Thursday, November 21, 2024
11/21/2024
Preterm infants born before 30 weeks gestation are at risk of developing bronchopulmonary dysplasia (BPD), a leading cause of death and long-term pulmonary insufficiency. Both hydrocortisone and synthetic glucocorticoid (sGC) are commonly used to prevent BPD in premature infants. Clinical trials have shown that hydrocortisone targeted to infants with emerging lung disease does not prevent BPD, while inhaled sGC therapy has shown mixed efficacy with potentially increased mortality. Dexamethasone (DEX) has been shown in clinical trials to reduce BPD rates in premature infants but is associated with short term and long-term adverse effects including cerebral palsy. There is an unmet need for efficacious GC therapy in premature infants to prevent BPD without encumbering serious adverse events. To address this challenge, our group has been investigating ciclesonide (CIC), a sGC pro-drug that in the inhaled form is FDA approved for use in asthma and allergic rhinitis in older children. We recently showed that DEX and CIC regulate GR transcriptional targets and several genes implicated in lung protective effects in neonatal rats. Remarkably, CIC does not suppress somatic growth, IGF- 1 levels, induce hyperglycemia or cause neuroanatomical changes in the cerebral cortex of neonatal rats, which are known pathologies caused by DEX in premature infants. Furthermore, ongoing studies reveal that CIC is as efficacious as DEX in preventing lung injury in a hyperoxia-model of experimental BPD. We hypothesize that CIC will have minimal systemic absorption and a favorable safety profile in premature infants at risk of developing BPD. In Aim 1, we will determine the maximum tolerable dose (MTD) of inhaled CIC in preterm infants that does not trigger adverse systemic side effects characteristic of GCs. An open label dose escalation study will be done in preterm infants born at <31 weeks gestation using a 3+3+3 study design. Infants requiring invasive mechanical ventilation between days of life 14 to 35 will be treated with inhaled CIC for 2 weeks. Data pertaining to growth, hyperglycemia, blood pressure, and adrenocortical suppression will be compared between infants treated with CIC and controls. In Aim 2, we will quantify serum levels of CIC metabolites and changes in the GR transcriptome after CIC therapy. Blood samples collected at days 3, 7 and 15 post-initiation of inhaled CIC will be used to measure CIC and des-CIC by liquid chromatography-high resolution mass spectrometry. Whole blood RNA will be subjected to qRT PCR analysis of GC responsive genes to assess activation of GR. The fear of long-term neurological adverse effects has limited optimal use of sGC therapy to prevent BPD. This application is significant as it proposes to repurpose CIC, an existing sGC, for novel therapeutic use in preterm infants to prevent BPD (PAR-23-131). We believe our study is impactful and translationally relevant as it addresses an unmet need for efficacious GC therapy to prevent BPD in premature infants without encumbering the neurological and somatic adverse effects. Successful testing of our hypothesis will pave the way for a large, multicenter randomized control trial of CIC therapy in premature infants to prevent BPD.
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