Cystic Fibrosis Transmembrane Conductance Regulator Research Articles

CFTR Exon 10 deleterious mutations in patients with congenital bilateral absence of vas deferens in a cohort of Pakistani patients.

Congenital bilateral absence of vas deferens (CBAVD) is a urological syndrome of Wolffian ducts and is responsible for male infertility and obstructive azoospermia. This study is designed to explore the integrity of exon 10 of CFTR and its role in male infertility in a cohort of CBVAD patients in Pakistan. Genomic DNA was extracted from 17 male patients with CBAVD having clinical symptoms, and 10 healthy controls via phenol-chloroform method. Exon 10 of the CFTR gene was amplified, using PCR with specific primers and DNA screening was done by Sanger sequencing. Sequencing results were analyzed using freeware Serial Cloner, SnapGene, BioEdit and FinchTV. Furthermore, bioinformatics tools were used to analyze the mutations and their impact on the protein function and stability. We have identified 4 mutations on exon 10 of CFTR in 6 out of 17 patients. Two of the mutations were missense variants V456A, K464E, and the other two were silent mutations G437G, S431S. The identified variant V456A was present in 4 of the studied patients. Whereas, the presence of K464E in our patients further weighs on the crucial importance for its strategic location to influence the gene function at post-transcriptional and protein level. Furthermore, Polyphen-2 and SIFT analyze the mutations as harmful and deleterious. The recurrence of V456A and tactically conserved locality of K464E are evidence of their potential role in CBAVD patients and in male infertility. The data can contribute in developing genetic testing and treatment of CBAVD.

Functional and radiological sinonasal outcomes of CFTR modulators for sinus disease in cystic fibrosis: A meta-analysis.

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators improve pulmonary outcomes in cystic fibrosis (CF) by stabilizing the CFTR protein on respiratory epithelial surfaces. To determine the efficacy of CFTR modulators on sinonasal outcomes in patients with CF, we performed a meta-analysis of clinical trials to date that include functional and radiographic evidence of sinus disease. English full-text articles were searched in PubMed, Embase, and Scopus databases. Two reviewers screened articles and a third reviewer resolved disagreements. Articles were included if they reported functional or radiological sinonasal outcomes in patients with CF before and after CFTR modulator therapies. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed, and the risk of bias in non-randomized studies of interventions tool was used for quality assessment. The generic inverse variance method with random effects model was used for meta-analysis. Standardized mean difference (SMD) and mean difference (MD) were used as effect measurements. Seven prospective and two retrospective studies representing 248 patients were included in this analysis. There was a significant improvement in sinonasal outcome test-22 scores on elexacaftor‒tezacaftor‒ivacaftor (MD=12.80, [95% confidence interval, CI: 10.46‒15.13], p<0.001, n=222), with no heterogeneity detected (I2=0%, p=0.820). There was also a significant improvement in Lund‒Mackay scores (SMD=1.25, [95% CI: 0.58‒1.91], p<0.001, n=88), with heterogeneity detected (I2=67%, p=0.030). CFTR modulators improve functional and radiologic sinonasal outcomes. Given the utility of CFTR modulators, the treatment paradigm for CF-related chronic rhinosinusitis promises to evolve.

Molecular responses in the intestine of Atlantic salmon (Salmo salar) following light and diet stimulation of smoltification: Potential molecular markers for a seawater-ready smolt

