Profile of cystic fibrosis transmembrane conductance regulator (CFTR) gene variants across India and their variability in different geographic regions.

Effect of elexacaftor-tezacaftor-ivacaftor on bronchial dilatations in adolescents with cystic fibrosis: a multicentre prospective observational study.

We present a case series describing the management and genetic findings in five neonates with meconium ileus, presenting within 48 h of birth. Whole-exome sequencing identified cystic fibrosis transmembrane conductance regulator mutations in three neonates, confirming cystic fibrosis, with one heterozygous variant of unknown significance. Two ultimately required surgical intervention after failed conservative management. One died of septic shock.

The management of cystic fibrosis (CF) has significantly improved with the approval of the CF transmembrane conductance regulator (CFTR) modulators. Elexacaftor/tezacaftor/ivacaftor (ETI) is approved for treatment in people with CF (pwCF) over the age of 2 years with eligible mutations. We report 2 cases highlighting improved clinical outcomes following exposure to ETI in an off-label use, including enhanced nutrition status, decrease in respiratory support, exacerbation rates, and need for antibiotics in one of the infants and resolution of echogenic bowel that was diagnosed in utero in the second.

Modulators of anion channels and transporters as alternative therapeutic agents to normalize airway surface liquid in cystic fibrosis.

Background: Several genes encoding proteins essential for normal bile production have been associated with progressive familial intrahepatic cholestasis in children, but there are few studies evaluating the frequency of variants in these genes among adults with chronic cholestatic disease. The aim of this study was to assess frequency of variants in progressive familial intrahepatic cholestasis–associated genes in adults with idiopathic or episodic cholestatic chronic liver disease (cCLD). Methods: Patients with cCLD of unknown cause followed in 4 different reference centers in Brazil were genotyped for ABCB11 , ABCB4 , ABCC2 , ATP8B1 , CFTR , JAG1 , KIF12 , LSR , MYO5B , NR1H4 , PPM1F , SERPINA1 , TJP2 , USP53 , VIPAS39 , VPS33B , PEX26 , and WDR83OS gene variants using Illumina platforms. Primary biliary cholangitis, primary sclerosing cholangitis, and other causes of cCLD were excluded. Results: Sixty-five patients (40 females; mean±SD age at disease onset, 26.8±13.4 y) were included. Most (65%) had either a family history of cholestatic liver disease or previous signs and symptoms of intrahepatic cholestasis of pregnancy or low phospholipid–associated cholelithiasis. Fifty-seven (88%) had cCLD, whereas 8 (12%) reported recurrent episodic cholestasis. Some had evidence at diagnosis of cirrhosis (n=20) or hepatocellular carcinoma (n=2) or had undergone liver transplantation (n=10). Sequencing revealed 28 variants in ABCB4 (n=25) and ABCB11 (n=3) genes in 42 patients [65%; heterozygous (n=31), homozygous (n=4), and compound heterozygous (n=7)]. Only 17 (61%) were previously reported. Most variants (57%) were classified as pathogenic or likely pathogenic. Conclusions: More than half of the patients with cCLD of unknown cause exhibited pathogenic or likely pathogenic variants in bile transporter genes, particularly ABCB4 . Genotyping may identify most of those patients as late-onset patients with multidrug resistance protein 3 deficiency.

Cystic fibrosis liver disease (CFLD) is a significant nonpulmonary complication of cystic fibrosis, affecting approximately 5-10% of patients. It encompasses a spectrum of hepatic abnormalities ranging from mild, transient elevations in liver enzymes to advanced CFLD (aCFLD), which is marked by clinically relevant portal hypertension due to cirrhotic or noncirrhotic liver pathology. This review focuses on aCFLD as the clinically meaningful form of the disease and summarizes recent mechanistic insights into its pathogenesis that may inform the development of targeted therapeutic strategies. CFLD pathogenesis has been traditionally linked to defective bile secretion. Emerging evidence, however, highlights additional contributors, including cholangiocyte immune dysregulation, gut dysbiosis, and intestinal barrier dysfunction, which together promote hepatic inflammation. Furthermore, recent studies underscore the role of vascular alterations independent of cirrhosis, specifically noncirrhotic portal hypertension, as the main clinical feature in aCFLD. These findings support a multifactorial, multihit model of disease in the pathogenesis of CFLD. The complex interplay of these factors suggests that effective treatment for aCFLD may require a multifaceted approach. Advances in understanding the gut-liver axis and vascular contributions provide new therapeutic targets. Future research should focus on validating these findings and evaluating the efficacy of cystic fibrosis transmembrane conductance regulator modulators and microbiome-targeted treatments in altering the course of CFLD.

