BACKGROUND: Despite the approval of CFTR modulator (CFTRm) drugs for specific variants, many people with cystic fibrosis with non-eligible genotypes may still benefit from these medications. Indeed, recent studies show that some rare CFTR variants can be rescued by approved CFTRm drugs. OBJECTIVE: we assessed the efficacy of CFTRm drugs on eight rare CFTR variants: p.Pro5Leu, p.Pro205Ser, p.Leu206Trp, p.Arg347Pro, p.Ile507del, p.Ser945Leu, p.Met1137Arg, and p.Asp1152His. METHODS: Patient-derived intestinal organoids with these variants in heterozygosity with other cystic fibrosis-causing ones were analyzed by the forskolin-induced swelling assay. Clinical data from individuals undergoing CFTRm therapy were collected both before and after treatment to evaluate clinical benefit. Furthermore, we characterized the molecular defect of those eight variants individually in cystic fibrosis bronchial epithelial cells. RESULTS: CFTR function in intestinal organoids with genotypes p.Asp1152His/p.Phe508del, p.Asp1152His/p.Asn1303Lys, p.Pro5Leu/p.Phe508del, p.Leu206Trp/p.Phe508del, p.Ser945Leu/p.Phe508del, p.Pro205Ser/p.Tyr1092Ter, and p.Met1137Arg/c.2657+5G>A was rescued by currently available CFTRm drugs, this was not observed for organoids with genotypes p.Arg347Pro/p.Phe508del (elexacaftor/tezacaftor/ivacaftor was not tested) and p.Ile507del/p.Gln890Ter. People with cystic fibrosis who, based on our data, started CFTRm therapy showed a clinical improvement, including an increase in lung function, and a reduction in sweat chloride levels. A positive correlation was observed between forskolin-induced swelling values and change in forced expiratory volume in 1 second. This study provides evidence that the forskolin-induced swelling assay using patient-derived intestinal organoids can effectively predict the clinical outcome of CFTRm treatment. In CFBE cells, all eight variants were found to have a processing defect and variants p.Pro5Leu, p.Pro205Ser, p.Leu206Trp, p.Arg347Pro, p.Ser945Leu, and p.Met1137Arg were functionally rescued by the current available CFTRm drug. The CFTRm drug did not elicit the appearance of mature p.Ile507del-CFTR and increased, albeit not significantly, the processing efficiency of p.Asp1152His-CFTR. CONCLUSIONS: This work highlights the importance of using patient-derived intestinal organoids as a theranostic tool to predict the clinical benefit and thus increase the number of people with cystic fibrosis with access to the currently approved CFTRm therapies. While theratyping in cell lines is a valuable approach, additional testing in cystic fibrosis-derived organoids provides more reliable predictions for the individuals carrying rare CFTR variants.

• Publication type
• Journal Article MeSH

Elevated human epididymis protein 4 (HE4) levels decreased in patients with CF (pwCF) in response to CFTR-specific drugs and negatively correlated with FEV1% predicted values (ppFEV1). Objectives: Although elexacaftor/tezacaftor/ivacaftor (ETI, Kaftrio®) demonstrates more substantial effectiveness than lumacaftor/ivacaftor (LUM/IVA, Orkambi®) in pwCF, plasma biomarkers have not been used to compare treatment efficacy. Hence, our aim was to correlate the change in HE4 levels and the clinical effects of these CFTR modulators (CFTRm). Methods: Serum HE4 concentrations were measured in a total of 123 pwCF homozygous for the p.Phe508del-CFTR variant before treatment and 1-6 months after either ETI or LUM/IVA administration. A correlation between serum HE4 and ppFEV1 was assessed using the Spearman test. HE4 protein levels were also analyzed in the supernatants of p.Phe508del-CFTR CFBE 41o- cells before and after treatment with these CFTRm, and their direct effect on CFTR function was monitored by the whole-cell patch-clamp technique. Results: Serum HE4 levels were reduced below baseline after 3 months of either ETI or LUM/IVA (mean delta HE4: -38.5 vs. -18.5 pmol/L, respectively) when the mean change of ppFEV1 was 13.6 vs. 1.6% and remained decreased up to 6 months. A significant inverse correlation between HE4 and ppFEV1 was observed in both study cohorts (r = -0.537 and r = -0.575, respectively; p < 0.0001). In agreement with ex vivo results, the effect on p.Phe508del-CFTR was more pronounced by ETI than LUM/IVA in CFBE cells, showing a larger improvement in p.Phe508del-CFTR function and reductions in HE4 levels at 24 h. Conclusions: Serum HE4 negatively correlates with lung function improvement and monitors better drug efficacy in pwCF under ETI than LUM/IVA.

