Danni Li, Martin Donnelley, David Parsons, Mark D. Habgood, Elena K. Schneider-Futschik
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引用次数: 0
Abstract
Background and Purpose
Cystic fibrosis (CF) patients are living longer and healthier due to improved treatments, e.g. cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI), with treatment possibly occurring in pregnancy. The risk of ETI to foetuses remain unknown. Thus the effect of maternally administered ETI on foetal genetic and structural development was investigated.
Experimental Approach
Pregnant Sprague Dawley rats were orally treated with ETI (6.7 mg·kg−1·day−1 elexacaftor + 3.5 mg·kg−1·day−1 tezacaftor + 25 mg·kg−1·day−1 ivacaftor) for 7 days from E12 to E19. Tissue samples collected at E19 were analysed using histology and RNA sequencing. Histological changes and differentially expressed genes (DEG) were assessed.
Key Results
No overt structural abnormalities were found in foetal pancreas, liver, lung and small intestine after 7-day ETI exposure. Very few non-functionally associated DEG in foetal liver, lung and small intestine were identified using RNA-seq. 29 DEG were identified in thymus (27 up-regulated and two down-regulated) and most were functionally linked to each other. Gene ontology enrichment analysis revealed that multiple muscle-related terms were significantly enriched. Many more DEG were identified in cortex (44 up-regulated and four down-regulated) and a group of these were involved in central nervous system and brain development.
Conclusion and Implication
Sub-chronic ETI treatment in late pregnancy does not appear to pose a significant risk to the genetic and structural development of many foetal tissues. However, significant gene changes in foetal thymic myoid cells and cortical neuronal development requires future follow-up studies to assess the risk to these organs.
期刊介绍:
The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries.
Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues.
In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.