Novel Therapeutic Strategy for Bronchopulmonary Dysplasia in Premature Infants

Project Summary:

Over 6,000 premature infants are born in Wisconsin each year. Bronchopulmonary dysplasia (BPD) is the most common complication of premature birth and increases the risk of long-term pulmonary and neurodevelopmental impairments. Exposure of the preterm lung to supplemental oxygen (hyperoxia) and mechanical ventilation increases the risk of BPD, characterized by alveolar and vascular growth arrest. Several therapeutic agents targeting lung inflammation, and reactive oxygen species failed to show significant benefit; thus, novel strategies are urgently needed. The project team's preclinical studies in neonatal rat and mouse pups exposed to hyperoxia identified downregulation of Liver Kinase B1 (LKB1)- 5’AMP activated Protein Kinase (AMPK) signaling, a critical regulator of cell metabolism. These changes led to decreased expression of PGC-1α, a key regulator of mitochondrial function, in hyperoxia. Administration of a daily dose of 25mg/kg of the LKB1-AMPK activator, metformin during hyperoxia restored AMPK function and lung alveolar and vascular growth in the mouse pups. The team's pharmacokinetic (PK) studies in mice and piglets found that this metformin dose leads to plasma levels below therapeutic levels reported in adult and pediatric patients, without causing hypoglycemia or acidosis. Based on these exciting observations, the team will conduct a phase-1 clinical trial of metformin in extremely premature infants born at <29 weeks' gestation, at 14-42 days postnatal age, who are at a high risk for BPD. Their aims are to test subtherapeutic and therapeutic doses (10-25 mg/kg) of metformin given enterally in a 3x3 dose escalation protocol to determine dose limiting toxicity, maximum tolerated dose, and optimum therapeutic dose and to measure the metformin plasma and urine levels in the study to investigate the developmental pharmacokinetics of metformin. Their studies are an essential prelude to future efficacy trials of metformin as a novel preventive approach for BPD in premature infants.