Exposure of dams to Elexacaftor/ Tezacaftor/Ivacaftor during pregnancy and breastfeeding induces reversible alterations in newborn wild type CD-1 mice

Abstract

Background: We previously demonstrated that Tezacaftor inhibits the enzyme (DEGS) that converts dihydroceramides (dHCer) into ceramides, thus producing accumulation of dHCer in various cells and tissues. We here conducted an in-vivo safety study, by administering ETI to CD-1 mice during pregnancy and breastfeeding.

Methods: ETI was incorporated into mouse food (in a high-fat diet regimen). Pups' behavior was measured with SHIRPA tests. ETI and dHCer levels in plasma and tissues, as well as changes in the global lipidome were measured by tandem mass spectrometry coupled to liquid chromatography.

Results: At 10 days after birth, we observed a significant accumulation of dHCer in the brains of pups born from ETI-fed dams compared to controls. No accumulation was observed in the sciatic nerve of these animals, likely due to much lower levels of ETI compared to the brain. We also conducted an untargeted lipidomics survey, which revealed other alterations in lipid metabolism associated with exposure to ETI during pregnancy. During breastfeeding, given the negligible exposure to the drug, these alterations revert and virtually disappear at P28, together with other differences in the phenotype and behavior of the pups observed earlier during development.

Conclusions: We here demonstrate that exposure to ETI during pregnancy is associated with observable molecular changes in the brain lipidome, which are not likely limited to the inhibition of DEGS. These changes are reverted when exposure to ETI ceases.

Keywords: Cystic fibrosis; Dihydroceramides; ETI; Myelin; Tezacaftor.