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

描述(申请人提供)：Omniox正在开发一种新的氧气输送疗法(H-NOX)，该疗法有可能极大地减少与中风相关的损害。在美国，中风导致的质量调整后损失的年数最多。在缺血性中风中，动脉闭塞会减少大脑的血液供应和氧气供应，导致组织死亡(脑梗塞)。H-NOX足够小，可以穿透过去的血管闭塞，可以给缺血组织充氧，并避免与先前测试的基于血红蛋白的氧气载体(HBOC)相关的毒性。因此，H-NOX代表了一种更安全的氧气载体，可能会彻底改变中风患者的治疗方法。对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，将氧合作用延伸到缺血和再灌流脑组织中的红细胞无法到达的地方。HBOCs在中风模型中表现出显著的疗效，显示梗死体积减少高达70%。然而，HBOC会引起患者不可接受的副作用，因为它们与一氧化氮(NO)具有很高的化学反应活性，NO是一种基本的心肌、肾脏和血管调节物质。HBOC会导致心血管功能障碍、肾脏毒性、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的监管批准。Omniox的H-NOX氧载体不与NO反应，与聚合物HBOC相比，到目前为止没有显示出心血管、肾脏或高血压毒性。对缺血创面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使其氧化。在这项提案中，已被证明能氧化缺血组织的H-NOX单体将被三聚化，以增加其循环半衰期，以延长脑氧合。将评估三聚体穿透缺血脑组织和缓解缺血的能力。疗效将在建立良好的中风模型中进行测试，以量化脑梗塞体积的减少和神经功能的保护。 公共卫生相关性：Omniox已经开发出一种氧气输送疗法，有可能减少急性中风后神经元的死亡，而不会出现与基于血红蛋白的氧气载体(HBOC)相关的戏剧性毒性。这种携氧蛋白体积小(与渗入脑组织的60-150 kDa的HBOC相当)，具有氧亲和力，使其能够在缺血的脑组织中释放氧气，并且没有与血红蛋白为基础的氧载体相关的NO相关毒性。这项提案将把Omniox的H-NOX氧气输送平台发展成为符合作为治疗急性中风的新制剂获得批准的必要标准的领先候选平台。！“#$%&‘#(%)*+”，-./01+%-23+4+5677+#“(+$”8+&%9(8%：；(%“#+

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%:;(%"#+