Search Results (45)

Kv11.1 (hERG1) channels, encoded by KCNH2, mediate the rapid delayed rectifier potassium current (I_Kr) crucial for cardiac repolarization. Disruptions, via mutations or antiarrhythmic drugs like dofetilide cause severe arrhythmogenic disorders, including Long QT Syndrome Type 2 (LQT2), Brugada Syndrome (BrS), and Torsades de Pointes (TdP). While Kv11.1’s role in channelopathies and drug-induced arrhythmias is established, understanding its complex regulation and therapeutic targeting remains a challenge. This review synthesizes the structural, functional, and regulatory aspects of Kv11.1 channels and their clinical implications. Recent studies using iPSC-derived cardiomyocytes highlight regulation by PI3K/Akt, PKC, and PKA signaling via phosphorylation (Ser283, Ser890) and interactions with proteins like 14-3-3. Beyond electrophysiology, Kv11.1 influences pathological hypertrophy and non-cardiac functions including insulin secretion. Pharmacological efforts focus on activators to shorten action potential duration and suppress TdP, and blockers with overdose risks. Mutation heterogeneity, exemplified by trafficking impairment (G785D) in LQT2 and gain-of-function (R397C) in BrS, complicates precision therapy. Clinically, systematic risk stratification using electrocardiographic parameters and genotype-specific approaches enables personalized management. Beta-blockers remain first-line therapy for LQTS2, while rigorous avoidance of QT-prolonging medications and electrolyte monitoring form the cornerstones of preventive care. Advancing Kv11.1-targeted therapies with approaches like CRISPR-Cas9 and pharmacological chaperones (e.g., lumacaftor) holds promise for personalized treatments, ultimately reducing arrhythmic events and sudden cardiac death. Full article

Background: Pediatric cataracts are a main cause of irreversible vision loss and a significant public health challenge. This study aimed to identify pharmacovigilance signals by analyzing large-scale data from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: Using real-world data from FAERS (Q1 2004 to Q3 2025), we investigated associations between medications and pediatric cataracts. Following data standardization, signal detection was performed using multiple disproportionality analyses, including the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS). The time to onset was also evaluated. Results: Among 690,374 reports for individuals aged 0–17 years, 671 reports involving 232 drugs were reported with cataracts. Disproportionality analysis identified 24 drugs with significant signals, predominantly glucocorticoids (11/24), followed by immunosuppressants, monoclonal antibodies, cystic fibrosis transmembrane conductance regulator (CFTR) modulators, antineoplastic agents, an antiepileptic drug, and a colony-stimulating factor. Difluprednate showed the highest pharmacovigilance signal (ROR: 963.67; 95% CI: 316.27–2936.31; n = 4). Notably, CFTR modulators exhibited striking signals: ivacaftor (ROR: 30.75; 95% CI: 18.06–52.37; n = 14), elexacaftor-ivacaftor-tezacaftor (ROR: 15.58; 95% CI: 9.86–24.63; n = 19), and ivacaftor-lumacaftor (ROR: 13.2; 95% CI: 7.9–22.07; n = 15). Conclusions: This study provides a comprehensive large-scale pharmacovigilance profile of drug-induced pediatric cataracts, identifying agents with high-risk pharmacovigilance signals and underscoring the need for proactive ocular monitoring. These findings can inform clinical decision making and prevention strategies and guide future mechanistic research. Full article

Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators have been reported to improve lung function and reduce CF exacerbations. We aimed to investigate the efficacy of CFTR-modulators in CF-associated liver disease (CFLD) during long-term treatment. Longitudinal data were collected from genetically confirmed adult CF patients receiving CFTR-modulators. CFLD was diagnosed using conventional criteria combined with liver stiffness measurement (LSM). A total of 57 patients [56.1% male; median age at baseline (T0), 26 years (interquartile range [IQR], 23–35)] were included. Patients received lumacaftor/ivacaftor and/or elexacaftor/tezacaftor/ivacaftor for a median of 43 months (range, 15–123) until last assessment (T2). The prevalence of CFLD decreased from 15 (26.3%) at T0 to 8 (14.0%) at T2 (p = 0.016), and no new cases of CFLD were observed. Median LSM decreased from 6.2 (IQR 4.9–8.0) to 5.0 kPa (IQR 4.1–6.2) in the overall cohort (p < 0.001) and from 10.2 (IQR 6.8–13) to 6.2 kPa (IQR 5.0–12.4) in the CFLD subgroup (p = 0.025). Mild, transient fluctuations in liver enzymes occurred in 26.3% of patients. In conclusion, adults with CF receiving long-term CFTR modulators, showed improvement of liver disease assessed by ultrasonography and transient elastography. At the last assessment, half of the patients no longer met the criteria for CFLD. Full article

