Ciclesonide as an improved therapeutic treatment for the respiratory consequences of preterm birth

Cole Timothy J.; Dhavan Rutu S.; Short Kelly L.; Jaumotte Juliann D.; Khoury Nathalie El; Tianhua Lei; Judy Ng; Megan Wallace; DeFranco Donald B.; Monaghan-Nichols A. Paula

doi:10.1530/endoabs.109.OC5.4

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Endocrine Abstracts (2025) 109 OC5.4 | DOI: 10.1530/endoabs.109.OC5.4

SFEBES2025 Oral Communications Adrenal and Cardiovascular (6 abstracts)

Ciclesonide as an improved therapeutic treatment for the respiratory consequences of preterm birth

Timothy J. Cole ¹ , Rutu S. Dhavan ¹ , Kelly L. Short ¹ , Juliann D. Jaumotte ² , Nathalie El Khoury ² , Tianhua Lei ³ , Judy Ng ¹ , Megan Wallace ¹ , Donald B. DeFranco ² & A. Paula Monaghan-Nichols ³

Author affiliations

¹Monash University, Melbourne, Australia; ²University of Pittsburgh, Pittsburgh, USA; ³University of Missouri, Kansas City, USA

Cortisol is an essential regulatory hormone for normal mammalian respiratory development prior to birth. The potent synthetic glucocorticoids betamethasone and dexamethasone (DEX) are used in the NICU to treat the respiratory complications of human preterm birth. There are however emerging concerns of their deleterious effects in other fetal organs such as the brain that has led to the search for more efficacious compounds with reduced systemic side-effect profiles. Here we have assessed the asthma steroid ciclesonide (CIC), a novel prodrug and agonist of the glucocorticoid receptor (GR) as an alternative treatment for the consequences of preterm birth. We have previously demonstrated that postnatal administration of CIC and DEX both stimulate key biomarkers of lung development, but unlike DEX, CIC does not induce growth retardation, reduce brain weight or reduce neural myelination levels. Here we show in primary cultures of mouse fetal lung fibroblasts that CIC and its active metabolite desisobutyryl-ciclesonide (Des-CIC) induce very similar but not identical transcriptome changes to Dex that were absent in GR-null fetal lung fibroblasts indicating that Des-CIC induced changes were mediated via the GR. Key target genes included known GR-regulated proteins, such as Fkbp5, Crispld2, Tgm2 and Zbtb16, that drive reduced cell proliferation and lung extracellular matrix remodelling. In contrast to Dex, neonatal rats treated with Des-CIC did not cause reduced body weight, reduced IGF-1 serum levels or chronic hyperglycaemia. However, Des-CIC was as effective as DEX in reducing expression of proinflammatory cytokine mRNAs in a bleomycin-induced rat model of lung injury. Structural studies indicate that Des-CIC acts as a GR super-agonist. Overall, these results suggest CIC may be an effective synthetic GC prodrug to promote lung maturation and reduce lung injury in the neonatal period driven by the selective GR modulator activity of its in vivo active metabolite, Des-CIC.