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Complications of preterm birth are the main cause of death in children before the age of 5 years. Bronchopulmonary dysplasia (BPD), the chronic lung disease that follows ventilator and O2 therapy for acute respiratory failure, is the most common complication of extreme prematurity. BPD accounts for life-long morbidity and lacks effective treatment. Preclinical data suggesting lung protective effects of human umbilical cord (UC)-derived mesenchymal stromal cell (MSC) form the rationale for the clinical translation of UC-MSCs for BPD. Helping Underdeveloped Lungs with Cells (HULC) was a Phase I, open-label, multicentre, dose-escalation trial to assess the safety and feasibility of a single, intravenous (i.v.) injection of allogeneic human UC-MSCs in preterm infants at high risk of developing BPD. Patients were included if they were born <28 weeks gestation, still intubated and on mechanical ventilation with FiO2 30% or higher between postnatal day 7-28. The first three patients received low dose 1.0 × 106 UC-MSC/kg, the next three patients received intermediate dose (3.0 × 106 UC-MSCs/kg), and the final three patients received high dose (10 × 106 UC-MSCs/kg). Primary outcomes included the incidence of prespecified infusion-associated events and serious adverse events. The trial is registered with ClinicalTrials.gov, number NCT04255147. Nine preterm infants were enrolled between Oct 13, 2022 and Nov 6, 2023 at a mean gestational age of 24.5±1.3 weeks and a mean birth weight of 647±131g. UC-MSC were given at a mean of 19.3±6.1 days after birth. No prespecified infusion-associated events or treatment-related adverse events were reported in any of the nine patients. There were no deaths. All patients had BPD. In the low dose group, all 3 patients had severe BPD (FiO2>30% or positive pressure at 36 weeks corrected). In the highest dosing group, no patient had severe BPD. Complications usually associated with prematurity included patent ductus arteriosus (n=3), necrotizing enterocolitis (n=1), severe retinopathy of prematurity (stage 3 or higher, n=2), intraventricular hemorrhage grade 1-2 (n=3), late-onset sepsis (n=5). None of these were MSC-related. In conclusion, a single i.v. infusion of allogeneic UC-MSCs was well tolerated in nine extreme preterm infants at high risk of developing BPD. A phase 2 trial is warranted to test the efficacy and safety of 10 × 106 UC-MSC/kg in a larger patient population. [ABSTRACT FROM AUTHOR]

The chronic lung disease bronchopulmonary dysplasia (BPD) is the most severe complication of prematurity. BPD occurs following ventilator treatment with supplemental oxygen for acute respiratory failure, and early inflammation. The hallmarks of the lung pathology are arrested lung development including fewer and larger alveoli with less septation, thickening of alveolar septa and impaired development of the capillary network. These changes may lead to life-long respiratory morbidity including asthma, reduced exercise capacity, early onset emphysema and pulmonary hypertension. Currently, there is no treatment for BPD. Mesenchymal stromal cells derived from the umbilical cord (UC-MSCs) improve lung structure and function in experimental BPD, and early phase clinical trials are underway. However, the optimal UC-MSC donor remains to be determined. The aim of this project is to compare healing effects of UC-MSC donors in hyperoxia-induced experimental BPD. UC-MSCs derived from 5 human donors (1st term delivery [TMSC], 2nd term delivery [T2MSC], preterm delivery [PMSC], preterm delivery with preeclampsia [PPMSC], preterm delivery with chorioamnionitis [PCMSC]) were administered intratracheally at postnatal day (P) 4 in rat pups exposed to 85% oxygen from P0 to P14. At P21, survival, lung function (flexivent), lung structure (mean linear intercept), right ventricular hypertrophy (Fulton index), as well as lung vasculature at P35 (microCT) were assessed. Treatment with UC-MSCs increased survival in hyperoxia-exposed developing pups. In addition, TMSC, PMSC, PPMSC and PCMSC, but not T2MSC, improved lung compliance, lung growth and attenuated pulmonary hypertension when compared to control hyperoxic pups. Thus, donor source impacts beneficial effects of UC-MSCs in a rat BPD model. In the future, understanding the differences at the transcriptomic level between UC-MSC donors might improve the identification of the optimal MSC source for treatment of complications of extreme prematurity, the number one killer of infants below the age of 5. [ABSTRACT FROM AUTHOR]