The transfer to seawater (SW) represents a critical stage in the production of Atlantic salmon. The success of the transfer links with the optimal development of hypo-osmoregulatory capacities during smoltification. While various strategies are adopted in aquaculture to stimulate smoltification, considerable fish loss still occurs after transfer to sea cages. Therefore, we investigated the molecular responses in the anterior and posterior intestine of Atlantic salmon, following 1) a photoperiod treatment (24 h light (L):0 h dark (D) → 24 L:0D vs. 7 L:17D → 24 L:0D) and 2) dietary treatment (regular feed or feed enriched with a salt mix/tryptophan), combined with, or without a photoperiodic treatment in freshwater (FW), to evaluate how intestinal osmoregulatory mechanisms are modulated by these treatments, and to identify potential intestinal markers indicative of a SW-ready smolt. Using quantitative real-time PCR (qPCR), we investigated transcript levels of transporters and channels involved in ion movements through the enterocytes, tight junction components, and receptors (i.e., calcium-sensing receptor and prolactin receptor). The two intestinal regions showed different gene profiles and responsiveness towards the experimental treatments. In the anterior intestine, the exposure to short photoperiod (7 L:17D) upregulated Na+/K+ − ATPase subunit alpha 1c (nkaα1c), Na+/K+/2Cl− cotransporter 1 (nkcc1), Na+/K+/2Cl− cotransporter 2 (nkcc2), Cl−/HCO3− exchanger Slc26a6 (slc26a6), and cystic fibrosis transmembrane conductance regulator I (cftrI), in FW and SW. Also, Na+/K+ − ATPase subunit alpha 1b (nkaα1b), occludin (ocln), and prolactin receptor (prlr) were upregulated in FW and claudin 15 (cldn15) in SW groups exposed to this photoperiod. The posterior intestine was less responsive to the experimental treatments, although upregulation of nkcc1, nkcc2, slc26a6, and cftrI was observed in FW in the short photoperiod groups. Hence, our findings show that exposure to a winter signal in FW more effectively activates hypo-osmoregulatory mechanisms in the intestine of Atlantic salmon, where a coordinated and complementary role of the anterior and posterior intestine ensures optimal SW processing. Dietary treatment had a positive but more marginal effect on the regulation of the genes investigated, mainly enhancing the impact of short photoperiod when the two treatments were combined. Overall, we propose the apical Na+/K+/2Cl− cotransporter, nkcc2, and the apical Cl−/HCO3− exchanger, slc26a6, as potential FW molecular markers in the anterior intestine to assess “SW-readiness” in Atlantic salmon smolts.

Successful Desensitization With ELX/TEZ/IVA

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was given US Food and Drug Administration approval based on its therapeutic benefits to treat patients with cystic fibrosis (CF) who had at least 1 allele of the CF transmembrane conductance regulator (CFTR) with phenylalanine deleted at position 508 (F508del). The increase in genotyping studies has increased the frequency of use of CFTR modulators; however, severe allergic reactions to CFTR modulators have also been described. It is critical to avoid the offending medication and select alternative treatments while dealing with drug allergies. Drug desensitization may be taken into consideration in situations where there is no other option. This article describes home desensitization treatment for a patient with CF who developed a maculopapular rash following CFTR modulator medication. There are currently no alternative drugs for CFTR modulators, which are crucial for patients with CF, and limited experience is available with allergic reactions to these drugs. It is important to establish desensitization protocols in order to control drug reactions to CFTR modulators, which are vital for individuals with CF.

Development of metabolic syndrome in people with Cystic Fibrosis one year after exposure to elexacaftor-tezacaftor-ivacaftor

BackgroundThe constellation of hypertension, truncal obesity, impaired fasting glucose, low high-density lipoprotein, and hypertriglyceridemia is known as metabolic syndrome (MetSyn) and is associated with cardiovascular and other diseases. Elexacaftor-tezacaftor-ivacaftor (ETI) in people with cystic fibrosis (pwCF) is associated with weight gain but effects on cardiovascular risk are unknown. This study sought to investigate ETI exposure and risk for development of MetSyn in pwCF. MethodsA prospective cohort study including pwCF ≥ 18 years old exposed to ETI was performed. All data for calculating MetSyn was collected from the electronic medical record at initiation and 1 year ± 3 months after starting ETI. A total of 152 pwCF exposed to ETI and 34 pwCF never exposed to CF transmembrane conductance regulator modulators were included in the analysis. Changes to hypertension classification was also examined over this period. ResultsAfter 1 year of ETI there was an increase in MetSyn from 13 to 30 pwCF, p < 0.0001. No new cases of MetSyn were seen in the group not exposed to ETI. After 1 year of ETI, more people met criteria for class 1 (BP 130–139/90–99 mm Hg) or class 2 hypertension (BP ≥140/≥90 mm Hg) regardless of prior modulator exposure, p < 0.0001. ConclusionsExposure to ETI for 1 year resulted in an increased number of cases of MetSyn. There was an increased incidence of hypertension associated with ETI exposure. Additional studies are needed to further examine this trend and to determine if these changes will translate to cardiovascular complications over time.