• Keywords
• CFTR modulator, HE4, biomarker, cystic fibrosis, ppFEV1, treatment efficacy,
• Publication type
• Journal Article MeSH

BACKGROUND: Primary ciliary dyskinesia (PCD) represents a group of rare hereditary disorders characterised by deficient ciliary airway clearance that can be associated with laterality defects. We aimed to describe the underlying gene defects, geographical differences in genotypes and their relationship to diagnostic findings and clinical phenotypes. METHODS: Genetic variants and clinical findings (age, sex, body mass index, laterality defects, forced expiratory volume in 1 s (FEV1)) were collected from 19 countries using the European Reference Network's ERN-LUNG international PCD Registry. Genetic data were evaluated according to American College of Medical Genetics and Genomics guidelines. We assessed regional distribution of implicated genes and genetic variants as well as genotype correlations with laterality defects and FEV1. RESULTS: The study included 1236 individuals carrying 908 distinct pathogenic DNA variants in 46 PCD genes. We found considerable variation in the distribution of PCD genotypes across countries due to the presence of distinct founder variants. The prevalence of PCD genotypes associated with pathognomonic ultrastructural defects (mean 72%, range 47-100%) and laterality defects (mean 42%, range 28-69%) varied widely among countries. The prevalence of laterality defects was significantly lower in PCD individuals without pathognomonic ciliary ultrastructure defects (18%). The PCD cohort had a reduced median FEV1 z-score (-1.66). Median FEV1 z-scores were significantly lower in CCNO (-3.26), CCDC39 (-2.49) and CCDC40 (-2.96) variant groups, while the FEV1 z-score reductions were significantly milder in DNAH11 (-0.83) and ODAD1 (-0.85) variant groups compared to the whole PCD cohort. CONCLUSION: This unprecedented multinational dataset of DNA variants and information on their distribution across countries facilitates interpretation of the genetic epidemiology of PCD and indicates that the genetic variant can predict diagnostic and phenotypic features such as the course of lung function.

• MeSH
• Axonemal Dyneins genetics   MeSH
• Cytoskeletal Proteins MeSH
• Child MeSH
• Adult MeSH
• Phenotype * MeSH
• Genetic Variation MeSH
• Genetic Association Studies * MeSH
• Genotype * MeSH
• Kartagener Syndrome genetics   physiopathology   MeSH
• Infant MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Mutation MeSH
• Child, Preschool MeSH
• Proteins MeSH
• Registries MeSH
• Aged MeSH
• Forced Expiratory Volume MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Infant MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Child, Preschool MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Europe MeSH
• Names of Substances
• Axonemal Dyneins MeSH
• CCDC39 protein, human MeSH Browser
• CCDC40 protein, human MeSH Browser
• Cytoskeletal Proteins MeSH
• DNAH11 protein, human MeSH Browser
• Proteins MeSH