Introduction: Classically known for their roles in facilitating lipid digestion and absorption, bile acids are now also appreciated as enterocrine hormones that modulate many aspects of intestinal physiology. We have previously shown lithocholic acid (LCA), a secondary bile acid, to be protective against colonic inflammation. Here, we investigated if LCA also regulates colonic epithelial fluid and electrolyte transport. Methods: T84 cell monolayers were mounted in Ussing chambers for measurements of transepithelial Cl- secretion. CFTR mRNA and protein expression were analyzed by qRT-PCR and Western blotting in T84 cells and human-derived colonic organoids. CFTR promoter activity was assessed using a luciferase promoter/reporter assay in HEK293 cells. Results: Pretreatment of T84 cells with LCA inhibited Cl- secretory responses to the cAMP-dependent agonist, forskolin (FSK), with maximal effects occuring at a concentration of 10 μM after 24hrs treatment. Under these conditions, LCA also inhibited responses to the Ca2+-dependent secretagogues, thapsigargin and histamine. In nystatin-permeabilized T84 monolayers, LCA reduced FSK-stimulated apical Cl- conductances, an effect that correlated with reduced CFTR Cl- channel expression. While LCA activated both FXR and vitamin D receptor (VDR), its effects on CFTR expression and Cl- conductances were mimicked only by an FXR agonist, GW4064, and not by a VDR agonist, calcitriol. Finally, LCA inhibited CFTR promoter activity in HEK3 cells, but only when FXR was expressed. Conclusion: LCA, at physiologically-relevant concentrations, chronically inhibits colonic epithelial Cl- secretion, likely via FXR-induced downregulation of CFTR. These data broaden our knowledge of the regulatory roles of LCA in the colon and highlight its potential as a therapeutic target for intestinal disorders.

Multiple cystic fibrosis transmembrane conductance regulator (CFTR) modulators are approved for the treatment of cystic fibrosis (CF) and show significant improvement in lung function, BMI, quality of life, and sweat chloride. However, their ability to impact liver disease is unclear. This review highlights the current published literature on CFTR modulators and liver health and briefly reviews considerations for clinical management of hepatobiliary disease in the CFTR modulator era. Currently, the primary data available on the clinical efficacy of CFTR modulators on CF hepatobiliary involvement (CFHBI) or advanced CF liver disease (aCFLD) is from small to moderate sized single-center studies, although more recently large, multicenter studies are emerging. Studies report opposing changes in aminotransferases, and mixed liver fibrosis index and elastography results. Yet, in total CFTR modulators generally do not worsen liver disease and may improve it in some individuals. Additional clinical management considerations are necessary in those on CFTR modulators who received an organ transplant or during nutritional evaluations. To better understand the possible benefit of CFTR modulator therapies on hepatobiliary health, additionally larger, longer-term, multicenter studies with sub-group phenotyping are necessary. Until then, providers should watch for liver-related adverse events, and be cognizant on how CFTR modulators may impact areas of clinical care for individuals with CF.

