Abstract WP259: Acute Stroke Neuroprotection With Intravenous Rns60 In The Cynomolgus Macaque

Abstract

Introduction: RNS60 is an experimental therapy comprised of stable oxygenated nanobubbles in a sodium chloride solution with an oxygen content of 55+/-5 ppm. Phase I/II clinical trials established a safety profile for RNS60 in patients with ALS and MS. In-vitro assays in neurons have demonstrated mitochondrial biogenesis with RNS60. Therefore, we hypothesized that RNS60 would protect the ischemic penumbra and delay stroke evolution. In this study, we assessed RNS60 in a cynomolgus macaque (CM) model of transient middle cerebral artery occlusion (MCAO). Methods: Experimenters were blinded and CMs randomly allocated to treatment. In the first experiment, 22 male CMs (2.6+/-0.55 kg) were anesthetized with physiologic monitoring and MCAO followed by immediate MRI imaging to define perfusion deficit. RNS60 (5cc/kg/h IV over 1h followed by 2.5cc/kg/h for 48h) or drug vehicle were administered starting 1h following MCAO. MCA was reperfused 90min after MCAO. CMs underwent MRI diffusion-weighted (DWI) and T2 imaging at 48h and 30d after MCAO. Serial Non-Human Primate Stroke Scale (NHPSS) assessments were collected over 30 days following MCAO. In the second experiment, 10 male CMs (4.95+/-0.18 kg) underwent permanent MCAO. RNS60 or drug vehicle were infused starting 5 minutes after MCAO (5cc/kg/h IV for 1 hour followed by 2.5cc/kg/h until sacrifice). Perfusion and DWI MRI images were obtained serially over 6 hours to measure the evolution of the penumbra. CMs were sacrificed at the completion of the experiment. Results: DWI stroke volume was significantly reduced 4.3+/-1.1mL vs. 9.1+/-0.92mL (P=0.0036) at 48 hours post MCAO in RNS60 vs. placebo treated CMs. This result was conserved on T2 imaging at 30 days where stroke volume was 3.5+/-0.86mL vs. 7.3+/-0.79mL (P=0.004). RNS60 significantly improved NHPSS scores over 30 days compared to controls after removing three outlier CMs (2 mortalities and one non-reperfused MCA). The results of the second experiment demonstrated a 6h DWI volume of 5.9cc in RNS60 treated CMs compared to 10.6cc in controls. Conclusion: RNS60 administered during acute ischemic stroke significantly reduces stroke volume and improves functional outcomes in male CMs. The evolution of penumbra to stroke is slowed following RNS60 administration.