BACKGROUND: Physical activity is a crucial demand on cystic fibrosis treatment management. The highest value of oxygen uptake (VO2peak) is an appropriate tool to evaluate the physical activity in these patients. However, there are several other valuable CPET parameters describing exercise tolerance (Wpeak, VO2VT1, VO2VT2, VO2/HRpeak, etc.), and helping to better understand the effect of specific treatment (VE, VT, VD/VT etc.). Limited data showed ambiguous results of this improvement after CFTR modulator treatment. Elexacaftor/tezacaftor/ivacaftor medication improves pulmonary function and quality of life, whereas its effect on CPET has yet to be sufficiently demonstrated. METHODS: We performed a single group prospective observational study of 10 adolescent patients with cystic fibrosis who completed two CPET measurements between January 2019 and February 2023. During this period, elexacaftor/tezacaftor/ivacaftor treatment was initiated in all of them. The first CPET at the baseline was followed by controlled CPET at least one year after medication commencement. We focused on interpreting the data on their influence by the novel therapy. We hypothesized improvements in cardiorespiratory fitness following treatment. We applied the Wilcoxon signed-rank test. The data were adjusted for age at the time of CPET to eliminate bias of aging in adolescent patients. RESULTS: We observed significant improvement in peak workload, VO2 peak, VO2VT1, VO2VT2, VE/VCO2 slope, VE, VT, RQ, VO2/HR peak and RR peak. The mean change in VO2 peak was 5.7 mL/kg/min, or 15.9% of the reference value (SD ± 16.6; p= 0.014). VO2VT1 improved by 15% of the reference value (SD ± 0.1; p= 0.014), VO2VT2 improved by 0.5 (SD ± 0.4; p= 0.01). There were no differences in other parameters. CONCLUSION: Exercise tolerance improved after elexacaftor/tezacaftor/ivacaftor treatment initiation. We suggest that the CFTR modulator alone is not enough for recovering physical decondition, but should be supplemented with physical activity and respiratory physiotherapy. Further studies are needed to examine the effect of CFTR modulators and physical therapy on cardiopulmonary exercise tolerance.

• Keywords
• Cardiopulmonary exercise testing, Cystic fibrosis, Elexacaftor/tezacaftor/ivacaftor,
• MeSH
• Aminophenols * therapeutic use   MeSH
• Benzodioxoles * therapeutic use   MeSH
• Quinolones * therapeutic use   MeSH
• Cystic Fibrosis * drug therapy   physiopathology   MeSH
• Child MeSH
• Drug Combinations * MeSH
• Indoles * therapeutic use   MeSH
• Cardiorespiratory Fitness MeSH
• Humans MeSH
• Adolescent MeSH
• Pilot Projects MeSH
• Prospective Studies MeSH
• Pyrazoles * therapeutic use   MeSH
• Pyridines * therapeutic use   MeSH
• Pyrrolidines MeSH
• Pyrroles therapeutic use   MeSH
• Oxygen Consumption MeSH
• Exercise Tolerance drug effects   MeSH
• Exercise Test MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Observational Study MeSH
• Names of Substances
• Aminophenols * MeSH
• Benzodioxoles * MeSH
• Quinolones * MeSH
• elexacaftor MeSH Browser
• Drug Combinations * MeSH
• Indoles * MeSH
• Pyrazoles * MeSH
• Pyridines * MeSH
• Pyrrolidines MeSH
• Pyrroles MeSH

The major cause of mortality in people with cystic fibrosis (pwCF) is progressive lung disease characterised by acute and chronic infections, the accumulation of mucus, airway inflammation, structural damage and pulmonary exacerbations. The prevalence of Pseudomonas aeruginosa rises rapidly in the teenage years, and this organism is the most common cause of chronic lung infection in adults with cystic fibrosis (CF). It is associated with an accelerated decline in lung function and premature death. New P. aeruginosa infections are treated with antibiotics to eradicate the organism, while chronic infections require long-term inhaled antibiotic therapy. The prevalence of P. aeruginosa infections has decreased in CF registries since the introduction of CF transmembrane conductance regulator modulators (CFTRm), but clinical observations suggest that chronic P. aeruginosa infections usually persist in patients receiving CFTRm. This indicates that pwCF may still need inhaled antibiotics in the CFTRm era to maintain long-term control of P. aeruginosa infections. Here, we provide an overview of the changing perceptions of P. aeruginosa infection management, including considerations on detection and treatment, the therapy burden associated with inhaled antibiotics and the potential effects of CFTRm on the lung microbiome. We conclude that updated guidance is required on the diagnosis and management of P. aeruginosa infection. In particular, we highlight a need for prospective studies to evaluate the consequences of stopping inhaled antibiotic therapy in pwCF who have chronic P. aeruginosa infection and are receiving CFTRm. This will help inform new guidelines on the use of antibiotics alongside CFTRm.

