Sweat chloride and lung function responses to elexacaftor-tezacaftor-ivacaftor in people with cystic fibrosis with two versus one responsive CFTR variants: an analysis of two real-world observational studies.

Background: Among people with cystic fibrosis, sweat chloride and lung function response to elexacaftor-tezacaftor-ivacaftor (ETI) is variable. We hypothesised that the presence of two versus one ETI-responsive CFTR variant could predict response variability.

Methods: In this analysis of two real-world observational studies, data from a French national cohort of adults (aged ≥18 years) with cystic fibrosis and at least one F508del variant treated with ETI and the French compassionate programme for ETI in people (aged ≥6 years) with cystic fibrosis without F508del were used to examine sweat chloride concentrations (SCCs) after ETI initiation, and the absolute change in SCC and percentage of predicted forced expiratory volume in 1 s (ppFEV) following ETI initiation.

Pulmonary endpoints in clinical trials for children with cystic fibrosis under two years of age.

Cystic fibrosis is a lifelong progressive disease in which lung disease is the main prognostic factor, where starting early treatment is crucial for improving long-term outcomes. Therefore, new treatment should be available as early as possible. However, choosing appropriate and feasible clinical trial endpoints in children under 2 years of age presents significant challenges.

Preliminary proposals for the follow-up of infants born to mothers with cystic fibrosis treated with CFTR modulators during the first two years of life.

The number of pregnancies in women with cystic fibrosis (CF) has significantly increased in recent years, leading to a corresponding rise in the number of healthy infants exposed to cystic fibrosis transmembrane conductance regulator modulator (CFTRm) such as elexacaftor-tezacaftor-ivacaftor (ETI) or Kaftrio/Kalydeco® (K/K) triple therapy. Currently, data on the immediate outcomes for these children is reassuring; however, some cases of abnormal liver tests and cataracts have been reported in a few newborns indirectly exposed to ETI in utero or postnatally. Long-term neurodevelopment remains a concern that requires further investigation.

Newborn Screening for Cystic Fibrosis Is Associated With the Lowest Healthcare Costs: A 10-Year Observational Follow-Up Study in France.

Objectives: This study aims to study the healthcare (HC) costs associated with cystic fibrosis (CF) in children diagnosed prenatally (ANT), through newborn screening (NBS), after birth due to meconium ileus (MI), or later based on symptoms (LS). Additionally, it seeks to clinically characterize children with CF (chCF) with different trajectories of HC costs.

Study Design: A retrospective observational study was conducted on data from the French CF Registry (FCFR) and the French National Claims Database (SNDS) linked from 2006 to 2021.

Elexacaftor/Tezacaftor/Ivacaftor Population Pharmacokinetics in Pediatric Patients With Cystic Fibrosis.

Elexacaftor/tezacaftor/ivacaftor (ETI) significantly improves treatment outcomes for people with cystic fibrosis (pwCF) with at least one F508del allele. In 2023, the Food and Drug Administration approved ETI for children with CF aged 2-5 years. However, real-world pharmacokinetic-pharmacodynamic data for ETI in pediatric and adult populations are still limited.

Adenine base editing with engineered virus-like particles rescues the mutation G542X in patient-derived intestinal organoids.

Cystic fibrosis (CF) is a life-shortening autosomal recessive disease, caused by loss-of-function mutations that affect the CF transmembrane conductance regulator (CFTR) anion channel. G542X is the second-most common CF-causing variant, and it does not respond to current CFTR modulator drugs. Our study explores the use of adenine base editing to edit G542X to a non-CF-causing variant, G542R, and recover CFTR function.

First real-world study of fetal therapy with CFTR modulators in cystic fibrosis: Report from the MODUL-CF study.

Background: We aimed to build a cohort of Maternal-Cystic Fibrosis (CF) fetal dyads treated in utero with Variant Specific Therapy (VST), to assess the efficacy on Meconium Ileus (MI) and potential adverse effects of treatment.

Methods: Dyads were included if the foetus had a genetic diagnosis of CF and carried at least one variant responsive to VST. Standardized assessment included pre-VST Magnetic Resonance Imaging (MRI), repeated ultrasound (US), and VST drug concentrations in cord blood, maternal and infant plasma.

Gynecological issues in children and adolescents seen at rare-disease referral centers: an observational retrospective cohort study.

Background: The current development of gynecology services for children and adolescents seeks to meet needs both in the overall population and in patients with rare diseases. In France, the referral center for rare gynecological diseases specializes in four major types of conditions, namely, uterovaginal malformations, hereditary hemorrhagic diseases, rare benign breast diseases, and gynecological repercussions of rare chronic diseases.

Objective: To describe consecutive patients who had a first visit in 2018-2023 at the referral center for rare gynecological diseases at the Necker Pediatric University Hospital in Paris, France, and who were diagnosed with a condition in any of the four categories listed above.

Beyond the Lung. Impact of Elexacaftor/Tezacaftor/Ivacaftor on Sinonasal Disease in Children With Cystic Fibrosis.

Background: Elexacaftor/tezacaftor/ivacaftor (ETI) is a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) therapy that improves pulmonary function and chronic rhinosinusitis (CRS) in cystic fibrosis (CF) adults with at least one copy of the F508del CFTR mutation. The purpose of this study is to evaluate the impact of ETI on CRS symptoms in children and adolescents with CF.

