Preliminary results of the PASSIoN trial (Perinatal Arterial Stroke treated with Stromal cells IntraNasally)

Abstract

Background: Perinatal arterial ischemic stroke (PAIS) is an important cause of perinatal brain damage in the term-born neonate with lifelong neurodevelopmental disorders in 50–75% of patients. Currently, there is no treatment available to alleviate neurological damage after PAIS. Mesenchymal stromal cells (MSCs) have shown promising results in animal studies of PAIS. In this study, we assessed the safety and feasibility of intranasal delivery of bone marrow-derived allogeneic MSCs in neonates with PAIS. Methods: We conducted a phase I/II, open-label, single-arm, nationwide intervention study in the NICU at the University Medical Center Utrecht, the Netherlands (ClinicalTrials.gov/show/NCT03356821). Ten (near-)term (≥36 weeks of gestation) neonates with MRI-confirmed PAIS in the middle cerebral artery (MCA) region, with presenting symptoms within the first week after birth and parental consent, were included. Neonates received one dose of ±50 × 106 MSCs via intranasal droplets as soon as possible after confirmation of the MCA stroke, but within the first week after presenting symptoms. We monitored (sub)acute safety by measuring vital parameters, blood markers and occurrence of adverse events, and we repeated the MRI at 3 months of age. Results: In all ten neonates, intranasal administrations of MSCs were feasible. We did not observe any adverse events, except for one patient that developed a mild transient fever shortly after MSC treatment without further clinical implications. Blood infection parameters (CRP, procalcitonin and leukocyte levels) remained stable pre- versus post-administration. MRI scans at 3 months of age (n = 8, 2 pending) did not show signs of infection or cerebral tumorigenicity and 63% (n = 5/8) of infants had minimal to no posterior limb of the internal capsule (PLIC) involvement while the corticospinal tract initially showed diffusion restriction on DWI. Visual inspection of the amount of tissue loss on MRI following MSC therapy looks promising; however, quantitative analysis still needs to be performed. Currently, most neonates are too young to report on their functional outcome. Conclusion: Intranasal MSC application of ten neonates with PAIS was safe and feasible. Most infants showed symmetrical myelination of the PLIC 3 months after MCA stroke. Future placebo-controlled studies with larger patient populations are needed to determine the therapeutic effect of MSCs.