Oral Presentation ESA-SRB-ANZBMS 2024 in conjunction with ENSA

Ciclesonide as a novel therapeutic strategy to treat the consequences of preterm birth (#105)

Rutu S Dhavan 1 , Kelly L Short 2 , Juliann D Jaumotte 3 , Nathalie El Khoury 3 , Tianhua Lei 4 , Judy Ng 1 , Megan J Wallace 5 , Donald D DeFranco 3 , A. Paula Monaghan-Nichols 4 , Timothy J Cole 1
  1. Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University , Clayton, Victoria, Australia
  2. Institute for Respiratory Health , Perth, Western Australia, Australia
  3. Pharmacology and Chemical Biology , University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
  4. Biomedical Sciences , University of Missouri Kansas City School of Medicine, Kansas City, Missouri, United States of America
  5. The Richie Centre , The Hudson Institute of Medical Research, Monash Medical Centre, Clayton, Victoria, Australia

Glucocorticoid (GC) signalling is critical for normal fetal organ development, particularly in the lungs, where it promotes the thinning of mesenchymal tissue. This increases the airway-gas exchange surface area and reduces the diffusion distance for gas-exchange, essential for effective lung function at birth. Potent synthetic GCs like betamethasone (Bet) and dexamethasone (Dex) are commonly used antenatally to accelerate fetal lung maturation and reduce the risk of respiratory distress in preterm births. However, concerns are growing about the potential adverse effects on the developing fetal and neonatal brain. We are investigating a novel selective glucocorticoid receptor (GR) agonist, ciclesonide (Cic), as an alternative treatment for preterm birth. Cic is activated in vivo to the GR agonist Des-Cic by intracellular enzymes, carboxylesterases (Ces). We have demonstrated that postnatal administration of Cic and Dex similarly stimulate key biomarkers specific to preterm lung development. Unlike Dex, Cic does not cause neonatal growth retardation, reduced brain weight, or alter neural myelination levels (1). Western blot and immunofluorescence analysis highlight the high expression of CES enzymes in epithelial cells and mesenchyme of peripheral organs like the lung and kidney, but lower levels in fetal and adult mouse brain tissues. Transcriptomic analysis of primary mouse fetal lung fibroblasts revealed that both Cic and Dex induced expression of key genes, including Fkbp5, Crispld2, Tgm2 and Zbtb16. This  effect was absent in GR-null fibroblasts, confirming GR specificity. In contrast to neonatal rats treated with Dex, the activated agonist Des-Cic didn’t cause reductions in body weight, insulin-like growth factor-1 serum levels, or chronic hyperglycaemia. Des-Cic effectively reduced proinflammatory cytokine mRNA in the lung following bleomycin induced lung injury. Overall, these results suggest that Des-Cic represents a novel selective GR modulator for the treatment of the respiratory complications of preterm birth.

  1. 1. Jaumotte JD, Franks AL, Bargerstock EM, Kisanga EP, Menden HL, Ghersi A, et al. Ciclesonide activates glucocorticoid signaling in neonatal rat lung but does not trigger adverse effects in the cortex and cerebellum. Neurobiol Dis. 2021;156:105422.