• Keywords
• Bacterial Infection, Bronchiectasis, Cystic Fibrosis, Respiratory Infection,
• MeSH
• Anti-Bacterial Agents * administration & dosage   therapeutic use   MeSH
• Administration, Inhalation MeSH
• Cystic Fibrosis * complications   microbiology   drug therapy   MeSH
• Humans MeSH
• Cystic Fibrosis Transmembrane Conductance Regulator * genetics   MeSH
• Pseudomonas Infections * drug therapy   MeSH
• Pseudomonas aeruginosa * drug effects   isolation & purification   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Anti-Bacterial Agents * MeSH
• Cystic Fibrosis Transmembrane Conductance Regulator * MeSH

INTRODUCTION: Cystic fibrosis transmembrane conductance regulator modulator therapy improves nutritional status and quality of life. Clinical trials have shown pancreatic insufficiency conversion, mostly in pediatric patients treated with ivacaftor. Studies with elexacaftor/tezacaftor/ivacaftor (ETI) in older patients have not suggested restoration of exocrine pancreas function, but quality data in adults are lacking. Our aim was to show the effect of ETI in adults with cystic fibrosis (CF) on nutritional status and digestive function. We hypothesized improvement of nutritional parameters and gastrointestinal symptoms, reduction of pancreatic enzyme replacement therapy, but uncertain improvement in exocrine pancreatic function. METHODS: We prospectively enrolled adults with CF treated with ETI from August 2021 to June 2022. We measured anthropometric parameters, laboratory nutritional markers, change of fecal elastase, pancreatic enzymes replacement therapy needs, and gastrointestinal symptoms. RESULTS: In the cohort of 29 patients (mean age 29.1 years), 82.8% suffered exocrine pancreatic insufficiency. After ETI, mean BMI increased by 1.20 kg/m2 (p < 0.001), mean body weight by 3.51 kg (p < 0.001), albumin by 2.81 g/L, and prealbumin by 0.06 (both p < 0.001). Only 1 patient, initially pancreatic insufficient (4.5%, p < 0.001), developed pancreatic sufficiency, indicated by increased fecal elastase from 45 μg/g to 442.1 μg/g. Mean change in lipase substitution decreased by 1,969 units/kg/day (p < 0.001) and stools frequency by 1.18 per day (p < 0.001). CONCLUSION: Our data suggest increased nutritional parameters, lower pancreatic substitution requirements, and improved defecation in adult CF patients on ETI. Improvement in exocrine pancreatic function might be mutation-specific and needs further study.

• Keywords
• Cystic fibrosis, Elexacaftor/tezacaftor/ivacaftor, Exocrine pancreas function, Nutrition, Pancreatic enzyme replacement therapy,
• MeSH
• Aminophenols therapeutic use   MeSH
• Benzodioxoles therapeutic use   MeSH
• Quinolines MeSH
• Quinolones therapeutic use   MeSH
• Cystic Fibrosis * drug therapy   complications   MeSH
• Adult MeSH
• Exocrine Pancreatic Insufficiency * drug therapy   etiology   complications   MeSH
• Drug Combinations * MeSH
• Gastrointestinal Diseases drug therapy   MeSH
• Indoles * therapeutic use   MeSH
• Humans MeSH
• Young Adult MeSH
• Nutritional Status * MeSH
• Pancreatic Elastase metabolism   MeSH
• Prospective Studies MeSH
• Pyrazoles therapeutic use   MeSH
• Pyridines therapeutic use   MeSH
• Pyrrolidines therapeutic use   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Aminophenols MeSH
• Benzodioxoles MeSH
• Quinolines MeSH
• Quinolones MeSH
• elexacaftor, ivacaftor, tezacaftor drug combination MeSH Browser
• elexacaftor MeSH Browser
• Drug Combinations * MeSH
• Indoles * MeSH
• Pancreatic Elastase MeSH
• Pyrazoles MeSH
• Pyridines MeSH
• Pyrrolidines MeSH