Background. Cystic fibrosis (CF) is a multisystem disease caused by variants in the CF transmembrane conductance regulator (CFTR) gene affecting ion transport. CFTR modulator therapy has become a significant treatment option for many CF patients. However, access to modulator therapy remains a challenge for cases with rare variants. Case Presentation. Our 9-year-old female patient, diagnosed with CF by elevated sweat chloride and history of steatorrhea from birth, carried the rare W1282X variant with no clear eligibility for modulator therapy. The family self-financed one month of elexacaftor / tezacaftor / ivacaftor (ETI) treatment. After one-month, clinical evaluation showed improvements in body mass index (BMI; 14.98 to 15.05 kg/m2), an increase in forced expiratory volume in 1 second (FEV1%) by 12% (72% to 84%), decreased sweat chloride levels (from 83 mEq/L to 9 mEq/L), and enhanced exercise capacity. No pulmonary exacerbations occurred during therapy. Based on these findings, modulator therapy approval was obtained for continued treatment. Our patient is currently 10 years old and has been on modulator therapy for approximately 12 months. Conclusions. Facilitating access to modulator therapies for patients with rare mutations is crucial, considering the potential long-term complications of CF. While organoid studies may not always predict clinical response, real-world cases demonstrate clinically meaningful benefit despite lack of organoid responsiveness. Short-term assessment of modulator response may not adequately reflect improvement in pulmonary function or exacerbation frequency, but decreases in sweat chloride, improvements in nutritional and functional parameters such as weight, BMI, and exercise capacity may be indicative of improvement in pulmonary function and exacerbation rates.

Cystic fibrosis (CF) is a life-shortening genetic disorder caused by mutations in the CFTR gene, leading to dysfunctional chloride ion transport and associated complications. This study employs computational chemistry to explore the molecular mechanisms underlying CF and to aid the development of targeted therapeutics. Twenty-seven ligand derivatives from 3-(2-benzyloxyphenyl) isoxazoles and isoxazolines previously reported as CFTR activators were analyzed and compared to genistein, a known CF therapeutic. Ligand structures were optimized using Density Functional Theory (DFT), and molecular descriptors were computed with PaDEL software. Using Genetic Function Approximation (GFA) via Material Studio, Quantitative Structure-Activity Relationship (QSAR) models were developed to correlate molecular features with biological activity (pIC₅₀). The top model (R² = 0.974) demonstrated high predictive power and reliability, validated through cross-validation and applicability domain analysis. Key descriptors such as SpDiam_Dt, GATS4v, and MATS7i significantly influenced model performance, offering insights into molecular traits critical for CF treatment efficacy. These findings highlight the potential of computational approaches in accelerating drug discovery for cystic fibrosis by identifying and optimizing promising lead compounds.

Cystic fibrosis (CF) is a life-shortening monogenic disease caused by mutations in the CFTR gene, but the functional expression of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl-/HCO3- channel is determined by more than its genetic sequence. Beyond the well-known folding defect of the common F508del mutation, CFTR activity is dynamically modulated by a network of intracellular signaling pathways that control the channel's gating, trafficking to, and retention at the apical membrane. Foremost is the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway, which drives CFTR opening via phosphorylation of its regulatory (R) domain and coordination by scaffolding proteins (e.g., A-kinase anchoring proteins (AKAPs) and Na+/H+ exchanger regulatory factor 1 (NHERF1)). Equally important, Ca2+-dependent signaling cascades provide complementary fine-tuning: Ca2+-bound calmodulin can directly bind and increase the CFTR open probability, Ca2+-activated kinases such as Ca2+/calmodulin-dependent protein kinase II (CaMKII) and the tyrosine kinase Pyk2 (with Src) can phosphorylate CFTR through noncanonical routes, and signaling intermediates such as IP3 receptor binding protein released with IP3(IRBIT) connect Ca2+ release to CFTR activation. These cAMP- and Ca2+-driven pathways intersect in specialized subcellular nanodomains, enabling precise spatiotemporal regulation of CFTR function. Clinically, although new CFTR modulator drugs have greatly improved outcomes, their effectiveness is limited by mutation-specific responses and incomplete restoration of channel activity. Understanding how cAMP-Ca2+ crosstalk governs CFTR in context can reveal novel therapeutic strategies targeting the channel's regulatory microenvironment. This review highlights how compartmentalized cAMP and Ca2+ signals orchestrate CFTR function and discusses emerging approaches to harness this insight for better therapies across CF-affected organs.

