Hallmarks of Cystic Fibrosis (CF) lung disease are chronic obstruction, infection, and inflammation dominated by lifelong, excessive influx of neutrophils (PMNs) into airways which is further exacerbated by CF-related diabetes (CFRD).

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.

People with Cystic Fibrosis (pwCF) often exhibit impaired insulin secretion, which may lead to Cystic Fibrosis-Related Diabetes (CFRD). The impact of CF variants in the complex relationship between CFTR channel function, pancreatic function, and glucose metabolism remains only partially understood.

Studies of CF therapies intended to reduce pulmonary exacerbations (PEx) balance future PEx risks across treatment groups. Recent PEx definitions capture any antimicrobial treatments, but future PEx risks using newer definitions and among people with CF (pwCF) receiving elexacaftor/tezacaftor/ivacaftor (ETI) remain undescribed.

Systematic screening for cystic fibrosis related diabetes (CFRD) is recommended for all people living with cystic fibrosis (pwCF) from the age of 10. However, adhering to these guidelines is challenging given the cumbersome nature and potential side effects of the current test of reference, the Oral Glucose Tolerance Test (OGTT). Continuous glucose monitoring (CGM) could become an alternative to OGTT, thanks to its ease of use and to the extensive information it provides.

Essential fatty acid deficiency (EFAD) is a common complication in people with cystic fibrosis (pwCF). While CFTR modulators (CFTRm) have become the standard of care, their effect on EFAD has been minimally explored. This study assesses the impact of CFTRm on fatty acid (FA) profiles in a large cohort of children/adolescents with CF and examines correlations with clinical outcomes.

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have transformed the management of cystic fibrosis (CF), but evidence on their safety during pregnancy remains limited and pregnancy-related adverse drug reactions (ADRs) are not well characterized.

The introduction of CFTR modulators has been transformative for many people with cystic fibrosis (CF). The drugs are generally well tolerated although adverse reactions such as delayed-type T-cell mediated hypersensitivity and drug-induced liver injury (DILI) have been reported. Here, we characterise a novel underlying immunological mechanism driving DILI post Elexacaftor/Tezacaftor/Ivacaftor (ETI) administration.

Cystic fibrosis (CF) lung disease begins early in life and progresses throughout childhood into adolescence. Children completing the Australasian CF Bronchoalveolar Lavage (ACFBAL) trial were followed longitudinally (CF-FAB study) to determine progression of CF lung disease during adolescence using visual and automatic methods and to correlate CT-derived metrics with spirometry outcomes.

Clarity and consistency of required knowledge and skills is crucial in supporting the development of members of cystic fibrosis (CF) multidisciplinary teams. Syllabi are effective frameworks for delivering a more uniform and evidence-based approach to high quality holistic care and research.

There are a paucity of data regarding the pharmacokinetics (PK) of elexacaftor (ELX)/tezacaftor(TEZ)/ivacaftor(IVA)(ETI) in pregnant and/or lactating mothers and their offspring. We conducted a PK assessment of ETI and their metabolites in maternal/neonatal/cord blood and breast milk from a cystic fibrosis (CF) carrier mother/affected fetus dyad, collecting specimens at delivery, 1 and 4 weeks after birth. The infant received on-label direct dosing after 1 month of life; all PK samples were collected prior to initiation of neonatal dosing and analyzed using LC-MS/MS. Measured metabolites were IVA-M1, IVA-M6, ELX-M23 and TEZ-M1. The female infant was born at 37 weeks gestation with successful meconium passage on the first day of life. Sweat chloride at 15 days (16 and 17 mmol/L) and immunoreactive trypsinogen (27.5 ng/mL) were normal. Neonatal genetics confirmed F508del/P67L genotype. Parent drug concentrations were measurable in cord blood and capillary heel sticks, indicating they cross the placenta. After delivery, the infant's only source of modulators was via breast milk. Breast milk concentrations were measured at 1 and 4 weeks of life. Relative to maternal concentrations, ETI and their metabolites were present at lower concentrations. Heel stick specimens revealed undetectable IVA, but ELX and TEZ were below the assay limit. IVA-M1 and IV-M6 concentrations were lower at 1 and 4 weeks relative to delivery. To our knowledge, this is the first report of ETI metabolite concentrations following in utero administration.