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CFTR gene, which encodes a cAMP-activated chloride channel essential for epithelial function. Beyond its canonical role, evidence suggests CFTR also influences mitochondrial function. Previous studies have identified CFTR- and Cl-dependent genes, including MTND4 and CISD1, which are downregulated in CF cells and play a critical role in mitochondrial function. CF cells exhibit altered mitochondrial complex I (mCx-I) activity and impaired electron transport chain function, although the underlying mechanisms remain unclear. In this study, the impact of the CFTR modulators lumacaftor (VX-809) and ivacaftor (VX-770) on mitochondrial morphology and function was investigated in heterozygous ΔF508/W1282X CF IB3-1 cells. Combined treatment with VX-809 (10 μM, CFTR corrector) and VX-770 (0.1 μM, CFTR potentiator) induced a fragmented mitochondrial morphology in both CF and CF expressing wt-CFTR cells, without affecting cell viability or mitochondrial membrane potential (ΔΨm). While individual treatments differentially modulated ROS production and ΔΨm, these effects were not statistically significant under combined treatment. These results highlight a previously unrecognized role for CFTR modulators in shaping mitochondrial morphology. A better understanding of these effects may reveal novel mechanisms underlying the regulation of mitochondrial structure and function. Full article

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. Full article

Background: An increase in hemoglobin (Hb) has been reported in subjects with CF treated with the CFTR modulator Ivacaftor and with the combination Lumacaftor/Ivacaftor (LI), while the literature about the impact of Elexacaftor/Tezacaftor/Ivacaftor (ETI) on Hb levels in the pediatric population is lacking. Materials and Methods: We retrospectively evaluated Hb levels in 35 subjects with CF (18 males, median age: 8 years; interquartile range (IQR): 6–13 years) treated with LI and 60 (24 males, median age: 10 years; IQR: 6–14 years) treated with ETI. For each subject we considered the values of Hb, serum potassium, total bilirubin (TB), and conjugated bilirubin (CB) at baseline, after 3 days, and 1, 3, 6, 9, and 12 months from the start of treatment. Results: In subjects with CF treated with LI, we observed a significant increase in Hb values 3 days after the introduction of the drug, which remained constant throughout the year of treatment. In subjects treated with ETI, a significant decrease in Hb was observed 3 days after the first dose up to 1 month. At 6 months, Hb returned to pre-treatment values remaining stable for up to 12 months. At 3 days of treatment, we also observed a significant increase in serum potassium, which returned to normal at one month, while both TB and CB values significantly increased at 3 days of treatment and remained significantly higher for the whole one-year period of ETI therapy. Conclusions: We confirmed an increase in Hb values over time in subjects treated with LI. While the Hb response in those treated with ETI showed a transient reduction that lasted for one month, this may have depended on hemolysis, and returned to pre-treatment levels. Further studies will clarify the mechanisms that govern changes in Hb in subjects with CF treated with ETI. Full article

Fibrosis transmembrane conductance regulator (CFTR) modulators (CFTRms) have significantly improved outcomes in people with cystic fibrosis (CF). Real-world evidence, particularly from national and international CF registries, is essential to assess their long-term effectiveness and safety. We reviewed published studies using registry data to evaluate the impact of CFTRms on clinical outcomes in individuals with CF. A narrative review of studies published between 2015 and 2025 was conducted, focusing on registry-based evaluations of ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor, and elexacaftor/tezacaftor/ivacaftor. Primary outcomes included lung function, pulmonary exacerbations, nutritional status, and survival. Fifty-seven registry-based studies confirmed the benefits of CFTRms across diverse CF populations. Ivacaftor has demonstrated sustained improvements in forced expiratory volume in one second (FEV₁), reduced exacerbations, and improved nutritional outcomes. Lumacaftor/ivacaftor and tezacaftor/ivacaftor have shown modest benefits, especially in homozygous F508del patients. The introduction of elexacaftor/tezacaftor/ivacaftor has led to unprecedented improvements in lung function and quality of life, along with a reduced need for lung transplantation. Methodological heterogeneity and incomplete data remain challenges. Registry data provide essential, complementary evidence to clinical trials and support the effectiveness of CFTRms in routine care. Continued efforts are needed to harmonize registry methodologies and outcome measures. Full article

