Oral Presentation ESA-SRB 2023 in conjunction with ENSA

Placental-specific ciclesonide to des-ciclesonide conversion is not impacted by gestational age or placental sex (#87)

Ashley Meakin 1 , Kathryn Gatford 2 , Yu-Chin Lien 3 , Michael Wiese 1 , Rebecca Simmons 3 , Janna Morrison 1
  1. University of South Australia, Adelaide, SA, Australia
  2. The University of Adelaide, Adelaide, SA, Australia
  3. Center for Research on Reproduction and Women's Health, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

Background: Current clinical management of pregnancies at risk of preterm delivery includes maternal antenatal corticosteroid (ACS; dexamethasone or betamethasone) treatment. ACS activate the glucocorticoid receptor (GR) in all fetal tissues, maturing the lungs at the cost of impaired brain development. This highlights a need for novel treatments. The prodrug ciclesonide (CIC) activates the GR only in tissues with specific enzymes, particularly carboxylesterase 1 and 2 (CES1, CES2), whose expression and activity are high in lungs but not the brain. However, the human placenta expresses CES, and might therefore convert CIC to its GR-activating metabolite des-CIC. This may preclude CIC use as a novel GR-agonist before preterm birth, since the fetus would be systemically exposed to des-CIC, causing GR activation in the brain and lung. We therefore investigated CES isoform expression and conversion of CIC to des-CIC in human placentas collected during the second trimester (Tri2), and at preterm and term birth.

Methods: Differential expression analysis was performed in Tri2 (n=27), preterm (n=34), and term (n=40) placentas using the DESeq2 R-package. A log fold change (logFC) of ±1 with a false discovery rate (FDR) of 0.05 was considered biologically significant. Conversion of CIC to des-CIC was measured in a subset of placenta samples (Tri2 n=7, preterm n=26, term n=20) using functional assays developed for Liquid Chromatography with tandem mass spectrometry. Data was analysed using KW-ANOVA.

Results: CES1 was higher in Tri2 compared with preterm (logFC=1.31, FDR= 1.74E-09) and term (logFC=1.61, FDR= 7.86E-15) placentas. CES2 expression did not differ between gestational ages. Human placenta converted CIC to des-CIC; however, activity was not impacted by gestational age.

Conclusion: Conversion of CIC to des-CIC by the human placenta highlights a need for preclinical studies to assess the efficacy of novel delivery methods to achieve GR activation in the developing lung but not brain.