Limited data exist on the real-world impact of elexacaftor/tezacaftor/ivacaftor (ETI) on use of chronic respiratory therapies. This post-hoc analysis evaluated long-term changes in use of chronic respiratory therapies following ETI initiation among people with (pw)CF aged ≥6 years in the United States and examined characteristics of those who were taking ≥2 chronic therapies at baseline and post-ETI.

Prevotella melaninogenica is enriched in the lungs of people with cystic fibrosis (pwCF), yet its functional impact on respiratory tract homeostasis remains incompletely understood. Prior studies identified immune modulatory effects following lung exposure to Prevotella, but the relevance of these findings for CF infections is unknown.

The Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulator VX-445 (Elexacaftor) used to treat cystic fibrosis presents both corrector and potentiator activities. This drug binds to a pocket within the CFTR membrane-spanning domain (MSD) assembly, in contact with the lasso motif. We have previously shown that the corrector activity of VX-445 is modulated by mutations within MSD1 and the nucleotide binding domain NBD1. Here, we evaluate if mutations affecting VX-445's corrector activity also affect its potentiator activity. Responses to increasing concentrations of VX-445 were measured using the halide sensitive fluorescent assay after transfection of CFTR mutants in HEK293 cells. Results show that VX-445 potentiated gating mutants causing cystic fibrosis located in the NBDs (NBD1 G551D and NBD2 G1349D) and in the IntraCellular Loops (ICL1 G178R and ICL3 G970R). Mutations within the VX-445 binding site inhibited potentiation of G551D, contrary to some mutations located outside this site that affected its corrector activity, two of which (M212A and F224A) were found to induce CFTR gain-of-function. Potentiation of G551D was also observed with correctors VX-809 and VX-121. In conclusion, CFTR modulator VX-445 can promote channel activity of gating mutants, an effect which is dependent on the integrity of its binding site. Potentiation could also be observed with correctors VX-809 and VX-121, indicating that more generally, CFTR correctors can promote channel activity.

The Elexacaftor/Tezacaftor/Ivacaftor (ETI) combination of cystic fibrosis transmembrane regulator modulators is safe and effective even in children with at least one F508del variant. However, cases of liver damage have been reported, and we observed an increase of serum bilirubin and alanine aminotransferase (ALT) in Cystic Fibrosis (CF) adults homozygous or compound heterozygous for the F508del after one year of ETI treatment. In the present study we followed 106 people with CF (pwCF) aged 8-15 years, who were homozygous or compound heterozygous for the F508del variant and treated with ETI, monitoring liver biochemical indices, lipid profile, and circulating cells. Treatment significantly improved sweat chloride, body mass index and forced expiratory volume in 1 s in both pwCF homozygous and compound heterozygous for the F508del variant (p < 0.001). On the other hand, ETI treatment caused a significant increase in total and conjugated bilirubin in both subgroups (p < 0.001). These changes were mostly found after six months of therapy but not continued after one and two years. Furthermore, we observed a significant reduction in the number of blood platelets after ETI treatment. These data suggest to further investigate the effects of ETI therapy on bilirubin metabolism and to search for biomarkers that can predict its increase, whereas we hypothesize that the reduction in platelet count may depend on the reduced systemic inflammation due to ETI treatment.

Cystic Fibrosis (CF) results from CFTR gene mutations, including splicing defects such as the polymorphic TGnTm repeat, which disrupts exon-10 inclusion and contributes to CF monosymptomatic forms. While recent advances in CF treatment have led to targeted therapies for specific CFTR defects, most splicing variants remain without an effective treatment. Small molecules, like the plant cytokine kinetin, have shown promise in correcting splicing defects in other genetic diseases, offering potential for personalized CF therapies.

The high prices of CFTR modulators present barriers to access for people with cystic fibrosis (CF), especially those in low- and middle-income countries. Costs of research and development (R&D) are often cited as key drivers of drug pricing. In the case of CFTR modulators, circumstances allow for a meaningful comparison of pre-marketing R&D spending and post-approval product revenues.

Chronic rhinosinusitis (CRS) is common in cystic fibrosis (CF) and affects quality of life (QoL), especially in children. Objective tools like Peak Nasal Inspiratory Flow (PNIF) may aid in assessing nasal obstruction and monitoring treatment, but their role in CF is not well established.