Anti-inflammatory effects of elexacaftor/tezacaftor/ivacaftor in adults with cystic fibrosis heterozygous for F508del.

Inflammation is a key driver in the pathogenesis of cystic fibrosis (CF). We assessed the effectiveness of elexacaftor/tezacaftor/ivacaftor (ETI) therapy on downregulating systemic and immune cell-derived inflammatory cytokines. We also monitored the impact of ETI therapy on clinical outcome. Adults with CF, heterozygous for F508del (n = 19), were assessed at baseline, one month and three months following ETI therapy, and clinical outcomes were measured, including sweat chloride, lung function, weight, neutrophil count and C-reactive protein (CRP). Cytokine quantifications were measured in serum and following stimulation of peripheral blood mononuclear cells (PBMCs) with lipopolysaccharide (LPS) and adenosine triphosphate and analysed using LEGEND plex™ Human Inflammation Panel 1 by flow cytometry (n = 19). ASC specks were measured in serum and caspase-1 activity and mRNA levels determined from stimulated PBMCs were determined. Patients remained stable over the study period. ETI therapy resulted in decreased sweat chloride concentrations (p < 0.0001), CRP (p = 0.0112) and neutrophil count (p = 0.0216) and increased percent predicted forced expiratory volume (ppFEV1) (p = 0.0399) from baseline to three months, alongside a trend increase in weight. Three months of ETI significantly decreased IL-18 (p< 0.0011, p < 0.0001), IL-1ß (p<0.0013, p = 0.0476), IL-6 (p = 0.0109, p = 0.0216) and TNF (p = 0.0028, p = 0.0033) levels in CF serum and following PBMCs stimulation respectively. The corresponding mRNA levels were also found to be reduced in stimulated PBMCs, as well as reduced ASC specks and caspase-1 levels, indicative of NLRP3-mediated production of pro-inflammatory cytokines, IL-1ß and IL-18. While ETI therapy is highly effective at reducing sweat chloride and improving lung function, it also displays potent anti-inflammatory properties, which are likely to contribute to improved long-term clinical outcomes.

Trivalent anions as probes of the CFTR channel pore.

The cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel uses positively charged amino-acid side-chains to form binding sites for permeating anions. These binding sites have been investigated experimentally using a number of anionic probes. Mutations that alter the distribution of positive and negative charges within the pore have differential effects on the binding of monovalent versus divalent anions. This study uses patch clamp recording from wild-type and pore-mutant forms of CFTR to investigate small trivalent anions (Co(NO2)63-, Co(CN)3- and IrCl63-) as potential probes of anion binding sites. These anions caused weak block of Cl- permeation in wild-type CFTR (Kd ≥ 700 µM) when applied to the intracellular side of the membrane. Mutations that increase the density of positive charge within the pore (E92Q, I344K, S1141K) increased the binding affinity of these anions 80-280-fold, and also greatly increased the voltage-dependence of block, consistent with fixed charges in the pore affecting monovalent : multivalent anion selectivity. However, high-affinity pore block by Co(NO2)63-apparently did not alter channel gating, a hallmark of high-affinity binding of divalent Pt(NO2)42- ions within the pore. This work increases the arsenal of probes available to investigate anion binding sites within Cl- channel pores.

HERC3 facilitates ERAD of select membrane proteins by recognizing membrane-spanning domains.

Aberrant proteins located in the endoplasmic reticulum (ER) undergo rapid ubiquitination by multiple ubiquitin (Ub) E3 ligases and are retrotranslocated to the cytosol as part of the ER-associated degradation (ERAD). Despite several ERAD branches involving different Ub E3 ligases, the molecular machinery responsible for these ERAD branches in mammalian cells remains not fully understood. Through a series of multiplex knockdown/knockout experiments with real-time kinetic measurements, we demonstrate that HERC3 operates independently of the ER-embedded ubiquitin ligases RNF5 and RNF185 (RNF5/185) to mediate the retrotranslocation and ERAD of misfolded CFTR. While RNF5/185 participates in the ERAD process of both misfolded ABCB1 and CFTR, HERC3 uniquely promotes CFTR ERAD. In vitro assay revealed that HERC3 directly interacts with the exposed membrane-spanning domains (MSDs) of CFTR but not with the MSDs embedded in liposomes. Therefore, HERC3 could play a role in the quality control of MSDs in the cytoplasm and might be crucial for the ERAD pathway of select membrane proteins.