Adeno-Associated Virus 1 (AAV1) CFTR Gene Therapy Successfully Reduces Cysts in a Mouse Model of Autosomal Dominant Polycystic Kidney Disease

Adeno-Associated Virus 1 (AAV1) CFTR Gene Therapy Successfully Reduces Cysts in a Mouse Model of Autosomal Dominant Polycystic Kidney Disease

TRPV4 Channel Modulators as Potential Drug Candidates for Cystic Fibrosis.

Cystic fibrosis (CF) is a genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, resulting in defective chloride ion channels. This leads to thick, dehydrated mucus that severely disrupts mucociliary clearance in the respiratory system and triggers infection that eventually is the cause of death of CF patients. Current therapeutic strategies primarily focus on restoring CFTR function, blocking epithelial sodium channels to prevent mucus dehydration, or directly targeting mucus to reduce its viscosity. Among the ion channels expressed in ciliated bronchial epithelial cells, the transient receptor potential vanilloid 4 (TRPV4) channel emerges as a significant channel in CF pathogenesis. Activation of TRPV4 channels affects the regulation of airway surface liquid by modulating sodium absorption and intracellular calcium levels, which indirectly influences CFTR activity. TRPV4 is also involved in the regulatory volume decrease (RVD) process and enhances inflammatory responses in CF patients. Here, we combine current findings on TRPV4 channel modulation as a promising therapeutic approach for CF. Although limited studies have directly explored TRPV4 in CF, emerging evidence indicates that TRPV4 activation can significantly impact key pathological processes in the disease. Further investigation into TRPV4 modulators could lead to innovative treatments that alleviate severe respiratory complications and improve outcomes for CF patients.

Гено-фенотипические особенности муковисцидоза у российских детей из Чеченской и Карачаево-Черкесской Республик

Background: Cystic fibrosis (CF) is an autosomal recessive disease that occurs with a frequency of 1:1,500 to 1:5,000 newborns, according to the World Health Organization. In the Russian Federation, the average incidence of the disease is 1:10,000 newborns. The medical and social significance of this disease is associated with the early disability of patients, the need for long-term treatment and constant follow-up, as well as the heterogeneity of phenotypic manifestations, which in turn requires early diagnosis using molecular genetic methods. The aim of the study: To study the clinical and molecular genetic characteristics of children with CF from the Chechen and Karachay-Cherkess Republics. Materials and methods: The study included 237 patients with a confirmed diagnosis of CF. Molecular genetic diagnostics was performed using the method of mass parallel sequencing using a hybridization target panel that includes the entire CFTR gene. Sequencing was performed on the MiSeq platform. All causal nucleotide variants were validated using Sanger sequencing. Results: The most common amino acid variants of the CFTR gene in patients with CF from the Chechen Republic are: p.Y515* (94 alleles/78.3%), p.E92K (18 alleles/15%). The presence of variants p.Y515* and p.E92K in the heterozygous state in the genotype is more often a favorable prognostic factor for the absence of pancreatic lesion. The main distinctive clinical feature of these patients is the onset of the disease with manifestations of pseudo-Bartter syndrome. The major amino acid variant of the CFTR gene in patients with CF from the Karachay-Cherkess Republic is: p.W1282* (28 alleles/70%). The number of patients with pseudo-Bartter syndrome was 54.5%. In 90% of cases, in patients who are homo- and heterozygous according to p.W1282*, a severe degree of pancreatic insufficiency was noted. Conclusion: Patients with cystic fibrosis from the Chechen and Karachay-Cherkess Republics are a difficult category of patients, despite neonatal screening, and cystic fibrosis therapy developed and implemented. This is partly due to the peculiarities of the phenotype and the unique distribution of alleles and genotypes of the CFTR gene. The high number of homozygous variants of the CFTR gene in patients from the Chechen and Karachay-Cherkess Republics is probably due to monoethnic marital assortativity.

