Abstract 2818: Safety, Feasibility and Signal of Activity of Intra-carotid Allogenic Mesenchymal Stem Cell therapy in a Large Animal Stoke Model

Abstract

INTRODUCTION: Promising pre-clinical data shows benefits of intra-carotid allogenic mesenchymal stem cell (MSCs) therapy in ischemic stroke (IS) in small animal stroke models. Intra-carotid (IC) delivery of MSCs may be superior to intravenous (IV) delivery. However, due to the large size (15-50 microns) of MSCs, there is a concern that they may cause microvascular occlusion during IC administration. There is a need for large animal experiments to confirm positive results in small animal models as has been recommended by STAIR and STEPS consortia. HYPOTHESIS: We tested the hypothesis that IC administration of allogeneic mesenchymal stem cells (MSCs) is feasible and safe in a large animal (canine) stroke model.. METHODS: We performed 1-3 hrs of reversible middle cerebral artery occlusion (rMCAo), in10 female mongrel dogs weighing 40-60 lbs, using an endovascular retrievable coil occlusion of the MCA with a transfemoral arterial approach. At 1 - 72 hrs after rMCAo, animals were assigned to the following treatment groups: A. IC saline placebo (saline) or B. IC allogeneic MSCs or C. IV allogeneic MSCs. Primary outcome measures were: development of angiographic occlusion post-IC MSC or saline infusion, change in MRI infarct volume or new ischemic lesions, and neurological deficit score (NDS) at 4 weeks. Dosing of MSCs was based on extrapolated maximum tolerated dose calculated in a rat study of IC MSCs in our laboratory. RESULTS: Successful IC administration of MSCs was possible in all animals assigned to the treatment group. Animals receiving IC MSCs at 1× 10^6 or 10 × 10^6 (n=6) there were no clinical adverse events or neurological worsening during or 4 weeks post treatment. There were no angiographic decreases in flow or occlusions during or after IC MSC delivery. In the two animals with additional TCD monitoring during IC MSC delivery there were no changes in flow velocity or HITS signals indicating emboli. There was no worsening in MRI infarct volume ( Fig 1 .) amongst the IC MSC groups. A dramatic decrease in infarct volume was noted, in 2 animals in the IC MSC group with minimal infarct related atrophy at one month. None of the animals in the IV MSC or IC saline groups (n=2 in each group) showed a significant change in MRI infarct volume, and major infarct related atrophy was noted. CONCLUSION: IC MSC administration in a large animal rMCAo model is feasible & safe. Fig1 : In vivo coronal MRI FLAIR sequences in IC delivery of MSCs in canine stroke model. There is a signal of biologic activity seen with IC MSC delivery. A. Baseline infarct at 48 hours after rMCAo. B. Infarct evolution at 29 days after IC administration of 10×10^6 MSCs.