Perinatal Arterial Stroke Treated With Stromal Cells Intranasally: 2-Year Safety and Neurodevelopment

• Published in: Stroke (1970) Vol. 56; no. 9; pp. 2410 - 2418
• Main Authors: Wagenaar, Nienke, Baak, Lisanne M., van der Aa, Niek E., Groenendaal, Floris, Dudink, Jeroen, Tataranno, Maria Luisa, Koopman, Corine, Verhage, Cornelia H., Eijsermans, Rian M.J.C., van Teeseling, Heleen C., Smit, Liesbeth S., Jellema, Reint K., de Haan, Timo R., ter Horst, Hendrik J., de Boode, Willem P., Steggerda, Sylke J., Mulder-de Tollenaer, Susanne M., Dijkman, Koen P., de Haar, Colin G., de Vries, Linda S., van Bel, Frank, Heijnen, Cobi J., Nijboer, Cora H., Benders, Manon J.N.L.
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01.09.2025
• Subjects: Administration, Intranasal; Cerebral Palsy; Child, Preschool; Clinical Trials; Female; Humans; Infant; Infant, Newborn; Ischemic Stroke - diagnostic imaging; Ischemic Stroke - therapy; Magnetic Resonance Imaging; Male; Mesenchymal Stem Cell Transplantation - adverse effects; Mesenchymal Stem Cell Transplantation - methods; Stroke - therapy; Treatment Outcome; cerebral palsy; child development; infant, newborn; mesenchymal stem cells; ischemic stroke
• ISSN: 0039-2499; 1524-4628
• DOI: 10.1161/STROKEAHA.125.050786

BACKGROUND: The PASSIoN study (Perinatal Arterial Stroke Treated With Stromal Cells Intranasally) demonstrated the feasibility and short-term safety of single-dose allogeneic mesenchymal stromal cells (MSCs) administered intranasally to neonates with perinatal arterial ischemic stroke between February 2020 and April 2021. In this study, we assessed long-term safety and neurodevelopmental outcomes and explored outcome differences with a non-MSC-treated cohort. METHODS: In this post hoc analysis, we evaluated the safety of MSC administration by assessing brain tissue loss, adverse events, and neurodevelopmental outcomes of PASSIoN participants (N=10). The tissue loss ratio was calculated using semi-automatic segmentation based on neonatal and 3-month magnetic resonance imaging. At the age of 2 years, we assessed the occurrence of cerebral palsy, motor and cognitive delays (Z score <−1 SD), behavioral and language problems, visual field defects, and epilepsy. We selected a non-MSC-treated registry cohort (N=39) born between 1994 and 2022, who would have met PASSIoN trial inclusion criteria to compare magnetic resonance imaging and outcome characteristics. RESULTS: At 3 months, the mean±SD tissue loss ratio of PASSIoN participants was 89±21%, indicating more preserved tissue than expected based on initial stroke volume. By the age of 2 years, no related adverse events were reported. Two children (20%) developed cerebral palsy (Gross Motor Function Classification System I) without motor developmental delays. Cognitive, behavioral, and language problems affected 10% to 20%, and none had developed epilepsy. Compared with the registry cohort, and PASSIoN participants showed less often asymmetry of the posterior limb of the internal capsule (40% versus 81%; P=0.02) and the cerebral peduncle (10% versus 61%; P=0.01) on 3-month magnetic resonance imaging and had a better motor performance at the age of 2 years (median [interquartile range] Z score, 0.3 [0.8] versus −0.4 [1.5]; P=0.003). CONCLUSIONS: This study demonstrates the long-term safety of intranasal MSC therapy in 10 infants with perinatal arterial ischemic stroke and may suggest better motor outcomes compared with the literature and a non-MSC-treated cohort. Randomized controlled trials are required to confirm MSC efficacy for children with perinatal arterial ischemic stroke. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03356821.