Impact of lumacaftor/ivacaftor on the bacterial and fungal respiratory pathogens in cystic fibrosis: a prospective multicenter cohort study in Sweden.

BACKGROUND: A significant decline in pulmonary exacerbation rates has been reported in CF patients homozygous for F508del treated with lumacaftor/ivacaftor. However, it is still unclear whether this reduction reflects a diminished microbiological burden. OBJECTIVES: The aim of this study was to determine the impact of lumacaftor/ivacaftor on the bacterial and fungal burden. DESIGN: The study is a prospective multicenter cohort study including 132 CF patients homozygous for F508del treated with lumacaftor/ivacaftor. METHODS: Clinical parameters as well as bacterial and fungal outcomes 1 year after initiation of lumacaftor/ivacaftor were compared to data from 2 years prior to initiation of the treatment. Changes in the slope of the outcomes before and after the onset of treatment were assessed. RESULTS: Lung function measured as ppFEV1 (p < 0.001), body mass index (BMI) in adults (p < 0.001), and BMI z-score in children (p = 0.007) were improved after initiation of lumacaftor/ivacaftor. In addition, the slope of the prevalence of Streptococcus pneumoniae (p = 0.007) and Stenotrophomonas maltophilia (p < 0.001) shifted from positive to negative, that is, became less prevalent, 1 year after treatment, while the slope for Candida albicans (p = 0.009), Penicillium spp (p = 0.026), and Scedosporium apiospermum (p < 0.001) shifted from negative to positive. CONCLUSION: The current study showed a significant improvement in clinical parameters and a reduction of some of CF respiratory microorganisms 1 year after starting with lumacaftor/ivacaftor. However, no significant changes were observed for Pseudomonas aeruginosa, Staphylococcus aureus, or Aspergillus fumigatus, key pathogens in the CF context.

COPII cage assembly factor Sec13 integrates information flow regulating endomembrane function in response to human variation.

How information flow is coordinated for managing transit of 1/3 of the genome through endomembrane pathways by the coat complex II (COPII) system in response to human variation remains an enigma. By examining the interactome of the COPII cage-assembly component Sec13, we show that it is simultaneously associated with multiple protein complexes that facilitate different features of a continuous program of chromatin organization, transcription, translation, trafficking, and degradation steps that are differentially sensitive to Sec13 levels. For the trafficking step, and unlike other COPII components, reduction of Sec13 expression decreased the ubiquitination and degradation of wild-type (WT) and F508del variant cargo protein cystic fibrosis transmembrane conductance regulator (CFTR) leading to a striking increase in fold stability suggesting that the events differentiating export from degradation are critically dependent on COPII cage assembly at the ER Golgi intermediate compartment (ERGIC) associated recycling and degradation step linked to COPI exchange. Given Sec13's multiple roles in protein complex assemblies that change in response to its expression, we suggest that Sec13 serves as an unanticipated master regulator coordinating information flow from the genome to the proteome to facilitate spatial covariant features initiating and maintaining design and function of membrane architecture in response to human variation.

Analysis of AlphaMissense data in different protein groups and structural context.

Single amino acid substitutions can profoundly affect protein folding, dynamics, and function. The ability to discern between benign and pathogenic substitutions is pivotal for therapeutic interventions and research directions. Given the limitations in experimental examination of these variants, AlphaMissense has emerged as a promising predictor of the pathogenicity of missense variants. Since heterogenous performance on different types of proteins can be expected, we assessed the efficacy of AlphaMissense across several protein groups (e.g. soluble, transmembrane, and mitochondrial proteins) and regions (e.g. intramembrane, membrane interacting, and high confidence AlphaFold segments) using ClinVar data for validation. Our comprehensive evaluation showed that AlphaMissense delivers outstanding performance, with MCC scores predominantly between 0.6 and 0.74. We observed low performance on disordered datasets and ClinVar data related to the CFTR ABC protein. However, a superior performance was shown when benchmarked against the high quality CFTR2 database. Our results with CFTR emphasizes AlphaMissense's potential in pinpointing functional hot spots, with its performance likely surpassing benchmarks calculated from ClinVar and ProteinGym datasets.