Dear Editor, Chronic obstructive pulmonary disease (COPD) is a disease related to the respiratory system which causes bronchoconstriction and excess release of mucus leading to airway remodeling and obstruction. This condition is also involved with airway inflammation and oedema. Statistically, according to WHO, chronic obstructive pulmonary disease is the third leading cause of death worldwide. (1) Over the past four decades, standard-of-care COPD treatment has been based on inhaled short- and long-acting bronchodilators [including long-acting beta 2 agonists (LABAs) and long-acting muscarinic receptor antagonists (LAMAs)] and inhaled corticosteroids. (1)Still, patients may remain largely symptomatic due to the wide range of spectrum of COPD complications, often requiring concomitant use of both bronchodilators and anti-inflammatory drugs. Furthermore, their use is limited due to several reasons. They are unable to reverse airway wall damage and they cannot stimulate lung regeneration. Also, there is very limited sensitivity of the inflamed airways to the available medical options. Lastly, there are side effects associated with their use hence these reasons limit their use. (2) Ensifentrine (RPL554) is the latest FDA-approved advancement available for COPD. It is a novel drug that works by dual inhibition of phosphodiesterase (PDE) 3 and 4 enzymes (PDE3, PDE4) and is delivered via inhalation. Inhibitors of PDE3 and PDE4 target multiple respiratory functions at the cellular and tissue level. PDE3 regulates cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) levels in the airway smooth muscles, which mediates bronchial tone. PDE4 regulates cAMP levels in the airway cells associated with inflammation and is involved in activation of these cells. PDE4 inhibitors also stimulate the cystic fibrosis transmembrane conductance regulator (CFTR) and improve bronchial epithelial cell ciliary movements (3) This dual inhibition of PDE3 and PDE4 enzymes results in a synergistic effect, making Ensifentrine the first ever drug to treat both COPD associated inflammation as well as bronchoconstriction. (4) Ensifentrine not only delivers significant improvement in lung function as sole therapy at doses of 3 mg and 6 mg (4) but also its pivotal role as an adjuvant to existing treatment regimens comprising long-acting muscarinic antagonists (LAMA) or long-acting beta-agonists with inhaled corticosteroids (LABA Plus ICS), as well as enhancing their combined efficacy over longer periods (5) has now been clearly demonstrated and documented.

Genetics is significant contributor to acute recurrent pancreatitis. This study evaluates the prevalence of genetic variants and assesses electrophysiological characteristics in Israeli patients. Patients with ≥ two episodes of acute pancreatitis, no history of drug use, normal IgG4 levels, and normal cholangiopancreatographic findings were included. Genetic analysis targeted the PRSS1, SPINK1, CTRC, CFTR, CPA1 and TRPV6 genes, as well as the CEL-HYB1 allele. Sweat testing and nasal potential difference measurements were also performed. Seventy-nine patients (median age 13 years; range 2-61) were referred between 2015 and 2021. 45 (57.0%) carried at least one genetic variant; 18 patients carried 2 or more variants. CFTR variants were the most common (35.4%), followed by PRSS1 (11.4%), SPINK1 (10.1%), and CTRC (10.1%). The rare PRSS1 p.Lys23Arg variant was prevalent among Jewish Georgian patients (n=8). Patients with genetic variants were younger than those without (P<0.0035). Of the 71 patients who underwent nasal potential difference testing, 2 (5.6%) had abnormal results. Sweat test in 66 patients showed a mean value of 36 ± 16mmol/L, six had results above 60mmol/L; two of these carried CFTR variants TG[11]T[5] and p.Leu997Phe but had normal nasal potential. More than half of acute recurrent pancreatitis cases had a genetic basis, presenting at a younger age. CFTR variants were the most prevalent. The high prevalence of the PRSS1 p.Lys23Arg variant among Jewish Georgian individuals suggests a potential founder effect. These findings highlight the importance of genetic evaluation in the diagnosis and management of acute recurrent pancreatitis.

