Translational Development of Physiologic IGF-1 Replacement for the Prevention of Bronchopulmonary Dysplasia

Bronchopulmonary dysplasia (BPD) remains the most common chronic respiratory complication of extremely preterm infants despite major advances in neonatal intensive care. Although contemporary therapies have improved survival by reducing secondary lung injury, they have had limited impact on the disrupted lung development that characterizes modern BPD. This has renewed interest in developmental therapeutics that seek to restore physiologic signaling pathways interrupted by premature birth rather than treat established disease. Among the developmental pathways disrupted by premature birth, observational studies consistently demonstrate that low postnatal IGF-1 concentrations in extremely preterm infants are associated with an increased risk of BPD and other complications of prematurity. Although these associations do not establish causality, they provide a biologically plausible basis for investigating physiologic IGF-1 replacement. This review summarizes the developmental biology of the IGF axis and the translational pathway supporting the clinical development of OHB-607, a recombinant human IGF-1/IGF-binding protein-3 complex intended to restore physiologic IGF-1 concentrations in extremely preterm infants at high risk for BPD. The program provides one example of how developmental biology, translational animal models, developmental pharmacology, and clinical implementation can be integrated into a framework for advancing mechanism-based therapies aimed at preserving normal lung development after extremely premature birth. Whether this approach improves clinically meaningful outcomes remains to be determined in adequately powered randomized clinical trials.