Structure and activity of the septal peptidoglycan hydrolysis machinery crucial for bacterial cell division.

The peptidoglycan (PG) layer is a critical component of the bacterial cell wall and serves as an important target for antibiotics in both gram-negative and gram-positive bacteria. The hydrolysis of septal PG (sPG) is a crucial step of bacterial cell division, facilitated by FtsEX through an amidase activation system. In this study, we present the cryo-EM structures of Escherichia coli FtsEX and FtsEX-EnvC in the ATP-bound state at resolutions of 3.05 Å and 3.11 Å, respectively. Our PG degradation assays in E. coli reveal that the ATP-bound conformation of FtsEX activates sPG hydrolysis of EnvC-AmiB, whereas EnvC-AmiB alone exhibits autoinhibition. Structural analyses indicate that ATP binding induces conformational changes in FtsEX-EnvC, leading to significant differences from the apo state. Furthermore, PG degradation assays of AmiB mutants confirm that the regulation of AmiB by FtsEX-EnvC is achieved through the interaction between EnvC-AmiB. These findings not only provide structural insight into the mechanism of sPG hydrolysis and bacterial cell division, but also have implications for the development of novel therapeutics targeting drug-resistant bacteria.

[A systemic gene therapy for the treatment of cystic fibrosis]. / Une thérapie génique systémique dans le traitement de la mucoviscidose.

Title: Une thérapie génique systémique dans le traitement de la mucoviscidose. Abstract: Le master I2VB se propose de donner les bases conceptuelles et pratiques des différents aspects de l'infectiologie. Il s'appuie sur une coopération exemplaire entre les équipes de recherche en infectiologie et en immunologie de l'Université de Tours, et celles, entre autres, de l'Unité Infectiologie et Santé Publique (ISP) du Centre INRAE de Tours-Nouzilly, concrétisée par une profonde interaction entre chercheurs et enseignants-chercheurs. Cette formation aborde aussi bien les aspects fondamentaux et appliqués de l'infectiologie et de l'immunologie allant de l'étude moléculaire des interactions entre le pathogène et son hôte, jusqu'à la conception et la mise sur le marché des produits de la vaccinologie, des biothérapies anti-infectieuses et des anticorps immuno-thérapeutiques. Le master I2VB (niveau M1) donne lieu aux parcours ICM, I&B et AcT (niveau M2). L'option Infectiologie Cellulaire et Moléculaire (ICM) (responsables : Françoise Debierre-Grockiego et Martine Braibant) a pour objectifs de : former des scientifiques dotés d'une culture générale et technique spécialisée dans les biotechnologies, l'infectiologie, les interactions hôte-pathogène et les mécanismes de la réponse immunitaire anti-infectieuse, contribuant à l'avancée des connaissances scientifiques et à ses applications industrielles, demandes sociétales en forte progression. former des pharmaciens, médecins, vétérinaires, ingénieurs agronomes aux enjeux actuels de l'infectiologie à la fois dans les domaines fondamentaux et appliqués. L'option Immunité et biomédicaments (I&B) (responsables : Anne di Tommaso et Isabelle Dimier-Poisson) a pour objectifs de : former des scientifiques dotés d'une culture générale et technique spécialisée dans les biotechnologies, l'infectiologie, la vaccinologie, les biomédicaments et les biothérapies anti-infectieuses contribuant à l'avancée des connaissances scientifiques et à ses applications industrielles, demandes sociétales en forte progression. former de jeunes scientifiques, pharmaciens, médecins, vétérinaires, ingénieurs agronomes aux enjeux actuels de l'infectiologie et des biomédicaments à la fois dans les domaines fondamentaux et appliqués. L'option Anticorps thérapeutiques (AcT) (responsables : Laurie Lajoie et Isabelle Dimier-Poisson) a pour objectifs de : former des scientifiques dotés d'une culture générale et technique spécialisée dans les biotechnologies, l'immunologie, la cancérologie et les biomédicaments dont les anticorps thérapeutiques, contribuant à l'avancée des connaissances scientifiques et à ses application industrielles et juridiques, demandes sociétales en forte progression. former de jeunes scientifiques, pharmaciens, médecins, vétérinaires, ingénieurs agronomes aux enjeux actuels de l'infectiologie et des biomédicaments à la fois dans les domaines fondamentaux et appliqués.