Background/Objectives: This study reports on findings from the first preconception screening performed in Russia and provides a comprehensive discussion of the significant results and challenges faced during the implementation of the project. Methods: Using a targeted sequencing panel of 33 genes (associated with 29 autosomal recessive and 4 X-linked diseases), we analyzed 165 couples considering pregnancy. The screening design also included analysis of the frequent pathogenic variants in the SMN1, DMD, CFTR, and CYP21A2 genes that may not be detected through the next-generation sequencing approach. The sequential screening protocol, wherein the female partner was tested first, was used. Results: The results revealed that 35.8% of women (n = 59) were carriers of at least one pathogenic or likely pathogenic (P/LP) variant, with 7.9% of women (n = 13) carrying variants in two or more genes. Notably, the analysis identified 5 deletions of exon 7 in the SMN1 gene, 1 deletion of the CYP21A2 gene, and 1 large duplication in the DMD gene in female participants. The most frequently identified pathogenic variants occurred in the CYP21A2, GJB2, SERPINA1, and ATP7B genes. The screening identified six couples (3.6% of the cohort) at high risk of having a child with an autosomal recessive or X-linked genetic disorder. Conclusions: This pilot study confirms the high clinical utility of the gene panel, effectively evaluating reproductive risk in couples without a known family history of monogenic diseases. The findings indicate that the observed frequencies of identified gene variants differ from those theoretically expected, with a notable percentage of identified couples being at relatively high risk. Furthermore, these results highlight the indispensable role of comprehensive genetic counseling both before and after testing to ensure an appropriate preconception testing algorithm and informed reproductive decision-making.

Cystic fibrosis (CF) is a genetic disorder caused by mutations in the CFTR gene, leading to multi-system impairment. Sleep respiratory disorders (SRDs) are frequent in individuals with CF—even in those with normal or mildly impaired lung function—and may adversely affect overall health. The triple combination of elexacaftor, tezacaftor, and ivacaftor (ETI) has markedly improved clinical outcomes in CF; however, its long-term impact on SRDs remains unclear. This study aimed to assess the effects of ETI on nocturnal cardiorespiratory parameters in individuals with CF over a two-year period. Thirty-five clinically stable patients aged ≥13 years, eligible for ETI therapy, were enrolled. Nocturnal cardiorespiratory polygraphy and spirometry were performed at baseline (T0), one year (T1), and two years (T2) after ETI initiation. After one year, significant improvements were observed in mean oxygen saturation (mSpO2), time with SpO2 ≤ 90% (t ≤ 90%), and respiratory rate. Spirometric indices (FEV1, FVC, FEF) also significantly increased (p < 0.05). Correlation analysis revealed positive associations between mSpO2 and FEV1 (ρ = 0.515, p = 0.002) and between FEV1 and FVC (ρ = 0.894, p < 0.001), while t ≤ 90% negatively correlated with FEV1 (ρ = −0.404, p = 0.016). No additional significant changes were found at T2. ETI therapy resulted in sustained improvements in nocturnal oxygenation and lung function, supporting the importance of nocturnal respiratory monitoring during follow-up.

Developing Type II F508del-CFTR correctors with a protective effect against respiratory viruses.

