1 专门破坏这种神经元细胞 死亡途径。 CM-EA1 正在开发用于治疗 AIS 患者，以防止大脑中的神经元损失 缺血半暗带，意味着 AIS 患者的伤残调整生命年 (DALY) 减少。 在此应用中，我们将通过严格的大鼠短暂大脑中动脉闭塞来证明功效 (tMCAO) 剂量递增研究。在这些关键功效研究之后，我们将把 CM-EA1 推广到老年啮齿动物身上 第二阶段开发计划中的模型和大型环脑动物。我们的多学科团队带来 学术、临床和商业专业知识的独特组合将允许开发 一种改变 AIS 患者生活的药物。