[Cystic fibrosis primarily presenting with pseudo-Bartter syndrome: a report of three cases and literature review]. / 以假性Bartter综合征为主要表现的囊性纤维化患儿3ä¾‹å¹¶æ–‡çŒ®å¤ä¹ .

OBJECTIVES: To summarize the clinical characteristics and genetic variations in children with cystic fibrosis (CF) primarily presenting with pseudo-Bartter syndrome (CF-PBS), with the aim to enhance understanding of this disorder. METHODS: A retrospective analysis was performed on the clinical data of three children who were diagnosed with CF-PBS in Hunan Children's Hospital from January 2018 to August 2023, and a literature review was performed. RESULTS: All three children had the onset of the disease in infancy. Tests after admission showed hyponatremia, hypokalemia, hypochloremia, and metabolic alkalosis, and genetic testing showed the presence of compound heterozygous mutation in the CFTR gene. All three children were diagnosed with CF. Literature review obtained 33 Chinese children with CF-PBS, with an age of onset of 1-36 months and an age of diagnosis of 3-144 months. Among these children, there were 29 children with recurrent respiratory infection or persistent pneumonia (88%), 26 with malnutrition (79%), 23 with developmental retardation (70%), and 18 with pancreatitis or extrapancreatic insufficiency (55%). Genetic testing showed that c.2909G>A was the most common mutation site of the CFTR gene, with a frequency of allelic variation of 23% (15/66). CONCLUSIONS: CF may have no typical respiratory symptoms in the early stage. The possibility of CF-PBS should be considered for infants with recurrent hyponatremia, hypokalemia, hypochloremia, and metabolic alkalosis, especially those with malnutrition and developmental retardation. CFTR genetic testing should be performed as soon as possible to help with the diagnosis of CF.

Considerations for the use of inhaled antibiotics for Pseudomonas aeruginosa in people with cystic fibrosis receiving CFTR modulator therapy.

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.

[Cystic fibrosis in childhood and adulthood]. / Mukoviszidose im Kindes- und im Erwachsenenalter.

BACKGROUND: Cystic fibrosis (CF, or mucoviscidosis) is one of the rare diseases with a fatal course and with the highest prevalence. Formerly known as a purely childhood disease, this multisystemic disease follows an autosomal recessive inheritance pattern and results in a malfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) channel, leading to the production of viscous secretions. The prognosis and outcome of CF are determined by the severity of the involvement of the lungs. Other typically affected organs include the pancreas, liver and intestines. OBJECTIVE: This article reviews the clinical presentation and evolution of CF with a focus on the new era of the highly effective CFTR modulator treatment. MATERIAL AND METHODS: An overview of the current state of knowledge on the care for CF patients is presented. RESULTS AND DISCUSSION: The introduction of the CF newborn screening, the increased understanding of the disease and the development of novel treatment options have substantially increased the quality of life and life expectancy of people with CF. As a result, more than half of CF patients in Germany are now older than 18 years of age and the complications of a chronic disease as well as organ damage due to the intensive treatment are gaining in importance. The highly effective CFTR modulator treatment results in a significant improvement in CFTR function, lung function, body mass index and quality of life and is available to approximately 90% of patients in Germany, based on the genotype. Nevertheless, further research including the development of causal treatment, e.g., gene therapy, targeting the underlying defect in the remaining 10% of CF patients, is urgently needed. Even in adult patients, CF with a mild course or a CFTR-related disease should be considered, e.g., in cases of bronchiectasis and/or recurrent abdominal complaints.

