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.

项目摘要 急性缺血性中风（AIS）每年影响795,000名美国人，造成90％的慢性残疾患者。 2017年，美国的AIS普遍案件估计为670万，转化为600万美国人 永久性中风相关的残疾。 AI的特征是脑血管阻塞，导致 形成中央梗塞，周围的缺血性半阴茎；神经保护的目标是基于 半支出的基本概念（又名半身冻结）。目前，唯一的批准 患有AIS患者的治疗是溶栓剂Alteplase（TPA），于1996年批准并负担重 通过广泛的副作用，许多禁忌症限制了符合条件的患者人群，并且有限 治疗时间窗口。重要的是，过去的机械血栓切除术的使用已大大增加 十年，带来了改善的临床结果。有人强烈认为血栓切除术结局 可以通过神经保护疗法进一步改善，从而挽救了阴茎神经元丧失的神经元丧失。我们的团队有 鉴定出一种缺血性损伤后无普遍激活的信号通路，使得完成 神经元编程细胞死亡。我们的铅神经保护性CM-EA1特别破坏了该神经元细胞 死亡道路。正在开发CM-EA1来治疗患有AIS的患者，以防止神经元丧失 缺血性半衰期，转化为患有AIS患者的残疾调整后的寿命（Dalys）。 在此应用中，我们将通过严格的大鼠短暂性中大脑闭塞来证明功效 （TMCAO）剂量降低研究。遵循这些关键疗效研究，我们将把CM-EA1推向老化的啮齿动物 II期发展计划中的模型和大型沟渠动物。我们的多学科团队带来 将学术，临床和商业专业知识的独特结合在一起，将允许开发 AIS患者改变生活的药物。