Cystic fibrosis (CF) is a life-threatening disorder caused by mutations in the CFTR gene, leading to defective chloride ion transport and thickened mucus in the respiratory and gastrointestinal systems. CFTR modulators, including ivacaftor, lumacaftor, tezacaftor, and elexacaftor, have improved patient outcomes, but interindividual pharmacokinetic variability and potential drug–drug interactions require therapeutic drug monitoring (TDM) for optimal efficacy and safety. In this context, a liquid chromatography–tandem mass spectrometry (LC-MS/MS) method has been developed and validated for the simultaneous quantification of CFTR modulators and their major active metabolites in human plasma to support pharmacokinetic studies and routine TDM. The multiplex LC-MS/MS assay was established using plasma protein precipitation, followed by chromatographic separation on an Xselect HSS T3 (Waters^®) column and positive electrospray ionization mode detection. The method was validated based on FDA and EMA guidelines for specificity, linearity, accuracy (89.8–107.8%), repeatability (1.1–8.1%), intermediate fidelity (1.3–10.9%), matrix effects, and stability, demonstrating a robust performance with excellent precision and accuracy. International interlaboratory comparisons confirmed the reliability of the assay. The developed method can be applied for the clinical monitoring of caftors’ plasma concentrations and preliminary data suggest that it can also be applied to alternative matrices, such as breast milk. This method will serve to characterize caftors’ pharmacokinetic variability and monitor drug–drug interactions to further refine personalized dosing strategies and enhance precision medicine treatments for patients with CF. Full article

Cystic fibrosis (CF) is a recessive genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a chloride and bicarbonate channel localized on the plasma membrane of epithelial cells. Over the last three decades, high-throughput screening assays have been extensively employed in identifying drugs that target specific defects arising from CFTR mutations. The two main categories of such compounds are potentiators, which enhance CFTR gating by increasing the channel’s open probability, and correctors, which improve CFTR protein folding and trafficking to the plasma membrane. In addition to these, other investigational molecules include amplifiers and stabilizers, which enhance the levels and the stability of CFTR on the cell surface, and read-through agents that promote the insertion of correct amino acids at premature termination codons. Currently, four CFTR modulators are clinically approved: the potentiator ivacaftor (VX-770), either as monotherapy or in combination with the correctors lumacaftor (VX-809), tezacaftor (VX-661), and elexacaftor (VX-445). Among these, the triple combination VX-445/VX-661/VX-770 (marketed as Trikafta^® in the US and Kaftrio^® in Europe) has emerged as the most effective CFTR modulator therapy to date, demonstrating significant clinical benefits in phase III trials for patients with at least one F508del CFTR allele. Despite these advancements, the mechanisms of action and binding sites of these modulators on CFTR have only recently begun to be elucidated. A deeper understanding of these mechanisms could provide essential insights for developing more potent and effective modulators, particularly in combination therapies. This narrative review delves into the mechanism of action, binding sites, and combinatorial effects of approved and investigational CFTR modulators, highlighting ongoing efforts to broaden therapeutic options for individuals with CF. Full article

Allergic bronchopulmonary aspergillosis (ABPA) is a well-known complication in children and young people with cystic fibrosis (CF) and without treatment causes structural lung damage. We performed a longitudinal observational study to identify clinical risk factors for ABPA in a cohort of children and young people with CF aged 8 to 17 years at baseline. Anonymised annual review UK CF Registry data from 2009 to 2019 for patients aged 8–17 years in 2009 were collected, with lung transplant recipients excluded. Baseline characteristics are presented for the whole group and cross-sectional comparisons made according to the presence of ABPA or not in 2009. Longitudinal analysis from 2009 to 2019 was completed on the group without ABPA in 2009 to identify predictors for the subsequent development of ABPA using a complementary log–log regression model. In 2009, there were 1612 patients, of which 1420 were ABPA-negative and 192 ABPA-positive. Aspergillus colonisation (p = 0.01) and IV antibiotic use (p < 0.0001) were associated with having ABPA in 2009. Longitudinal analysis of the group without ABPA in 2009 identified male gender, younger age, lower lung function, Pseudomonas aeruginosa infection, and Aspergillus colonisation to be significantly associated with the development of ABPA (p < 0.0001). Ivacaftor was significantly associated with reduced ABPA (OR 0.46, p = 0.01) but not lumacaftor/ivacaftor (OR 0.64, p = 0.28). Chronic oral macrolide use was significantly associated with increased risk of development of ABPA (OR 1.30, p < 0.0001). This study shows that lower lung function, Aspergillus colonisation, and Pseudomonas aeruginosa infection in children with CF were associated with the development of ABPA, highlighting the need for enhanced surveillance in these patients. This is the first study to show a protective association of ivacaftor and ABPA. Full article

