TOP 26 - Assessing feasibility, safety and efficacy of intravenous versus intratracheal administration of umbilical cord derived mesenchymal stromal cells in a neonatal piglet of acute lung injury

Publication Number: 1786.TOP 26

Marc-Olivier Deguise, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada; Ewa Henckel, Karolinska University Hospital, Ekero, Stockholms Lan, Sweden; Doreen Engelberts, Ottawa Hospital Research Institute, Ottawa, ON, Canada; Luke GZ. Moore, Ottawa Hospital Research Institute, Ottawa, ON, Canada; Shumei Zhong, ottawa hospital research institute, Ottawa, ON, Canada; Arul Vadivel, OHRI, Ottawa, ON, Canada; Momina Ejaz, Ottawa Hospital Research Institute, Ottawa, ON, Canada; Saad Khan, Ottawa Hospital Research Institute, Ottawa, ON, Canada; Bernard Thébaud, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada

Background: Most extremely premature infants develop bronchopulmonary dysplasia (BPD). With no cure, BPD has long-lasting complications. Umbilical cord derived mesenchymal stromal cells (UC-MSC) can support lung growth/repair. We provided initial safety foundations in a phase I clinical trial of a single intravenous (IV) administration of UC-MSC in infants at risk of BPD.

Objective: Key questions remain to optimize therapeutic efficacy of UC-MSC to ensure successful translation. The assessment of safety, feasibility and efficacy under different delivery methods such as IV vs intratracheal (IT) is essential to inform upcoming clinical trial design.

Design/Methods: We tested the safety, feasibility and efficacy of UC-MSCs when administered via IV or IT route in a blinded pre-clinical study using a clinically relevant neonatal piglet model (marked by surfactant removal (respiratory distress syndrome), hyperoxia, injurious ventilation and inflammation followed by 6h of ventilation - Fig 1) mirroring several insults in the initial acute lung injury in the preterm lung preceding BPD. The UC-MSCs were produced at the Ottawa Hospital Research Institute's Biotherapeutics Manufacturing Center. Safety was monitored via vital signs (heart rate, blood pressure, temperature) and end-organ damage markers (pH, lactate, creatinine, hemoglobin). The American Thoracic Society acute lung injury criteria were used to assess efficacy of UC-MSCs. This includes physiological dysfunction in oxygenation (Ratio PaO2/FiO2, PaO2, Oxygen index) and ventilation (ventilatory efficiency index), alteration in alveolar-capillary membrane (wet/dry ratio), inflammation (neutrophil infiltration, pro-inflammatory cytokines) and histological injury (through a validated hematoxylin & eosin injury score with systematic coverage of the full lung).

Fig. 1: Multi-hit neonatal piglet model.
Piglets are intubated, lungs are lavaged for surfactant removal with injurious ventilation strategies, and LPS is injected IT. Piglets are then ventilated for 6 hours for ongoing physiologic data collection and sample collection with final euthanasia for tissue collection and analysis.