Reducing Brain Injury After Focal Ischemia Using a Nitric Oxide-Neutral Oxygen Carrier

 描述(申请人提供)：大约一半的中风患者存在半影区，半影区的定义是紧邻缺血区周围的组织，由于血管闭塞，缺血区的血流受到影响。由于侧支血管提供了足够的氧气和营养以维持神经元结构，但不足以支持功能，半影区组织可能在缺血事件后几个小时内保持存活。随着中风发作后时间的推移，氧气供应的稀缺会导致半暗带组织梗塞，导致神经恶化。Omniox已经设计出一种安全的一流氧气载体(OMX)，可以改善中风后的脑氧合，保护缺氧半暗带组织内的神经元和神经胶质细胞网络的活性，从而改善神经功能。由于对维持中风患者半暗带生存能力的治疗有很高的需求，OMX是一个很有前途的候选治疗药物。在SBIR I期研究中，Omniox已成功实现根据卒中治疗学术行业圆桌会议(STAIR)和Rigor指南设定的里程碑：1)在大脑中动脉一过性和永久性闭塞(tMCAO和pMCAO)的卒中模型中，OMX在缺氧的脑区积聚；2)OMX渗透到犬卒中患者的大脑皮层；3)持续改善脑氧合和减少脑细胞死亡；4)防止脑梗塞扩大和长期增加神经元存活率；5)显著改善发病后至少一个月的老年大鼠的感觉运动功能。重要的是，OMX在存在半影区的tMCAO卒中模型中是有效的。因此，这些数据支持OMX在明确定义的患者群体中的临床翻译，在这种患者群体中，可以使用去除血栓和恢复血流的机械设备来挽救半影区组织。由于在大多数缺血性中风患者中检测到半暗带，OMX可能从根本上改变中风治疗的格局。这个第二阶段的提案建立在我们第一阶段数据的基础上，以进一步探索OMX的潜力，以惠及呈现可挽救半影区的扩大患者群体，以及完整的额外阶梯标准，以展示OMX的翻译潜力。为此，我们将在多个物种和卒中模型中测试OMX，这些模型具有不同的半影区和脑梗塞体积的时空分布，模拟一系列临床卒中情景，如：1)支持治疗不适合再通的患者的永久性闭塞模型(目标1)；2)基于血栓的模型以模拟患者使用IVtPA溶栓再通(目标2)；以及3)非人灵长类动物模型的暂时性闭塞模型，其具有适合纵向成像的大脑回脑，以模拟人脑的复杂性(目标3)。这些II期研究将指导未来临床试验的剂量、治疗窗口和患者群体的选择。机密(C)2015 Omniox，Inc.仅供审查之用。

 DESCRIPTION (provided by applicant): About half of stroke patients present with penumbra, defined as the tissue immediately surrounding an ischemic area in which blood flow is compromised due to vascular occlusion. The penumbra tissue may remain viable for several hours after an ischemic event due to collateral vessels that provide sufficient oxygen and nutrients to maintain neuronal structure but not enough to support function. As time elapses after stroke onset, the scarcity of oxygen supply causes the penumbra tissue to infarct, resulting in neurological deterioration. Omniox has engineered a safe first-in-class oxygen carrier (OMX) that improves brain oxygenation after stroke to preserve the neuronal and glial cell network viability within the oxygen-deprived penumbra tissue, resulting in the amelioration of neurological function. Because there is a high unmet need for therapeutics that preserve penumbra viability in stroke patients, OMX is a promising therapeutic candidate. In SBIR Phase I studies, Omniox has successfully achieved each of the milestones set out in accordance with the Stroke Therapy Academic Industry Roundtable (STAIR) and RIGOR guidelines demonstrating: 1) accumulation of OMX in the oxygen-deprived brain areas in stroke models of transient and permanent occlusion of the middle cerebral artery (tMCAO and pMCAO), 2) penetration of OMX into the brain parenchyma of the larger brain of a dog stroke patient; 3) sustained improvement of brain oxygenation and reduction of brain cell death; 4) prevention of infarct growth and long-term increase of neuronal survival; 5) significant amelioration of sensorimotor function in aged rats for at least a month after stroke onset. Importantly, OMX is efficacious in tMCAO stroke models in which penumbra exists. Therefore, these data support clinical translation of OMX in a well-defined patient population in which penumbra tissue can be salvaged using mechanical devices that remove the clot and restore blood flow. Since penumbra is detected in a majority of ischemic stroke patients, OMX could fundamentally change the landscape of stroke treatment. This Phase ll proposal builds upon our Phase I data to further explore the potential of OMX to benefit an expanded patient population presenting salvageable penumbra as well as complete additional STAIR criteria to demonstrate the translational potential of OMX. To do so, we will test OMX in multiple species and stroke models with varying spatio-temporal profiles of penumbra and infarct volume that mimic a range of clinical stroke scenarios such as: 1) a permanent occlusion model to support treating patients ineligible for recanalization (Aim 1), 2) a clot-based model to mimic thrombolytic recanalization with IV tPA in patients (Aim 2), and 3) a transient occlusion model in a non-human primate model with a large gyrencephalic brain suitable for longitudinal imaging to model the complexity of the human brain (Aim 3). These Phase II studies will guide the dose, therapeutic window, and selection of patient population for future clinical trials. CONFIDENTIAL (c)2015 Omniox, Inc. For review purposes only.