Methods: The MODUL-CF observational study is a multicenter prospective cohort study enrolling CF children with at least 1 F508del mutation in France.

Impact of elexacaftor/tezacaftor/ivacaftor on glucose tolerance in adolescents with cystic fibrosis.

Background: Highly effective CFTR modulators, such as elexacaftor/tezacaftor/ivacaftor (ETI), herald a new era in therapeutic strategy of cystic fibrosis (CF). ETI impact on glucose tolerance remains controversial.

Methods: All the participants underwent a baseline oral glucose tolerance test (OGTT) before ETI initiation (M0) and 12 months (M12), and at 24 months if possible.

Specific airway resistance according to early maternal vitamin D status during pregnancy in children aged 5 to 6 years old from the FEPED cohort (RESPIFEPED).

Unlabelled: There are conflicting results on the association between maternal vitamin D concentrations during pregnancy and respiratory outcomes for their offspring. However, published studies have mainly focused on the second and third trimesters of pregnancy or on high-risk population. The main objective of this study was to evaluate the association between vitamin D plasma concentrations in the first trimester (T1) of pregnancy and effective specific airway resistance (sR) for children aged 5 to 6.

Psychometric validation of the Cystic Fibrosis Impact Questionnaire (CF-IQ): A patient-reported outcome assessing impacts of cystic fibrosis.

The Cystic Fibrosis (CF) Impact Questionnaire (CF-IQ) was qualitatively developed to assess the impact of CF in the context of treatment advancements and increased longevity. This study reports the CF-IQ validation. In this noninterventional validation study, people with CF completed the 40-item CF-IQ and validating patient-reported outcome measures (PROMs) via electronic diaries at enrollment (baseline) and at the 4-week follow-up.

Short-term modification of breathprint by Elexacaftor/Tezacaftor/Ivacaftor in a paediatric cohort.

Background: The triple combination Elexacaftor/Tezacaftor/Ivacaftor (ETI) translates into major respiratory improvements in adults; yet current clinical endpoints may prove insufficiently sensitive in young children. We hypothesised that ETI rapidly modifies the lungs' metabolism, resulting in changes in breath composition.

Methods: Eleven children with CF were enrolled in a longitudinal pilot study at the paediatric Necker hospital.

Practical Guidance for Clinical Microbiology Laboratories: Updated guidance for processing respiratory tract samples from people with cystic fibrosis.

SUMMARYThis guidance presents recommendations for clinical microbiology laboratories for processing respiratory samples from people with cystic fibrosis (pwCF). Appropriate processing of respiratory samples is crucial to detect bacterial and fungal pathogens, guide treatment, monitor the epidemiology of cystic fibrosis (CF) pathogens, and assess therapeutic interventions. Thanks to CF transmembrane conductance regulator modulator therapy, the health of pwCF has improved, but as a result, fewer pwCF spontaneously expectorate sputum.

The expanded French compassionate programme for elexacaftor-tezacaftor-ivacaftor use in people with cystic fibrosis without a F508del CFTR variant: a real-world study.

Background: Elexacaftor-tezacaftor-ivacaftor has been approved in Europe for people with cystic fibrosis with at least one F508del CFTR variant. Additionally, it is approved by the US Food and Drug Administration (FDA) for people with cystic fibrosis with at least one of 177 rare variants. The aims of this study were to describe the clinical response to elexacaftor-tezacaftor-ivacaftor for people with cystic fibrosis without a F508del CFTR variant in France and to determine CFTR variant responsiveness to elexacaftor-tezacaftor-ivacaftor based on the observed clinical response.

Unmet challenges in cystic fibrosis treatment with modulators.

Introduction: 'Highly effective' modulator therapies (HEMTs) have radically changed the Cystic Fibrosis (CF) therapeutic landscape.

Areas Covered: A comprehensive search strategy was undertaken to assess impact of HEMT in life of pwCF, treatment challenges in specific populations such as very young children, and current knowledge gaps.

Expert Opinion: HEMTs are prescribed for pwCF with definite genotypes.

Prime editing functionally corrects cystic fibrosis-causing CFTR mutations in human organoids and airway epithelial cells.

Prime editing is a recent, CRISPR-derived genome editing technology capable of introducing precise nucleotide substitutions, insertions, and deletions. Here, we present prime editing approaches to correct L227R- and N1303K-CFTR, two mutations that cause cystic fibrosis and are not eligible for current market-approved modulator therapies. We show that, upon DNA correction of the CFTR gene, the complex glycosylation, localization, and, most importantly, function of the CFTR protein are restored in HEK293T and 16HBE cell lines.

[Therapeutics in cystic fibrosis: Clinical revolution and new challenges].

Over time, cystic fibrosis has become a model of synergy between research in pathophysiology and cell biology, and clinical advances. Therapies targeting the CFTR protein, in particular CFTR modulators, have transformed the prognosis of patients, bringing the hope of a normal life with the possibility of starting a family and growing old, challenging established statistics. However, patients are not yet cured, and side effects remain insufficiently documented.