Stroke is a leading cause of disability with limited options for promoting recovery beyond acute intervention. Previously, we have shown that continuous intraventricular infusion of STC-2 enhances stroke recovery in young adult rodents. For clinical translation, however, it is essential to optimize STC-2 dosing and administration for efficacy in clinically relevant stroke models, including aged male and female animals, while addressing the limitations of continuous infusion.

To identify an optimal dose, we conducted dose-response experiments using iPSC-derived neurons subjected to oxygen-glucose deprivation (OGD) to simulate ischemic conditions. Pharmacokinetic analysis in aged rats (18–24 months) informed the use of an intrathecal injection regimen. Aged rats were administered two bolus injections of STC-2 one-week post-stroke in a distal middle cerebral artery occlusion (dMCAO) model. Recovery was assessed over six weeks using sensorimotor (vibrissae-forepaw and hind-rearing), locomotor (open field), and cognitive (novel object recognition) tests. Additionally, human CSF samples were analyzed to explore the correlation between STC-2 levels and age.

Two bolus intracisternal injections of STC-2 significantly improved recovery in both aged male and female rats across behavioral assessments in comparison to controls (p<0.05, n=10 per group). Enhanced sensorimotor recovery, improved locomotion, and better cognitive performance were observed in the STC-2 treated group. Human CSF analysis revealed a negative correlation between STC-2 levels and age (Pearson correlation: -0.68, p<0.01), suggesting an age-related decline in STC-2 that may enhance therapeutic relevance for older stroke patients.

This study highlights the potential for STC-2 as a novel protein therapeutic to address neurological deficits following ischemic events, warranting further investigation into its molecular mechanisms and translation into a clinical stroke therapeutic.