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. These findings were subsequently validated in patient-derived rectal organoids and human nasal epithelial cells. Through analysis of predicted and experimentally identified candidate off-target sites in primary stem cells, we confirm previous reports on the high prime editor (PE) specificity and its potential for a curative CF gene editing therapy. To facilitate future screening of genetic strategies in a translational CF model, a machine learning algorithm was developed for dynamic quantification of CFTR function in organoids (DETECTOR: "detection of targeted editing of CFTR in organoids").

Distribution of pathogenic variants in the CFTR gene in a representative cohort of people with cystic fibrosis in the Kingdom of Bahrain.

BACKGROUND: Cystic fibrosis (CF) is a rare multi-systemic recessive disorder. The spectrum and the frequencies of CFTR mutations causing CF vary amongst different populations in Europe and the Middle East. In this study, we characterised the distribution of CF-causing mutations (i.e. pathogenic variants in the  CFTR gene) in a representative CF cohort from the Kingdom of Bahrain based on a three-decade-long analysis at a single tertiary centre. We aim to improve CF genetic diagnostics, introduce of CF neonatal screening and provide CFTR modulator therapy (CFTRm). METHODS: CFTR genotyping  and associated clinical information were drawn from a longitudinal cohort. We sequenced 56 people with CF (pwCF) that had one or both CFTR mutations unidentified and carried out comprehensive bioinformatic- and family-based segregation analyses of detected variants, including genotype-phenotype correlations and disease incidence estimates. The study methodology could serve as a basis for other non-European CF populations with a high degree of consanguinity. RESULTS: Altogether 18 CF-causing mutations  were identified, 15 of which were not previously detected in Bahrain, accounting for close to 100% of all population-specific alleles. The most common alleles comprise c.1911delG [2043delG; 22.8%], c.2988+1G > A [3120+1G>A; 16.3%], c.2989-1G>A [3121-1G>A; 14.1%], c.3909C>G [N1303K; 13.0%], and c.1521_1523delCTT [p.PheF508del; 7.6%]. Although the proportion of 1st cousin marriages has decreased to 50%, the frequency of homozygosity in our pwCF is 67.4%, thereby indicating that CF still occurs in large, often related, families. pwCF in Bahrain present with faltering growth, pancreatic insufficiency and classical sino-pulmonary manifestations. Interestingly, two pwCF also suffer from sickle cell disease. The estimated incidence of CF in Bahrain based on data from the last three decades is 1 in 9,880 live births. CONCLUSION: The most commonCF-causing  mutations in Bahraini pwCF were identified, enabling more precise diagnosis, introduction of two-tier neonatal screening and fostering administration of CFTRm.

A new era of targeting cystic fibrosis with non-viral delivery of genomic medicines.

Cystic fibrosis (CF) is a complex genetic respiratory disorder that necessitates innovative gene delivery strategies to address the mutations in the gene. This review delves into the promises and challenges of non-viral gene delivery for CF therapy and explores strategies to overcome these hurdles. Several emerging technologies and nucleic acid cargos for CF gene therapy are discussed. Novel formulation approaches including lipid and polymeric nanoparticles promise enhanced delivery through the CF mucus barrier, augmenting the potential of non-viral strategies. Additionally, safety considerations and regulatory perspectives play a crucial role in navigating the path toward clinical translation of gene therapy.

STUB1 exacerbates calcium oxalate-induced kidney injury by modulating reactive oxygen species-mediated cellular autophagy via regulating CFTR ubiquitination.

