Safety and Efficacy of Intra-arterial Mesenchymal Stem Cell Therapy in an Endovascular Canine Model of Ischemic Stroke
Year: 2023
Type: preprint
Abstract: The safety and benefit of intra-arterial (IA) allogeneic Mesenchymal Stem Cells (MSCs) administered within 1-2 days of stroke in rodent models hold transformative potential for treating acute ischemic stroke (AIS). However, the lack of large animal studies of this approach is a significant gap in predicting success in human clinical trials, given the small size of the rodent brain and arterial vasculature and the lower white-to-gray-matter ratio. Another critical gap is the inability to extrapolate IA MSC dose ranges of MSCs and their therapeutic index from rodent models in a predictable manner. Here we employed an endovascular canine stroke model to evaluate the safety and efficacy of escalating IA doses of allogeneic MSCs at 10, and 40 million (m), and 80m MSCs versus phosphate buffer saline (PBS) controls. The IA MSC group showed safety on the primary endpoints of no worsening of neurological deficit and no new ischemia on imaging up to 40m dose. There was a significantly higher improvement in the treatment group in primary efficacy endpoints of neurological function and reduction in infarct volume on MRI and on the secondary endpoint of recovery of corticospinal tract caliber and fractional anisotropy on DTI compared to controls at 15- and 30-days post-stroke. A significant increase in neuronal survival was also seen in the IA MSC group vs the PBS control. Upon further dose escalation to 80m, there was worsened neurological score and worsened infarct at 4 days post-injection. Thus this study shows the safety and efficacy of IA MSCs over a dose range of 10-40m in a large animal model and its therapeutic index. In conclusion, these findings suggest a high translational success of IA allogeneic MSCs for AIS and provide critical information for the design of future clinical trials.
Source: Research Square
Authors: Dileep Yavagal, Roshni Thakkar, Luis Guada, Mitsuyoshi Watanabe, Karen Bates, Kengo Nishimura, Vasu Saini, Ami Raval, Pallab Bhattacharya, Diego Ojeda Pedraza, Amanda Torress, Phillip Garza, Kevin Ramdas, Charif Sidani, Aisha khan, Tatjana Rundek, Joshua Hare
Institutions: University of Miami, Jikei University School of Medicine, National Institute of Pharmaceutical Education and Research, National Institute of Pharmaceutical Education and Research, National Institute of Pharmaceutical Education and Research, National Institute of Pharmaceutical Education and Research, National Institute of Pharmaceutical Education and Research, National Institute of Pharmaceutical Education and Research
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4367679332