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

项目摘要 急性缺血性卒中（AIS）每年影响795，000名美国人，使90%的患者患有慢性残疾。 据估计，2017年美国AIS的流行病例为670万例，相当于600万美国人患有 中风导致的永久性残疾AIS的特征是脑血管阻塞， 形成中央梗死伴周围缺血半暗带;神经保护的目标是基于 半影保存的基本概念（也称为半影冻结）。目前，唯一获得批准的 AIS患者的治疗方法是1996年批准的溶栓药物阿替普酶（tPA）， 由于广泛的副作用，大量禁忌症限制了合格的患者人群， 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，带来了沿着改善的临床结果。血栓切除术的结果 可以通过挽救半影区神经元损失的神经保护疗法进一步改善。我们的团队已被 确定了一种在缺血性损伤后普遍激活的信号通路， 神经元程序性细胞死亡我们的主要神经保护，CM-EA 1，专门破坏这种神经细胞 死亡之路CM-EA 1正在被开发用于治疗患有AIS的患者，以防止神经元丢失。 缺血性半暗带，转化为患有AIS患者的残疾调整生命年（DAI）减少。 在本申请中，我们将通过严格的大鼠短暂大脑中动脉闭塞来证明疗效。 （tMCAO）剂量递增研究。在这些关键疗效研究之后，我们将把CM-EA 1推进到老年啮齿动物中。 模型和大型脑回动物在第二阶段的发展计划。我们的多学科团队 结合学术，临床和商业专业知识的独特组合， 一种改变AIS患者生活的药物。

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.