Introduction: Seminal clinical trials with the triple combination of elexacaftor-tezacaftor-ivacaftor (ETI) demonstrated clinical efficacy in people with cystic fibrosis (pwCF) who carry at least one F508del mutation. However, due to exclusion criteria of these clinical trials, the effect of ETI was not studied in a substantial number of pwCF. Thus, we ran a single center trial to evaluate a clinical efficacy of ETI treatment in adult pwCF who were ineligible for enrollment in registration studies. Methods: PwCF on ETI with prior lumacaftor-ivacaftor therapy, severe airway obstruction, well-preserved lung function, or with airway infection with pathogens at risk of more rapid decline in lung function formed the study group, while all the others on ETI formed the control group. Lung function, nutritional status and sweat chloride concentration were assessed before and after initialization of ETI therapy over a 6-month period. Results: Approximately a half of the ETI-treated pwCF at the adult Prague CF center (49 of 96) were assigned to the study group. Their mean changes in body mass index ( + 1.04 kg/m2) and in sweat chloride concentration (-48.4 mmol/L) were similar to the control group ( + 1.02 kg/m2; -49.7 mmol/L), while the mean change in percent predicted forced expiratory volume in 1 s (ppFEV1; + 10.3 points) was significantly lower than in the control group ( + 15.8 points) (p = 0.0015). In the subgroup analysis, pwCF with severe airway obstruction (ppFEV1 <40) and pwCF with well-preserved lung function (ppFEV1 >90) showed a less potential for improvement in lung function during the ETI treatment than controls (median change in ppFEV1 + 4.9 points and + 9.5 points, respectively). Conclusion: PwCF not eligible for inclusion in clinical trials demonstrated improvement in lung function and nutritional status following the initiation of treatment with the ETI combination. Moderate increase in ppFEV1 was observed in those with severe airway obstruction or well-preserved lung function.

• Keywords
• cystic fibrosis, elexacaftor-tezacaftor-ivacaftor, lung function, nutritional status, sweat chloride concentration, variant specific therapy,
• Publication type
• Journal Article MeSH

Cystic fibrosis (CF) is the most common autosomal recessive genetic disease in Caucasians, affecting more than 100,000 individuals worldwide. It is caused by pathogenic variants in the gene encoding CFTR, an anion channel at the plasma membrane of epithelial and other cells. Many CF pathogenic variants disrupt the biosynthesis and trafficking of CFTR or reduce its ion channel function. The most frequent mutation, loss of a phenylalanine at position 508 (F508del), leads to misfolding, retention in the endoplasmic reticulum, and premature degradation of the protein. The therapeutics available for treating CF lung disease include antibiotics, mucolytics, bronchodilators, physiotherapy, and most recently CFTR modulators. To date, no cure for this life shortening disease has been found. Treatment with the Triple combination drug therapy, TRIKAFTA®, is composed of three drugs: Elexacaftor (VX-445), Tezacaftor (VX-661) and Ivacaftor (VX-770). This therapy, benefits persons with CF, improving their weight, lung function, energy levels (as defined by reduced fatigue), and overall quality of life. We examined the effect of combining LAU-7b oral treatment and Triple therapy combination on lung function in a F508deltm1EUR mouse model that displays lung abnormalities relevant to human CF. We assessed lung function, lung histopathology, protein oxidation, lipid oxidation, and fatty acid and lipid profiles in F508deltm1EUR mice.

