UMKC-Led Team IDs Safer Treatment Option for Premature Infants

UMKC-Led Team IDs Safer Treatment Option for Premature Infants

Preterm birth, defined as birth between 23 and 36 gestation weeks, is a significant health risk and economic burden on the US health care system, affecting approximately 12% of all pregnancies. Infants born pre-term have immature organs, leading to complications including respiratory distress syndrome, necrotizing enterocolitis and interventricular hemorrhage that cause significant morbidity and mortality.   

 Bronchopulmonary dysplasia (BPD) is a secondary complication of preterm birth, affecting nearly 70% of infants born less than 28 weeks and develops in those who require mechanical ventilation and oxygen therapy for acute respiratory distress. Corticosteroids (CS), such as Dexamethasone (DEX) are used pharmacologically to mitigate the development and progression of BPD.  

Several randomized clinical trials establish that CS therapy, targeted to preterm infants with evolving lung injury, greatly decreases BPD risk but leads to significant risks related to reduced growth rate and long-lasting alterations in brain structure, function, and behavior. Many of the detrimental effects of postnatal CS exposure observed in humans also occur in rodent models. In particular, repeated administration of DEX in preterm infants with BPD negatively impacts somatic growth and is associated with an increased risk for cerebral palsy, decrease in brain volumes and white matter tracks in the cortex, thalamus, and basal ganglia by age 18 years. There remains an urgent need for GC pharmacotherapy for BPD that provides beneficial anti-inflammatory and lung maturation effects, with limited adverse effects on the brain.  

An interdisciplinary team at the University of Missouri Kansas City (Paula Monaghan-Nichols, PhD), Children’s Mercy Hospital Kansas City (Venkatesh Sampath, MBBS) and the University of Pittsburgh School of Medicine (Donald B. DeFranco, PhD), tested the hypothesis that Ciclesonide (CIC), an FDA approved inhaled CS for the treatment of asthma and allergic rhinitis in children over 2-years old could be used to treat BPD and improve lung function, with limited systemic effects and neurological damage.  

Reasoning followed that CIC is a pro-drug that is converted to active form, des-CIC, by carboxyesterases that are enriched in lower lung airways, with limited effects elsewhere in humans. In a neonatal rat model as compared to control animals, the authors demonstrated that repeated administration of biologically equivalent doses of DEX led to similar systemic effects to those observed in infants exposed to repeated DEX exposure, including reduced body weight, brain weight, and white matter deficits.  

In contrast, a reduction in rat body weight was not observed with repeated biologically equivalent doses of CIC. Using biochemical and molecular studies, the team demonstrated that DEX and CIC both activate the glucocorticoid receptor and equally induce expression of select target genes implicated in lung protective and anti-inflammatory effects. Therefore, similar to DEX, CIC can mobilize multiple genomic responses in neonatal lung that ameliorate lung injury and promote recovery from BPD. Importantly, CIC did not trigger the permanent reduction in brain size or myelin basic protein expression in white matter tracks exhibited with neonatal DEX exposure. Thus, CIC is a compelling alternative to DEX for BPD treatment, maintaining the pulmonary benefits, while minimizing neurologic injury.  

 By: UMKC