Elsevier

The Lancet Neurology

Volume 21, Issue 6, June 2022, Pages 528-536
The Lancet Neurology

Articles
Feasibility and safety of intranasally administered mesenchymal stromal cells after perinatal arterial ischaemic stroke in the Netherlands (PASSIoN): a first-in-human, open-label intervention study

https://doi.org/10.1016/S1474-4422(22)00117-XGet rights and content

Summary

Background

Perinatal arterial ischaemic stroke (PAIS) is an important cause of neurodevelopmental disabilities. In this first-in-human study, we aimed to assess the feasibility and safety of intranasally delivered bone marrow-derived allogeneic mesenchymal stromal cells (MSCs) to treat PAIS in neonates.

Methods

In this open-label intervention study in collaboration with all neonatal intensive care units in the Netherlands, we included neonates born at full term (≥36 weeks of gestation) with MRI-confirmed PAIS in the middle cerebral artery region. All eligible patients were transferred to the neonatal intensive care unit of the Wilhelmina Children's Hospital. Neonates received one dose of 45–50 × 106 bone-marrow derived MSCs intranasally within 7 days of presenting signs of PAIS. The primary endpoints were acute and subacute safety outcomes, including vital signs, blood markers, and the occurrence of toxicity, adverse events, and serious adverse events. The occurrence of unexpected cerebral abnormalities by a repeat MRI at 3 months of age was a secondary endpoint. As part of standard clinical follow-up at Wilhelmina Children's Hospital, we assessed corticospinal tract development on MRI and performed motor assessments at 4 months of age. This study is registered with ClinicalTrials.gov, NCT03356821.

Findings

Between Feb 11, 2020, and April 29, 2021, ten neonates were enrolled in the study. Intranasal administration of MSCs was well tolerated in all ten neonates. No serious adverse events were observed. One adverse event was seen: a mild transient fever of 38°C without the need for clinical intervention. Blood inflammation markers (C-reactive protein, procalcitonin, and leukocyte count) were not significantly different pre-administration versus post-administration and, although thrombocyte levels increased (p=0·011), all were within the physiological range. Follow-up MRI scans did not show unexpected structural cerebral abnormalities. All ten patients had initial pre-Wallerian changes in the corticospinal tracts, but only four (40%) patients showed asymmetrical corticospinal tracts at follow-up MRI. Abnormal early motor assessment was found in three (30%) infants.

Interpretation

This first-in-human study demonstrates that intranasal bone marrow-derived MSC administration in neonates after PAIS is feasible and no serious adverse events were observed in patients followed up until 3 months of age. Future large-scale placebo-controlled studies are needed to determine the therapeutic effect of intranasal MSCs for PAIS.

Funding

Netherlands Organization for Health Research and Development (ZonMw).

Introduction

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.

Section snippets

Study design and participants

PASSIoN is an open-label, single-arm, nationwide intervention study designed to determine if intranasal MSC treatment in neonates with PAIS is both feasible and safe. Feasibility was defined as the workability to diagnose, transfer, and treat patients within 7 days after presenting with signs of PAIS, and to restrict the time between MSC preparation and administration to a maximum of 4 h. Safety was assessed by vital signs at the time of treatment, blood sampling before and after MSC treatment,

Results

Between Feb 11, 2020, and April 29, 2021, 24 patients were eligible for the study, of whom 14 neonates were excluded. Ten did not meet inclusion criteria, two could not be included because they became eligible during the predefined pause in enrolment while waiting for follow-up MRI scans of the first three included patients, and two parents declined to provide their consent. Following MSC administration, one patient was found to have microcephaly and minor facial dysmorphisms. Assessment by the

Discussion

The first-in-human PASSIoN trial demonstrated short-term feasibility and safety of intranasal MSC administration for term neonates with PAIS. No serious adverse events were observed up to 3 months after intranasal MSC administration. Only one patient had a mild transient fever shortly after administration, an adverse event that has also been described in adults who received intravenous bone marrow-derived MSCs.15 No signs of infection or inflammatory reactions to MSC administration were

Data sharing

Data collected for the study cannot be made available for others, since the parents of study participants did not give consent to share data with other parties. Study details can be found on ClinicalTrials.gov, and the study protocol is available in the appendix (pp 6–67).

Declaration of interests

We declare no competing interests.

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