ETI (elexacaftor/tezacaftor/ivacaftor) is a successful drug combination, which has improved the expectancy and quality of life of many people with CF (pwCF).  After dedicated safety studies, FDA recently approved the use of Kaftrio in children from 2 to 6 years old. Despite being a generally well-tolerated drug, some side effects are reported. Furthermore, thanks to its undeniable success, women with CF are increasingly planning pregnancy and the number of babies born to mothers undergoing ETI is increasing. Data on ETI safety during pregnancy, while generally reassuring, only refer to a few ETI exposed pregnancies.
Thanks to previous projects (FFC#1/2021 e FFC#1/2023), researchers found that Trikafta/Kaftrio induce the accumulation of important fat molecules, known as dihydroceramides (dHCer). While increased dHCer might be beneficial for the effective CFTR rescue itself, it is important to ensure that excessive accumulation, if any, does not translate into negative health effects on young CF patients. Since the accumulation of these molecules has an impact on some key aspects of the development of the nervous system, the present study will be specifically aimed at ruling out this potential safety concern. By performing in vivo studies on an animal model, researchers aim at understanding if the exposure to Trikafta/Kaftrio during pregnancy (for fetuses) and/or during breastfeeding (for newborns and infants), as well as the treatment of young individuals is indeed associated with an accumulation of these fat molecules in the tissues.
Both possible outcomes (ETI causes dHCer accumulation and myelin impairment or not) are to be regarded with favor as they will improve the therapeutic options for CF mothers and young CF subjects.
Lastly, the experimental plan will also provide the technology to monitor, in blood, the molecular biomarkers of dHCer accumulation, that might be used as tools to tune and continue the treatment itself.