Cystic Fibrosis: A Review of Current Knowledge, Treatment Methods and Diagnostics

Introduction: Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by a mutation in the CFTR gene. Characteristic symptoms include persistent lung infection, pancreatic insufficiency, and elevated sweat chloride, although many patients have mild or atypical symptoms. Diagnosis of CF is based primarily on the detection of genetic and/or functional abnormalities in the CFTR gene. Treatment includes pancreatic enzyme replacement therapy, mucolytic drugs, respiratory physiotherapy, and antibiotic therapy. Purpose of the work: This study aims to review and characterize the clinical and pathophysiological aspects of cystic fibrosis. Materials and methods: A comprehensive analysis of research papers available on PubMed, Google Scholar, Web of Science, Embase and Scopus was undertaken using the searchterms encompassing the following keywords: Cystic fibrosis, CFTR, Chloride Channels, Lung Inflammation, Diagnosis, Gene therapy, Treatment. Results: Cystic fibrosis is the most common, multisystem, life-threatening recessive disease in the white race. Although many organs are affected, the leading cause of morbidity and mortality is lung disease. Treatment requires pharmacotherapy, extensive physiotherapy, and nutritional support. In recent years, there has been significant progress in the diagnosis and treatment of cystic fibrosis, and the average survival has increased from a few to almost 50 years.

Comparison of Reporting Quality in National Cystic Fibrosis Patient Registries: Implications for Identifying Use of Novel CFTR Modulators.

Advances in development of cystic fibrosis transmembrane conductance regulator modulator (CFTRm) therapies mean that now people who are heterozygous (instead of having to be homozygous) for the common F508del variant can benefit from these therapies. Recent economic estimates suggest only approximately 15% of the global population have CFTRm access, yet it is unknown how prevalence of F508del and economic factors may affect this availability. Data related to prevalence of cystic fibrosis (CF), CFTRm usage, and prevalence of F508del in 10 countries were extracted from publicly accessible registry reports from 2021. National gross domestic product (GDP) was obtained via open access World Bank data. Descriptive statistics and correlation coefficients assessed relationships. Notable discrepancies were noted in the equity of availability of data between national registries-only four countries reported number of patients eligible for CFTRm. Registry data represented 70,694 patients, with 42,858 found to be using CFTRm (60.6%). Prevalence of CFTRm usage ranged from 1.8% to 76.7% and prevalence of F508del ranged from 35.2% to 94.4%. The correlation between prevalence of CFTRm usage and F508del is positive (r = 0.56, p = 0.10), and the correlation between CFTRm usage and GDP (per capita) was also positive, and significant (r = 0.72, p = 0.02). Both F508del prevalence and GDP are associated with variable CFTRm usage rates, although a predominant reason is unclear as a result of poor consistency in registry reporting. Urgent action is needed to create uniform reporting of registry data and increase availability of novel CFTRm therapies to the global CF population.

Estimation of Chloride Channel Residual Function and Assessment of Targeted Drugs Efficiency in the Presence of a Complex Allele [L467F;F508del] in the CFTR Gene.

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.

The interactome of cystic fibrosis transmembrane conductance regulator and its role in male fertility: A critical review.

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cyclic adenosine monophosphate (cAMP)-regulated chloride and bicarbonate ion channel found in many human cells. Its unique biochemical characteristics and role as a member of the adenosine triphosphate (ATP)-binding cassette transporters superfamily are pivotal for the transport of several substrates across cellular membranes. CFTR is known to interact, physically and functionally, with several other cellular proteins. Hence, its properties are essential for moving various substances across cell membranes and ensuring correct cell functioning. Genetic mutations or environmental factors may disrupt CFTR's function resulting in different possible phenotypes due to gene variations that affect not only CFTR's function, localization, and processing within cells, but also those of its interactors. This has been reported as an underlying cause of various diseases, including cystic fibrosis. The severe clinical implications of cystic fibrosis have driven intense research into the role of CFTR in lung function but its significance to fertility, particularly in men, has been comparatively understudied. However, ongoing and more recent research into CFTR and its interacting proteins in the testis or specific testicular cells is beginning to shed light on this field. Herein, we provide a comprehensive and up-to-date overview of the CFTR, its interactome, and its crucial role in male reproduction, highlighting recent discoveries and advancements in understanding the molecular mechanisms involved. The comprehension of these complex interactions may pave the way for potential therapeutic approaches to improve fertility of men suffering from alterations in the function of CFTR.

