Development of an extended animal model for perinatal drug testing for Bronchopulmonary Dysplasia

Premature birth affects 11% of all pregnancies and is the leading cause of death in neonates worldwide. Advances in perinatal medicine have resulted in the more accurate prediction of preterm birth and more timely interventions leading to increased neonatal survival rates also for extreme preterm babies (≤28 weeks). However, the associated morbidity in survivors remains significant, especially in the pulmonary and central nervous system. At present 45% of extremely preterm infants (≤28 weeks) develop bronchopulmonary dysplasia (BPD). The disease develops over the first weeks of life and is defined by the need for supplementary oxygen at 28 days of life or at 36 weeks post-menstrual age. BPD is characterized by alveolar and pulmonary vascular development disruption with variable lung inflammation and fibrosis. It is invalidating throughout life because of its subsequent morbidity and its health system implications because of increased resource use. A second major problem are the neurocognitive sequelae after both early (<34 weeks’ gestation) and late (34–36 weeks’ gestation) preterm birth. The term ‘encephalopathy of prematurity’ (EoP) has been proposed to define the typical brain injury and resulting neurological sequelae of preterm birth. Both for BPD and EoP there is currently no available treatment, so the development of novel therapies remains imperative. The reason lies in the lack of an ideal lab animal model for perinatal drug research. In this regard. In this regard, the Toelen-Deprest Lab at KU Leuven has developed a preterm rabbit model of BPD that combines prematurity (pups delivered at day 28 of gestation, term 31 days) with a gradual transition to a BPD-like phenotype in the course of 7 days. Preterm rabbit pups exposed to high level of hyperoxia (≥95%O2) develop lung functional abnormalities, morphologically simplified alveoli and signs of pulmonary hypertension. In parallel, this research group has also developed a preterm rabbit model (without hyperoxia) with clear neurobehavioral, brain histopathological and characteristic MRI outcomes that mimic the key features of EoP. These models have also been identified by Chiesi Belgium as suitable models for advancing the preclinical development of drug candidates for the treatment of BPD and EoP. Although the model has shown undeniable value, this project aims to improve the model’s translational power and to expand its timeframe up to 28 days, in order (1) to follow the onset and development of BPD over time, to investigate, for the first time, the related cerebral effects and to address the long-term effects of pharmacological intervention. Currently, the preterm rabbit pups are exposed to extreme hyperoxia (≥ 95%O2) for just 7 days, during which they are fed with artificial milk. In this project, ì conditions where pups will be exposed to oxygen levels lower than 95% in the first days (with a gradual further weaning to normoxia after day 7) will be evaluated. Rabbit pups will be lactated by foster mother. This should allow to prolong the survival of the pups (to 28 days) thereby better reproducing the chronicity observed in the clinical neonatal scenario of BPD. Next to the BPD-related changes, this project also aims to investigate the cerebral effects induced by preterm birth and hyperoxia, in order to create a preterm hyperoxia-fostered rabbit model that can be followed up to day 28 and can be analyzed in terms of pharmacokinetics, histology, biochemistry, MRI imaging, lung function and neurobehavioral testing. This enhanced BPD/EoP model will be a unique chronic model for translational perinatal research.