Background/objectives: Cystic fibrosis (CF) is a life-limiting genetic disorder affecting multiple organ systems. This study compared clinical outcomes, hospitalization rates, and survival between children and adolescents with CF who received CFTR modulator therapies (ivacaftor, lumacaftor, tezacaftor, and elexacaftor). Methods: A retrospective cohort study was conducted using data from the TriNetX global collaborative network. Patients with CF aged 2–12 years (children) and 13–18 years (adolescents) who received CFTR modulator therapies were included. The propensity score matching balanced baseline characteristics between the two age groups. Results: After propensity score matching, 946 patients per group were analyzed. The incidence of respiratory failure (3.81% vs. 1.06%, p < 0.001) and respiratory infections (62.7% vs. 57.5%, p = 0.021) were significantly higher in adolescents compared to children. Adolescents had a higher risk of respiratory failure (HR = 3.6, 95% CI = 1.79–7.21, p < 0.001) and respiratory infections (HR = 1.09, 95% CI = 1.01–1.17, p < 0.001). Adolescents also had a higher hospitalization rate (29.6% vs. 20.3%, p < 0.001), with a 47% higher risk (HR = 1.47, 95% CI = 1.22–1.77, p = 0.001), more hospital visits per person (8.8 vs. 3.7, p = 0.004), and longer hospital stays (32.7 vs. 20.4 days, p = 0.006). Mortality rates were similar between the groups (1.58% vs. 1.26%, p = 0.56). Conclusions: CF patients who initiated CFTR modulator therapies during adolescence had a higher incidence of respiratory failure, respiratory infections, hospitalization rates, and healthcare resource utilization compared to those who started therapy in childhood, despite similar mortality rates. These findings highlight the importance of the early initiation of CFTR modulator therapies. Full article

Complex alleles of the CFTR gene complicate the diagnosis of cystic fibrosis (CF), the classification of its pathogenic variants, affect the clinical picture of the disease and can affect the efficiency of targeted drugs. The total frequency of complex allele [L467F;F508del] in the Russian population of patients with CF is 0.74%, and in patients with the F508del/F508del genotype, its frequency reaches 8%. This article presents multi-faceted study of the complex allele [L467F;F508del] in a cohort of patients with genotypes [L467F;F508del]/class I (c.3532_3535dup, c.1766+2T>C, W1310X, 712-1G>T), and data for a unique patient with the genotype [L467F;F508del]/[L467F;F508del]. Using the intestinal current measurement method, it was demonstrated the absence of CFTR function for [L467F;F508del]/class I and [L467F;F508del]/[L467F;F508del] genotypes. In intestinal organoids, it was shown that [L467F;F508del] in combination with class I variants and in the homozygotes abolishes the efficacy of both two-component (ivacaftor+lumacaftor; ivacaftor+tezacaftor) and three-component (ivacaftor+tezacaftor+elexacaftor) targeted drugs. When prescribing ivacaftor+tezacaftor+elexacaftor to three patients, they did not have a clinical effect after 6–12 months. Full article