Effect of CFTR Modulators on Oxidative Stress and Autophagy in Non-CFTR-Expressing Cells.

The triple combination therapy for cystic fibrosis (CF), including elexacaftor, tezacaftor and ivacaftor (ETI or Trikafta), has been shown to improve lung function and reduce pulmonary exacerbations, thereby enhancing the quality of life for most CF patients. Recent findings suggest that both the individual components and ETI may have potential off-target effects, highlighting the need to understand how these modulators impact cellular physiology, particularly in cells that do not express CF transmembrane conductance regulator (CFTR). We used HEK293 cells, as a cell model not expressing the CFTR protein, to evaluate the effect of ETI and each of its components on autophagic machinery and on the Rab5/7 components of the Rab pathway. We firstly demonstrate that the single modulators Teza and Iva, and the combinations ET and ETI, increased ROS production in the absence of their target while decreasing it in cells expressing the CFTR ∆F508del. This increase in cellular stress was followed by an increase in the total level of polyubiquitinated proteins as well as the p62 level and LC3II/LC3I ratio. Furthermore, we found that ETI had the opposite effect on Rabs by increasing Rab5 levels while decreasing Rab7. Interestingly, these changes were abolished by the expression of mutated CFTR. Overall, our data suggest that in the absence of their target, both the individual modulators and ETI increased ROS production and halted both autophagic flux and plasma membrane protein recycling.

Arsenic exposure is associated with elevated sweat chloride concentration and airflow obstruction among adults in Bangladesh: a cross sectional study.

Arsenic is associated with lung disease and experimental models suggest that arsenic-induced degradation of the chloride channel CFTR (cystic fibrosis transmembrane conductance regulator) is a mechanism of arsenic toxicity. We examined associations between arsenic exposure, sweat chloride concentration (measure of CFTR function), and pulmonary function among 285 adults in Bangladesh. Participants with sweat chloride ≥ 60 mmol/L had higher arsenic exposures than those with sweat chloride < 60 mmol/L (water: median 77.5 µg/L versus 34.0 µg/L, p = 0.025; toenails: median 4.8 µg/g versus 3.7 µg/g, p = 0.024). In linear regression models, a one-unit µg/g increment in toenail arsenic was associated with a 0.59 mmol/L higher sweat chloride concentration, p < 0.001. We found that toenail arsenic concentration was associated with increased odds of airway obstruction (OR: 1.97, 95%: 1.06, 3.67, p = 0.03); however, sweat chloride concentration did not mediate this association. Our findings suggest that sweat chloride concentration may be a novel biomarker for arsenic exposure and also that arsenic likely acts on the lung through mechanisms other than CFTR dysfunction.

Ivacaftor for Chronic Obstructive Pulmonary Disease - Results from a Phase 2, Randomized Controlled Trial.

Patients with chronic obstructive pulmonary disease (COPD) exhibit acquired cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction. CFTR modulators may improve outcomes in patients with COPD, although recent data regarding magnitude of benefit have been inconclusive and effects on mucociliary clearance are unknown. We conducted a phase 2, randomized, double blind placebo control trial to determine safety and tolerability, and explore the potential mechanism of ivacaftor for the treatment of COPD. We randomized 40 patients with moderate to severe COPD and symptoms of chronic bronchitis to ivacaftor (N=30) or placebo (N=10) 150mg BID for 12 weeks. Primary endpoints included evaluation of safety of ivacaftor and pharmacokinetics (PK). Secondary endpoints included measures of CFTR activity and clinical outcomes. Ivacaftor was safe and tolerable with similar rates of adverse events rates between groups. Most common adverse event was diarrhea in the ivacaftor group and acute COPD exacerbation in the placebo group. PK analysis found the mean area under the curve over 12 hours (AUC12) to be 72% of the previously reported AUC12 in cystic fibrosis (CF). Treatment with ivacaftor did not improve sweat chloride, whole lung mucociliary clearance, lung function or respiratory symptoms. Ivacaftor was safe and well tolerated, but did not improve measures of CFTR activity or mucus clearance. As serum concentrations achieved were lower than observed in CF at the same dose, and modulation of wild type CFTR differs from G551D, further dose determination studies are needed to better understand treatment efficacy of CFTR potentiators in COPD. Clinical trial registration available at www. gov, ID: NCT03085485.