Cystic fibrosis (CF) is a universal exocrine disorder that affects virtually all organs and systems containing exocrine glands. A genetic defect in the cystic fibrosis transmembrane conductance regulator gene leads to increased viscosity of exocrine gland secretions, primarily in the respiratory tract. CFTR modulators improve the synthesis, processing, and/or function of the defective CFTR protein, which is a chloride channel. Objective. To evaluate the efficacy of the generic drug ivacaftor + tezacaftor + elexacaftor/ivacaftor (trade name Trilexa®), in a group of patients not previously receiving triple targeted therapy after 3 months of treatment in patients who have not previously received the first threecomponent CFTR modulator. Methods. Data from the Russian CF Patient Registry, entered into the “Targeted Therapy” block, were analyzed for the period from January to August 2025 (main group) and for the period from January 2022 to August 2022 (comparison group). Two groups of patients were identified: Group 1 included 28 pediatric patients (12 boys/16 girls) with a confirmed diagnosis of cystic fibrosis, who started receiving triple targeted therapy generic drug ivacaftor + tezacaftor + elexacaftor/ivacaftor. Group 2, the comparison group, consisted of 34 pediatric patients (14 boys/20 girls) who started receiving the original triple targeted drug ivacaftor + tezacaftor + elexacaftor/ivacaftor (trade name Trikafta®). Results. When assessing the nutritional status, a significant increase in BMI was shown in both groups of patients at the start and after 3 months; p &lt; 0.001. Sweat test parameters (conductivity in mmol/L) differed significantly both at the start of therapy and after a month in both groups. The difference between the average sweat test values (Δ mmol/L) in both groups were comparable and did not differ from each other. The groups did not differ in the number of adverse events, which were mild and did not lead to drug discontinuation. Both drugs, the original and the generic, demonstrated safety and good tolerability. Group 1 value was 43 (35.5; 55), and Group 2 value was 42 (32; 50.3); p = 0.86. FEV1 and FVC indicators showed a tendency to increase with both drugs, but it was not significant in both groups. Conclusion. The triple targeted therapy with the use of generic drug ivacaftor + tezacaftor + elexacaftor/ivacaftor is effective and safe in this sample of pediatric patients with cystic fibrosis. No significant differences were found between generic drug and the original drug in relation to the main efficacy criteria during 3 months of use. The frequency, spectrum, and severity of reported adverse events associated with the use of generic drug were comparable to those associated with the use of the original drug.

Cystic fibrosis (CF) is a progressive, life-limiting, autosomal recessive monogenic disease caused by mutations in the CFTR gene, leading to dysfunction of chloride channels in epithelial cells of almost all human exocrine systems, disrupting the function of sweat and salivary glands, the exocrine part of the pancreas, the hepatobiliary and reproductive systems, the intestines, and the respiratory tract. The development of CFTR modulators has revolutionized the treatment of CF by correcting CFTR protein dysfunction at the cellular level. The aim . In our review, we tried to answer the question of whether the new three-component modulator vanzacaftor/tezacaftor/deutivacaftor (VTD) represents a significant step forward in the treatment of people with CF and whether all susceptible patients should switch from elexacaftor/tezaftor/ivacaftor (ETI) to VTD. Methods. We analyzed all available scientific literature on the comparative efficacy of VTD and ETI. The search was conducted in the PubMed, Scopus, and Web of Science databases. Results. It has been found that to date (October 2025) there is no proven clinical superiority of VTD over ETI. The drugs are comparable in terms of improving lung function, the number of exacerbations of the bronchopulmonary process, and the number of adverse reactions. Based on sweat test results, VTD demonstrates an advantage in restoring CFTR protein function, indicating the potential for early restoration of normal chloride channel function and prevention of the development or progression of cystic fibrosis, which still needs to be confirmed in real-world clinical practice. The once-daily dosing regimen of VTD could be considered a desirable feature of the drug, but its high cost does not provide ethical arguments in favor of a mass switch from ETI to VTD for the public health benefit. VTD can be prescribed to patients aged 6 years and older who have at least one of 31 additional pathogenic variants not listed in the prescribing information for ETI. Conclusion. The advisability of discontinuing successful pathogenetic treatment with ETI and prescribing VTD requires further study in real clinical practice.

Protein folding in vivo is biologically tuned to minimize off-pathway events and optimize native folding outcomes. A key factor in this process is biased synonymous codon usage, in which synonymous codons modulate local translation rate while maintaining the native amino acid sequence. Here, we demonstrate that native codon usage within the first nucleotide-binding domain (NBD1) of the cystic fibrosis transmembrane conductance regulator (CFTR) induces a translational pause during a critical window of synthesis that affects CFTR folding, processing, and function. Eliminating this pause by substituting synonymous codons increased the aggregation propensity of immature CFTR and induced conformational and functional changes that persisted during CFTR processing and plasma membrane expression. Interestingly, the resulting mature CFTR protein at the plasma membrane exhibited enhanced ATP-dependent chloride channel gating. Thus, during protein synthesis, cotranslational events dictated by codon usage can imprint persistent conformational and functional properties upon CFTR. Our findings suggest that CFTR codon usage has evolved and adapted to balance a compromise between protein aggregation and a modest loss of channel function.