Abstract/Project Summary In this proposal, we outline our strategy to advance a novel preclinical therapy for the treatment of cortical injury. Our preliminary data in rodents and monkeys indicate that delivery of exosomes derived from bone marrow mesenchymal stem cells (MSCs) aid in functional recovery after cortical injury, likely through enhancement of cortical plasticity. We have gathered in vivo data showing that rats injected with exosomes derived from MSCs score better on behavioral tests for weeks after stroke than animals injected with vehicle control. In keeping with STAIR recommendations that treatments be tested in gyrencephalic animals, such as monkeys, we have begun testing exosomes derived from bone marrow MSCs in our non-human primate model (NHP) of cortical injury. Following injury to primary motor cortex, we administered exosomes and tested recovery in three monkeys. All three monkeys demonstrated functional recovery of fine motor function of the hand that represented a return to pre-injury type of grasp. It is important to note that our preliminary results with only 3 monkeys show an unprecedented level of recovery ? monkeys given exosomes showed a pattern and magnitude of fine motor recovery equivalent to a more complete, full recovery of individual digits. This is rarely observed in human patients post-stroke or TBI. These data show the feasibility of this treatment in monkeys and the importance of continued investigation of exosomes as a neuroregenerative treatment. We have previously submitted an expanded version of this proposal twice to NINDS as an R01 application. However, based on reviewer comments requesting that data on the role of exosomes in recovery of function in our model be obtained prior to launching a full-scale study, we now seek support for additional monkeys in order to produce this pilot data. Following the completion of the studies outlined in this proposal, we feel we would then be in a better position to submit a competitive R01 application in the future to conduct an extensive study of exosomes as a novel treatment in our NHP model of cortical injury. Accordingly, we propose two aims. In Aim 1, we will assess the functional recovery after exosome delivery in male and female aged monkeys. In Aim 2, we will measure the effects of exosomes on cortical plasticity by characterizing synaptic and network mechanisms underlying plasticity. This will be the first study to administer exosomes in a NHP model of cortical injury to investigate their role in mediating recovery of function and cortical plasticity. The study is highly translational, and the data gathered in this study will take a step toward developing a safe and translatable neurorestorative therapy.