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

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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%:;(%"#+