Perinatal arterial ischaemic stroke (PAIS) has an incidence of one in 5000–10 000 full-term livebirths1, 2 and is an important cause of neurodevelopmental disabilities later in life. Depending on the artery involved, lifelong consequences of PAIS occur in 50–75% of patients, which include unilateral spastic cerebral palsy, cognitive dysfunction, epilepsy, visual field deficits, and language deficits.3 Currently, no treatment is available to alleviate the neurological consequences in these infants, which leaves an urgent need to develop novel protective or regenerative therapeutic interventions. Advances made in the past decade in early treatment options for neonates, such as hypothermia used in perinatal asphyxia,4 or thrombolytic therapy used in adult stroke,5 are unfortunately not applicable to PAIS. Promising experimental treatment regimens, such as erythropoietin, are currently being assessed in clinical trials, but their efficacy is still unknown.6
Mesenchymal stromal cells (MSCs) show neuroregenerative potential in animal models of hypoxic ischaemic brain injury.7 Intranasal administration is a minimally invasive route for MSC delivery. In animal models, this method enabled MSCs to migrate directly into the brain within several hours,8 thereby preventing the loss of cells in other organs (such as the liver and lungs) after systemic (eg, intravenous) administration.9, 10 Intranasal application of MSCs, isolated from human or mouse bone marrow, led to substantial neuroregeneration in murine models of ischaemic brain injury, with reduction of infarct size as well as improved long-term motor and cognitive outcomes.8, 11
Research in context
Evidence before this study
We searched MEDLINE, Cochrane, and ClinicalTrials.gov for papers published in English, French, or Dutch between database inception and Nov 20, 2021, that reported on the use of mesenchymal stromal cells (MSCs) in neonates. Our search had no restrictions on the type of publication. Our search returned no clinical trials in which MSCs were intranasally administered to neonates. Three clinical trials assessed intratracheal or intraventricular umbilical cord-derived allogeneic MSC therapy in preterm neonates for the indication of bronchopulmonary dysplasia and intraventricular haemorrhage. These trials did not report any deaths, serious adverse events, or dose-limiting toxicities attributable to MSC transplantation.
Added value of this study
To our knowledge, this study provides the first evidence for the feasibility and safety of intranasally administered bone marrow-derived allogeneic MSCs after perinatal arterial ischaemic stroke in full-term neonates (≥36 weeks gestation). Consistent with preclinical research and clinical trials with MSCs in different patient populations, we did not observe any serious adverse events in patients followed up until 3 months of age.
Implications of all the available evidence
Until now, treatment for neonates with perinatal arterial ischaemic stroke has focused on supportive care; however, such care has no long-term protective or curative effect on the brain, leaving the patients with an unmet need for a repair-promoting treatment strategy. This study serves as a starting point for future trials using cell-based therapies for intranasally administered neuroregeneration or tissue repair in neonates. Future large-scale, placebo-controlled studies are needed to determine the therapeutic efficacy of intranasal MSCs.
Until now, no clinical trials with intranasally administered MSCs have been conducted in neonates. Three clinical trials were performed with intratracheal or intraventricular allogeneic umbilical cord-derived MSCs in preterm neonates.12, 13, 14 In these trials, no deaths, serious adverse events, or dose-limiting toxicities were observed. However, clinically significant effects of MSCs on neurodevelopmental outcome up to 2 years of age have not yet been demonstrated. Several clinical trials for adult stroke showed that intravenously delivered autologous bone marrow-derived MSCs improved clinical neurological outcome without any serious adverse events, although efficacy has not been demonstrated in large randomised controlled trials.15 In sum, MSCs have shown promising neuroregenerative potential in preclinical studies and appear to be safe in human clinical trials.
To the best of our knowledge, the safety of intranasal MSC therapy in neonates has never been assessed. Therefore, in the PASSIoN (Perinatal Arterial Stroke treated with Stromal cells IntraNasally) trial, we aimed to assess for the first time the feasibility and safety of intranasal delivery of allogeneic bone marrow-derived MSCs to treat PAIS.