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

描述（由申请人提供）：Omniox正在开发一种新的氧输送治疗（H-NOX），具有显着减少中风相关损伤的潜力。在美国，中风造成的质量调整年损失是最多的。在缺血性中风中，动脉闭塞减少了大脑的血液供应和氧气，导致组织死亡（梗死）。H-NOX足够小，可以穿透过去的血管闭塞，可以为缺血组织充氧，并避免与先前测试的基于血红蛋白的氧载体（hboc）相关的毒性。因此，H-NOX代表了一种更安全的氧载体，可以彻底改变中风患者的治疗方法。HBOCs的临床前研究已经证实，小蛋白可以穿透闭塞的动脉和缺血半暗带，将缺血和再灌注脑组织中的氧合扩展到红细胞无法到达的地方。hboc在脑卒中模型中表现出显著的疗效，显示梗死面积减少高达70%。然而，由于hboc与一氧化氮（NO）（一种重要的心肌、肾脏和血管调节剂）具有高度的化学反应性，因此会对患者产生不可接受的副作用。hboc会引起心血管功能障碍、肾毒性、高血压和一系列其他严重的副作用，这些副作用已经停止了FDA对其的监管批准。Omniox的H-NOX氧载体不与NO反应，与聚合HBOC相比，迄今为止没有显示出心血管、肾脏或高血压毒性。缺血伤口和缺氧肿瘤的初步体内研究表明，H-NOX单体可以穿透组织并充氧。在这一建议中，已被证明氧合缺血组织的H-NOX单体将被三聚体化，以延长其循环半衰期，延长脑氧合。该三聚体将评估其穿透缺血性脑组织和缓解缺血的能力。疗效将在一个完善的卒中模型中进行测试，以量化脑梗死体积的减少和神经功能的保存。

DESCRIPTION (provided by applicant): Omniox is developing a new oxygen delivery therapeutic (H-NOX) that has the potential to dramatically reduce the damage associated with stroke. Stroke causes the largest number of quality-adjusted years lost in the U.S. In ischemic stroke, arterial occlusion reduces blood supply and oxygen to the brain, leading to tissue death (infarction). H-NOX is small enough to penetrate past vascular occlusions, can oxygenate ischemic tissue, and avoids toxicities associated with previously tested hemoglobin-based oxygen carriers (HBOCs). Thus, H-NOX represents a safer oxygen carrier that could revolutionize therapy for stroke patients. Preclinical studies with HBOCs have established that small proteins can penetrate the occluded artery and the ischemic penumbra to extend oxygenation beyond the reach of red blood cells in ischemic and reperfused brain tissue. HBOCs exhibit remarkable efficacy in stroke models, showing reductions in infarct volume up to 70%. However, HBOCs cause unacceptable side effects in patients due to their high chemical reactivity with nitric oxide (NO), an essential myocardial-, renal- and vaso-regulator. HBOCs induce cardiovascular dysfunction, renal toxicity, hypertension, and a range of other serious side effects that have halted their regulatory approval by the FDA. Omniox' class of H-NOX oxygen carriers are not reactive with NO and to date show no cardiovascular, renal or hypertensive toxicities when compared with a polymeric HBOC. Preliminary in vivo studies in ischemic wounds and hypoxic tumors show that H-NOX monomers can penetrate and oxygenate tissue. In this proposal, H-NOX monomers that have been shown to oxygenate ischemic tissue will be trimerized to increase their circulation half-life for extended brain oxygenation. The trimers will be evaluated for their ability to penetrate into ischemic brain tissu and relieve ischemia. Efficacy will be tested in a well-established model of stroke to quantify reduction in brain infarct volume and preservation of neurological function. PUBLIC HEALTH RELEVANCE: Omniox has developed an oxygen delivery therapeutic that has the potential to reduce neuronal death after an acute stroke, without the dramatic toxicities associated with hemoglobin-based oxygen carriers (HBOCs). The oxygen-carrying protein is small in size (comparable to HBOCs of 60-150 kDa that extravasate into cerebral tissue), has an oxygen affinity allowing it to release oxygen in ischemic brain tissue, and has none of the NO- related toxicities associated with hemoglobin-based oxygen carriers. This proposal will develop Omniox' H- NOX oxygen delivery platform into a lead candidate that meets the necessary criteria for approval as a new agent in the treatment of acute stroke. !"#$%&'#(%)*+ ",-./01+%-23+4+5677+ #"(+$"8+&%9(8%:;(%"#+