Amphiphilic shuttle peptide delivers base editor ribonucleoprotein to correct the CFTR R553X mutation in well-differentiated airway epithelial cells.

Base editing could correct nonsense mutations that cause cystic fibrosis (CF), but clinical development is limited by the lack of delivery methods that efficiently breach the barriers presented by airway epithelia. Here, we present a novel amphiphilic shuttle peptide based on the previously reported S10 peptide that substantially improved base editor ribonucleoprotein (RNP) delivery. Studies of the S10 secondary structure revealed that the alpha-helix formed by the endosomal leakage domain (ELD), but not the cell penetrating peptide (CPP), was functionally important for delivery. By isolating and extending the ELD, we created a novel shuttle peptide, termed S237. While S237 achieved lower delivery of green fluorescent protein, it outperformed S10 at Cas9 RNP delivery to cultured human airway epithelial cells and to pig airway epithelia in vivo, possibly due to its lower net charge. In well-differentiated primary human airway epithelial cell cultures, S237 achieved a 4.6-fold increase in base editor RNP delivery, correcting up to 9.4% of the cystic fibrosis transmembrane conductance regulator (CFTR) R553X allele and restoring CFTR channel function close to non-CF levels. These findings deepen the understanding of peptide-mediated delivery and offer a translational approach for base editor RNP delivery for CF airway disease.

The challenged urine bicarbonate excretion test in cystic fibrosis: A comprehensive analysis of urine acid/base parameters.

Renal excretion of excess HCO3 - depends on renal cystic fibrosis transmembrane conductance regulator (CFTR) and is impaired in people with cystic fibrosis (pwCF). Urine HCO3 - excretion following oral NaHCO3-loading may be a simple invivo biomarker of CFTR function. In this study, we investigated changes in urine acid/base parameters following oral NaHCO3-loading to comprehensively assess the physiological response to the test and evaluate HCO3 - as the primary test result. Urine acid/base parameters (titratable acid(TA), NH4 +, net acid excretion (NAE) and pH) were measured in bio-banked urine samples from controls (n = 10) and pwCF (n = 50) who completed the challenged urine HCO3 - test. The association between urine acid/base excretion parameters and clinical CF disease characteristics and CFTR modulator therapy-induced changes were assessed. Before treatment, challenged urine acid/base excretion associated with important CF disease characteristics. TA excretion and NAE were lower in pwCF with residual function mutations, 7.9 and 16.6 mmol/3 h, respectively, and lower TA excretion and NAE associated with pancreatic sufficiency. A lower excretion of TA, NH4 +, and NAE associated with a higher percentage of predicted FEV1 (1.3%, 2.5% and 0.8% per mmol/3 h higher, respectively). Modulator treatment decreased TA excretion and NAE (-2.9 and -5.3 mmol/3 h, respectively). Following acute NaHCO3-loading, increased base excretion is mirrored by decreased acid excretion. Urine HCO3 - excretion sufficiently represents the additional urine acid/base parameters as test result. The observed changes in acid excretion support CFTR modulator-induced increase of CFTR-dependent type B intercalated cell HCO3 - secretion and the use of the challenged urine HCO3 - test as a possible CFTR-biomarker.

Absorption, Distribution, Metabolism, and Excretion of Icenticaftor (QBW251) in Healthy Male Volunteers at Steady State and In Vitro Phenotyping of Major Metabolites.