The formation of calcium oxalate (CaOx) crystals in the kidneys leads to renal epithelial damage and the progression of crystalline nephropathy. This study investigated the role of STIP1 homology and U-box protein 1 (STUB1), an E3 ubiquitin ligase, and cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel, in CaOx-related renal damage and autophagy regulation. HK-2 cells were treated with various doses of CaOx monohydrate (COM) to simulate kidney injury in vitro. Cell viability, reactive oxygen species (ROS) production, and apoptosis were assessed. The regulation of CFTR ubiquitination by STUB1 was confirmed by immunoprecipitation. An in vivo model was established by injecting mice with glyoxylate. COM treatment dose-dependently decreased cell viability, increased TNF-α and ROS production, and induced apoptotic cell death in HK-2 cells. COM-treated cells also showed decreased CFTR protein expression. CFTR overexpression improved cell viability and reduced ROS production in COM-stimulated HK-2 cells. Bioinformatics analysis predicted CFTR's ubiquitination binding site for STUB1. Further analysis confirmed the role of STUB1 as a ubiquitin ligase in CFTR degradation. Knockdown of STUB1 upregulated CFTR expression, while STUB1 overexpression had the opposite effect. Knockdown of CFTR reversed the impact of STUB1 deficiency on autophagy. The in vivo experiments showed that CFTR overexpression attenuated kidney tissue damage and CaOx deposition in mice. STUB1-mediated CFTR ubiquitination plays a crucial role in mitigating calcium oxalate-related renal damage by regulating autophagy. Targeting the STUB1/CFTR axis may hold therapeutic potential for treating kidney injury associated with calcium oxalate deposition.

In vitro platform to model the function of ionocytes in the human airway epithelium.

BACKGROUND: Pulmonary ionocytes have been identified in the airway epithelium as a small population of ion transporting cells expressing high levels of CFTR (cystic fibrosis transmembrane conductance regulator), the gene mutated in cystic fibrosis. By providing an infinite source of airway epithelial cells (AECs), the use of human induced pluripotent stem cells (hiPSCs) could overcome some challenges of studying ionocytes. However, the production of AEC epithelia containing ionocytes from hiPSCs has proven difficult. Here, we present a platform to produce hiPSC-derived AECs (hiPSC-AECs) including ionocytes and investigate their role in the airway epithelium. METHODS: hiPSCs were differentiated into lung progenitors, which were expanded as 3D organoids and matured by air-liquid interface culture as polarised hiPSC-AEC epithelia. Using CRISPR/Cas9 technology, we generated a hiPSCs knockout (KO) for FOXI1, a transcription factor that is essential for ionocyte specification. Differences between FOXI1 KO hiPSC-AECs and their wild-type (WT) isogenic controls were investigated by assessing gene and protein expression, epithelial composition, cilia coverage and motility, pH and transepithelial barrier properties. RESULTS: Mature hiPSC-AEC epithelia contained basal cells, secretory cells, ciliated cells with motile cilia, pulmonary neuroendocrine cells (PNECs) and ionocytes. There was no difference between FOXI1 WT and KO hiPSCs in terms of their capacity to differentiate into airway progenitors. However, FOXI1 KO led to mature hiPSC-AEC epithelia without ionocytes with reduced capacity to produce ciliated cells. CONCLUSION: Our results suggest that ionocytes could have role beyond transepithelial ion transport by regulating epithelial properties and homeostasis in the airway epithelium.

Elexacaftor/tezacaftor/ivacaftor influences body composition in adults with cystic fibrosis: a fully automated CT-based analysis.

A poor nutritional status is associated with worse pulmonary function and survival in people with cystic fibrosis (pwCF). CF transmembrane conductance regulator modulators can improve pulmonary function and body weight, but more data is needed to evaluate its effects on body composition. In this retrospective study, a pre-trained deep-learning network was used to perform a fully automated body composition analysis on chest CTs from 66 adult pwCF before and after receiving elexacaftor/tezacaftor/ivacaftor (ETI) therapy. Muscle and adipose tissues were quantified and divided by bone volume to obtain body size-adjusted ratios. After receiving ETI therapy, marked increases were observed in all adipose tissue ratios among pwCF, including the total adipose tissue ratio (+ 46.21%, p < 0.001). In contrast, only small, but statistically significant increases of the muscle ratio were measured in the overall study population (+ 1.63%, p = 0.008). Study participants who were initially categorized as underweight experienced more pronounced effects on total adipose tissue ratio (p = 0.002), while gains in muscle ratio were equally distributed across BMI categories (p = 0.832). Our findings suggest that ETI therapy primarily affects adipose tissues, not muscle tissue, in adults with CF. These effects are primarily observed among pwCF who were initially underweight. Our findings may have implications for the future nutritional management of pwCF.