Stroke affects more than 795, 000 patients per year in the US, kills approximately 140, 000 and is the single largestcause of expense for long-term medical care in the US. About 87% of strokes are ischemic, 40% of which are largevessel occlusions (LVO). Acute ischemic stroke (AIS) can be treated by restoring blood flow, e.g. by using the clot-busting drug t-PA for eligible patients. Recently, mechanical thrombectomy (MT) has emerged as standard of carefor LVO stroke. As MT is a specialized procedure, up to 60% of thrombectomy patients are first evaluated at spokehospitals and then transferred to a hub hospital for MT. The duration of time for patient transfer from the spoke tothe hub is variable and may be in excess of several hours. Reperfusion with tPA also takes time, usually severalhours for adequate blood flow to be obtained. A safe drug which maintained oxygenation within the at-risk regionin AIS could preserve the tissue until reperfusion is attained, thereby increasing the utility of reperfusion therapy.NuvOx Pharma is developing a novel oxygen therapeutic, NanO2TM (2% w/vol dodecafluoropentane emulsion). Inmultiple animal studies in stroke, NanO2 maintained the tissue viability in the penumbra and reduced the volumeof infarct by 85%. In a Phase Ib/II trial in AIS patients, NanO2 was safe at all dose levels (0.05, 0.10 & 0.17 mL/kg)administered 3 times 90 minutes apart and was shown to be efficacious. The high dose cohort had a significantimprovement compared to placebo in the functional end-point of the modified Rankin scale at 30 and 90 days (P =0.01 and P=0.03, respectively). NuvOx has an active IND for a Phase II trial called the PROVEN trial (Phase II toRestore Oxygen in LVO patients En Route for MT using NanO2). We hypothesize that early administration of NanO2to AIS patients will maintain viability of tissue in the penumbra until reperfusion can be attained.The NINDS has developed the Stroke Preclinical Assessment Network (SPAN) program to find neuroprotectiveagents to bring to the clinic. To make the NanO2 program competitive with these neuroprotectants in an applicationto NIH StrokeNet in the future, NuvOx must ensure the scientific rigor and reproducibility of our preclinical studiesmatch the standard of SPAN. Our preclinical data is promising, but lacks the inclusion of aged animals, othercomorbidities for stroke and long-term functional outcome measurements. In this Phase I STTR grantapplication, we propose to conduct studies of NanO2 in a transient middle cerebral artery occlusion(tMCAO) mouse model using the intraluminal filament technique. The study will be conducted in two phases, first in healthy mice to establish the model with less confounding variables followed by a second phase in agedmice and mice with comorbidities. Successful completion of the Aims of this study will fulfill the NIH's requirementfor rigor and reproducibility so that NanO2 can be considered as a candidate for clinical trials in StrokeNet andother organizations supported by NIH. PROJECT NARRATIVE
Stroke affects more than 795, 000 Americans each year, kills approximately 140, 000 and costs the US $34B per
year. NanO2TM is a novel oxygen therapeutic that has been shown preclinically to decrease acute ischemic
stroke damage by about 85%, but this data lacks the inclusion of aged animals, other comorbidities for stroke
and long-term functional outcome measurements. The proposed preclinical study using a transient middle
cerebral artery occlusion mouse model will address the gaps in the preclinical data for NanO2 so that the drug
can be further advanced clinically and be more competitive as a candidate for organizations supported by the
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