Regenerative Neural Stem Cell Therapy Improves Multidomain Neurological Deficits after Traumatic Brain Injury in Nonhuman Primates

Traumatic brain injury (TBI) produces persistent multidomain disability spanning motor, cognitive, emotional and sleep-wake function, with no approved restorative therapy. Here, we tested pd.S6.133.hNSC, a cryopreserved, GMP-like human neural stem cell (hNSC) product derived from Shef-6 and FACS-sorted on CD133+/CD34-, in a randomized dose-ranging study in common marmosets subjected to controlled cortical impact (n = 18). Seven weeks after injury, animals received MRI-guided stereotactic transplantation into perilesional cortex bilaterally under tacrolimus immunosuppression, with either vehicle or pd.S6.133.hNSC at 1 million (1e6) or 5 million (5e6) cell dose. At 3 months post-transplantation, 5e6 dosage improved executive and problem-solving performances (Object Retrieval Task with Barrier Detour), gait dynamics (CatWalk assay), anxiety-like behavior (Human Intruder Test), and actigraphy-derived sleep-wake and circadian rhythm measures relative to vehicle and 1e6 dose. Longitudinal 7T MRI demonstrated a dose-dependent reduction in lesion volume and preservation of corpus callosum white matter volume in the 5e6 group. Transplantation was well tolerated, with no observed adverse events across 1,197 cumulative post-transplant animal-days. Histopathology at 3 months post-transplantation in NHPs showed engraftment without tumor formation or abnormal tissue overgrowth. These findings support the safety and multidomain efficacy of a cryopreserved hNSC product in a nonhuman primate TBI model and inform translational development toward first-in-human testing with clinically aligned endpoints.