• Keywords
• LAU-7b, TRIKAFTA, ceramides, cystic fibrosis, fenretinide (4-HPR), lung physiology, sphingolipids, triple therapy,
• Publication type
• Journal Article MeSH

BACKGROUND: Specialized clinical care for cystic fibrosis (CF) in Cyprus, a small island country, has been implemented since the 1990s. However, only recently, a national CF patient registry has been established for the systematic recording of patients' data. In this study, we aim to present data on the epidemiological, genotypic and phenotypic features of CF patients in the country from the most recent data collection in 2019, with particular emphasis on notable rare or unique cases. RESULTS: Overall, data from 52 patients are presented, 5 of whom have deceased and 13 have been lost to follow-up in previous years. The mean age at diagnosis was 7.2 ± 12.3 years, and the mean age of 34 alive patients by the end of 2019 was 22.6 ± 13.2 years. Patients most commonly presented at diagnosis with acute or persistent respiratory symptoms (46.2%), failure to thrive or malnutrition (40.4%), and dehydration or electrolyte imbalance (32.7%). Sweat chloride levels were diagnostic (above 60 mmol/L) in 81.8% of examined patients. The most common identified mutation was p.Phe508del (F508del) (45.2%), followed by p.Leu346Pro (L346P) (6.7%), a mutation detected solely in individuals of Cypriot descent. The mean BMI and FEV1 z-scores were 0.2 ± 1.3 and - 2.1 ± 1.7 across all age groups, respectively, whereas chronic Pseudomonas aeruginosa colonization was noted in 26.9% of patients. The majority of patients (74.5%) were eligible to receive at least one of the available CFTR modulator therapies. In 25% of patients we recovered rare or unique genotypic profiles, including the endemic p.Leu346Pro (L346P), the rare CFTR-dup2, the co-segregated c.4200_4201delTG/c.489 + 3A > G, and the polymorphism p.Ser877Ala. CONCLUSIONS: CF patient registries are particularly important in small or isolated populations, such as in Cyprus, with rare or unique disease cases. Their operation is necessary for the optimization of clinical care provided to CF patients, enabling their majority to benefit from evolving advances in precision medicine.

• Keywords
• CFTR gene, CFTR modulators, Cystic fibrosis, Next-generation sequencing, Patient registry,
• MeSH
• Cystic Fibrosis * genetics   MeSH
• Demography MeSH
• Child MeSH
• Adult MeSH
• Laboratories MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Mutation genetics   MeSH
• Cystic Fibrosis Transmembrane Conductance Regulator * genetics   MeSH
• Registries MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• CFTR protein, human MeSH Browser
• Cystic Fibrosis Transmembrane Conductance Regulator * MeSH

As CFTR modulator therapy transforms the landscape of cystic fibrosis (CF) care, its lack of uniform access across the globe combined with the shift towards a new standard of care creates unique challenges for the development of future CF therapies. The advancement of a full and promising CF therapeutics pipeline remains a necessary priority to ensure maximal clinical benefits for all people with CF. It is through collaboration across the global CF community that we can optimize the evaluation and approval process of new therapies. To this end, we must identify areas for which harmonization is lacking and for which efficiencies can be gained to promote ethical, feasible, and credible study designs amidst the changing CF care landscape. This article summarizes the counsel from core advisors across multiple international regions and clinical trial networks, developed during a one-day workshop in October 2019. The goal of the workshop was to identify, in consideration of the highly transitional era of CFTR modulator availability, the drug development areas for which global alignment is currently uncertain, and paths forward that will enable advancement of CF therapeutic development.

• Keywords
• CFTR modulators, Clinical trials, Drug development, Global perspective,
• MeSH
• Cystic Fibrosis drug therapy   genetics   MeSH
• Humans MeSH
• International Cooperation * MeSH
• Cystic Fibrosis Transmembrane Conductance Regulator drug effects   MeSH
• Drug Development organization & administration   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• CFTR protein, human MeSH Browser
• Cystic Fibrosis Transmembrane Conductance Regulator MeSH