Human amnion epithelial cells for the prevention of bronchopulmonary dysplasia: a phase 1 dose escalation study

Abstract

Background & Aim Background: Advances in neonatal intensive care have been associated with improved survival of preterm infants. But along with survival, the morbidity bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, is also increasing. BPD is associated with adverse respiratory outcomes into adulthood and greater risk of adverse neurodevelopment. Infants born ≤ 28 weeks’ gestation, during the canalicular phase of lung development prior to alveolar and distal capillary development, are at greatest risk of BPD. Disruption of lung maturation by the pro-inflammatory environment created by lifesaving neonatal intensive care interventions results in the BPD we see today – a disease characterised by arrested development with simplified alveoli and abnormal angiogenesis. As the role of inflammation in BPD comes into focus, cell therapy presents a promising intervention for its prevention. Human amnion epithelial cells (hAECs), stem-like cells derived from placental tissues, have multi-lineage potential, are immune privileged and, in small animal models are non-teratogenic. Preclinical work demonstrates the cells capacity to modulate the inflammatory environment to both prevent injury and aid repair of established injury in diverse models of lung disease. A first-in-human study recently demonstrated the safety of low dose hAECs in preterm infants with established BPD. However, hAECs are likely to have greater therapeutic potential when used to prevent lung injury thus, the next step in translation is to evaluate the safety of hAECs in less mature infants at high risk of developing BPD. Aim To evaluate the safety of escalating doses of intravenous hAECs in infants born ≤ 28 weeks’ gestation at high risk of BPD. Methods, Results & Conclusion Method In this phase 1 study, 24 infants born at ≤28 weeks’ gestation at high risk of BPD will each receive intravenous hAECs from Day 14 of life. The infusion dose will escalate from 2 million cells/kg to 10 million cells/kg. Further dose escalation will be achieved by repeat infusions at 5 day intervals to achieve a maximum cumulative dose of 30 million cells/kg. Safety is the primary outcome. Infants will be followed until 2 years of age corrected for prematurity. Results The first dose cohort, comprising of 4 infants, has been recruited. Infants received an intravenous infusion of 2 million hAECs/kg. Infusions have been well tolerated with no short term adverse events observed.