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

 描述（由申请人提供）：大约一半的卒中患者存在半暗带，半暗带定义为紧邻缺血区域周围的组织，其中血流由于血管闭塞而受损。由于侧支血管提供足够的氧气和营养以维持神经元结构，但不足以支持功能，因此半暗带组织在缺血事件后可保持存活数小时。随着中风发作后时间的推移，氧气供应的缺乏导致半影组织梗死，导致神经功能恶化。 Omniox设计了一种安全的一流氧载体（OMX），可改善中风后的脑氧合，以保护缺氧半影组织内的神经元和神经胶质细胞网络活力，从而改善神经功能。由于对保留中风患者半影区活力的治疗方法的需求很高，因此OMX是一种有前途的治疗候选药物。在SBIR I期研究中，Omniox成功实现了根据卒中治疗学术行业圆桌会议（STAIR）和RIGOR指南设定的每个里程碑，证明：1）在大脑中动脉短暂性和永久性闭塞的中风模型中，OMX在缺氧脑区中的积聚（tMCAO和pMCAO），2）OMX渗透到狗中风患者的较大脑的脑实质中; 3）脑氧合的持续改善和脑细胞死亡的减少; 4）预防梗塞生长和长期增加神经元存活; 5）在中风发作后至少一个月内显著改善老年大鼠的感觉运动功能。 重要的是，OMX在存在半暗带的tMCAO卒中模型中有效。因此，这些数据支持OMX在明确定义的患者人群中的临床转化，在该患者人群中，可以使用去除凝块并恢复血流的机械器械挽救半暗带组织。由于在大多数缺血性卒中患者中检测到半暗带，OMX可能从根本上改变卒中治疗的前景。 该II期提案建立在我们的I期数据基础上，以进一步探索OMX的潜力，使出现可挽救半影区的扩大患者人群受益，并完成额外的STAIR标准，以证明OMX的转化潜力。为此，我们将在多个物种和中风模型中测试OMX，这些模型具有不同的半暗带和梗死体积的时空分布，模拟一系列临床中风场景，例如：1）永久性闭塞模型，以支持治疗不适合再通的患者（目标1），2）基于凝块的模型，以模拟患者中IV tPA溶栓再通（目标2），以及3）具有大的脑回的非人灵长类动物模型中的瞬态闭塞模型，其适于纵向成像以对人脑的复杂性建模（目的3）。 这些II期研究将指导未来临床试验的剂量、治疗窗和患者人群的选择。机密（c）2015 Omniox，Inc.仅供参考。

 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.