NanO2 as a Cerebroprotectant in a tMCAO Stroke Model in Mice

点击翻译按钮获取中文摘要

PROJECT SUMMARY/ABSTRACT Stroke affects more than 795,000 patients per year in the US, kills approximately 140,000 and is the single largest cause of expense for long-term medical care in the US. About 87% of strokes are ischemic, 40% of which are large vessel 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 care for LVO stroke. As MT is a specialized procedure, up to 60% of thrombectomy patients are first evaluated at spoke hospitals and then transferred to a hub hospital for MT. The duration of time for patient transfer from the spoke to the hub is variable and may be in excess of several hours. Reperfusion with tPA also takes time, usually several hours for adequate blood flow to be obtained. A safe drug which maintained oxygenation within the at-risk region in 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). In multiple animal studies in stroke, NanO2 maintained the tissue viability in the penumbra and reduced the volume of 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 significant improvement 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 to Restore Oxygen in LVO patients En Route for MT using NanO2). We hypothesize that early administration of NanO2 to 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 neuroprotective agents to bring to the clinic. To make the NanO2 program competitive with these neuroprotectants in an application to NIH StrokeNet in the future, NuvOx must ensure the scientific rigor and reproducibility of our preclinical studies match the standard of SPAN. Our preclinical data is promising, but lacks the inclusion of aged animals, other comorbidities for stroke and long-term functional outcome measurements. In this Phase I STTR grant application, 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 aged mice and mice with comorbidities. Successful completion of the Aims of this study will fulfill the NIH’s requirement for rigor and reproducibility so that NanO2 can be considered as a candidate for clinical trials in StrokeNet and other organizations supported by NIH.