Background: In recent years, cystic fibrosis transmembrane regulator (CFTR) modulating therapy has made it possible to treat the underlying pathophysiological defect in children with cystic fibrosis (CF). Response to therapy varies among patients. We investigated the immune responses and exhaled breath profile changes after the initiation of CFTR modulator therapy to explore their potential as markers of therapy response. Methods: We performed a prospective, longitudinal proof-of-principle study, investigating immune responses and exhaled breath volatile organic component (VOC) profiles prior to and during the initiation of therapy with Lumacaftor/Ivacaftor in a cohort of 17 patients with CF aged 2 to 6 years old. Response to therapy was assessed based on clinical markers and the decrease in sweat chloride. Whole blood stimulation assays were performed at t = 0, 6 and 18 weeks, while VOC analysis was performed at t = 0 and 18 weeks. Results: A pattern of immune reconstitution was found in the first 4 months of therapy. The same pattern was found in responders and non-responders. Exhaled breath VOC profiles were significantly affected by therapy. A trend toward a significant difference was found between responders and non-responders. Conclusions: Pediatric CF patients show a pattern of immune reconstitution after the initiation of CFTR modulating therapy. We hypothesize that this could be explained by the need for a pro-inflammatory profile for a more effective clearance of latent airway pathogens in the initial phase. The exhaled breath profile also clearly changes after the initiation of therapy, indicating the therapy’s influence on airway inflammation and oxidative stress; thus, it might predict the response to therapy. Full article

Most neurodegenerative diseases share a common etiopathogenesis, the accumulation of protein aggregates. An imbalance in homeostasis brought on by the buildup of misfolded proteins within the endoplasmic reticulum (ER) results in ER stress in the cell. Three distinct proteins found in the ER membrane—IRE1α, PERK, and ATF6—control the unfolded protein response (UPR), a signal transduction pathway that is triggered to restore normal physiological conditions. Buildup of misfolded proteins in ER lumen leads to a shunting of GRP78/BiP, thus triggering the UPR. PERK autophosphorylation leads to activation of ATF4, the transcription factor; finally, ATF6 activates the UPR’s target genes, including GRP78/Bip. Accordingly, the UPR is a cellular reaction to an ER stress state that, if left unchecked for an extended period, results in apoptosis and irreversible damage. The identification of caspase 4, which is in the ER and is selectively activated by apoptotic stimuli caused by reticular stress, further demonstrated the connection between reticular stress and programed cell death. Moreover, oxidative stress and ER stress are linked. Oxidative stress is brought on by elevated quantities of radical oxygen species, both mitochondrial and cytosolic, that are not under the enzymatic regulation of superoxide dismutases, whose levels fall with increasing stress. Here, we evaluated the activity of Vx-809 (Lumacaftor), a drug used in cystic fibrosis, in SH-SY5Y neuronal cells, in which an ER stress condition was induced by Thapsigargin, to verify whether the drug could improve protein folding, suggesting its possible therapeutic use in proteinopathies, such as neurodegenerative diseases (NDs). Our data show that Vx-809 is involved in the significant reduction in protein produced under ER stress, particularly in the levels of Bip, ATF4, and ATF6 by Western blotting analysis, the reduction in ROS in the cytosol and mitochondria, and the reduction in the activation of the apoptotic pathway, measured by flow cytofluorimetry analysis and in restoring calcium homeostasis. Full article

p.Asn1303Lys (N1303K) is a common missense variant of the CFTR gene, causing cystic fibrosis (CF). In this study, we initially evaluated the influence of CFTR modulators on the restoration of N1303K-CFTR function using intestinal organoids derived from four CF patients expressing the N1303K variant. The forskolin-induced swelling assay in organoids offered valuable insights about the beneficial effects of VX-770 + VX-661 + VX-445 (Elexacaftor + Tezacaftor + Ivacaftor, ETI) on N1303K-CFTR function restoration and about discouraging the prescription of VX-770 + VX-809 (Ivacaftor + Lumacaftor) or VX-770 + VX-661 (Ivacaftor + Tezacaftor) therapy for N1303K/class I patients. Then, a comprehensive assessment was conducted on an example of one patient with the N1303K/class I genotype to examine the ETI effect on the restoration of N1303K-CFTR function using in vitro the patient’s intestinal organoids, ex vivo the intestinal current measurements (ICM) method and assessment of the clinical status before and after targeted therapy. All obtained results are consistent with each other and have proven the effectiveness of ETI for the N1303K variant. ETI produced a significant positive effect on forskolin-induced swelling in N1303K/class I organoids indicating functional improvement of the CFTR protein; ICM demonstrated that ETI therapy restored CFTR function in the intestinal epithelium after three months of treatment, and the patient improved his clinical status and lung function, increased his body mass index (BMI) and reduced the lung pathogenic flora diversity, surprisingly without improving the sweat test results. Full article