Icenticaftor (QBW251) is a potentiator of the CFTR protein and is currently in clinical development for the treatment of chronic obstructive pulmonary disease and chronic bronchitis. An absorption, distribution, metabolism, and excretion (ADME) study was performed at steady state to determine the pharmacokinetics, mass balance, and metabolite profiles of icenticaftor in humans. In this open-label study, six healthy men were treated with unlabeled oral icenticaftor (400 mg b.i.d.) for 4 days. A single oral dose of [14C]icenticaftor was administered on Day 5, and unlabeled icenticaftor was administered b.i.d. from the evening of Day 5 to Day 12. Unchanged icenticaftor accounted for 18.5% of plasma radioactivity. Moderate to rapid absorption of icenticaftor was observed (median Tmax: 4 hours), with 93.4% of the dose absorbed. It exhibited moderate distribution (Vz/F: 335 L) and was extensively metabolized, principally through N-glucuronidation, O-glucuronidation, and/or O-demethylation. The metabolites M8 and M9, formed by N-glucuronidation and O-glucuronidation of icenticaftor, respectively, represented the main entities detected in plasma (35.3% and 14.5%, respectively) in addition to unchanged icenticaftor (18.5%). The apparent mean T1/2 of icenticaftor was 15.4 hours in blood and 20.6 hours in plasma. Icenticaftor was eliminated from the body mainly through metabolism followed by renal excretion, and excretion of radioactivity was complete after 9 days. In vitro phenotyping of icenticaftor showed that cytochrome P450 and uridine diphosphate glucuronosyltransferase were responsible for 31% and 69% of the total icenticaftor metabolism in human liver microsomes, respectively. This study provided invaluable insights into the disposition of icenticaftor. Significance Statement The ADME of a single radioactive oral dose of icenticaftor was evaluated at steady state to investigate the nonlinear pharmacokinetics observed previously with icenticaftor. [14C]Icenticaftor demonstrated good systemic availability after oral administration and was extensively metabolized and moderately distributed to peripheral tissues. The most abundant metabolites, M8 and M9, were formed by N-glucuronidation and O-glucuronidation of icenticaftor, respectively. Phenotyping demonstrated that [14C]icenticaftor was metabolized predominantly by UGT1A9 with a remarkably low Km value.

Dynamics of inflammatory markers in patients with normal and impaired glucose metabolism during lung exacerbation treatment

Cystic fibrosis (CF) is one of the most common autosomal-recessive inherited diseases. The primary genetic defect in CF is aligned CFTR gene mutation which encodes a membrane protein functioning as cAMP-depended chloride channel. Classic phenotypical manifestations of CF include chronic obstructive pulmonary disease with bronchiectasis, persisting infection (St. aureus, Ps. aeruginosa, B. cepacia) and aberrant inflammatory response, as well as exocrine pancreatic insufficiency with malabsorption, hypotrophy and growth retardation. CFTR deficiency is also accompanied by β-cell pancreatic dysfunction, causing glucose metabolism disturbances and CF-related diabetes. The aim of the study was the comparison of inflammatory markers dynamics in patients with normal and disturbed glucose metabolism during pulmonary exacerbation treatment. The study included 10 patients with impaired glucose tolerance (Group 1) and 24 patients with normal carbohydrate metabolism (Group 2). Patients of the two groups did not significantly differ in demographic characteristics, pulmonary function test and body mass index parameters, as well as in the number of F508del mutation carriers and in the number of those who were infected with Ps. aeruginosa and B. cepacia complex. Blood sampling was performed twice: before and after a routine course of antibiotic therapy. Plasma levels of biomarkers including the antibodies to single- and double-stranded DNA (ss-DNA-IgG, ds-DNA-IgG, respectively), the hormones (dehydroepiandrosterone (DHEA) and DHEA sulfate), C-reactive protein (CRP), Mn-dependent superoxide dismutase (Mn-SOD), and the cytokines (tumor necrosis factor-α (TNFα), interferon-γ (IFNγ), IFNα, tissue growth factor-β1 (TGF-β1), interleukin-4 (IL-4), IL-6, IL-10, IL-17A) were assessed using commercial immunoassay kits. Our study shows that antibiotic treatment did not have a sufficient influence on levels of inflammatory markers in patients with disturbances of glucose metabolism while patients with normal glucose tolerance demonstrated a significant reduction in inflammatory marker values after the therapy. The data may suggest both impaired effectivity of antibiotic treatment and aberrant inflammatory response in patients with glucose intolerance.

Allergic Bronchopulmonary Aspergillosis (ABPA) in the Era of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulators.

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity disease caused by Aspergillus fumigatus (Af), prevalent in persons with cystic fibrosis (CF) or asthma. In ABPA, Af proteases drive a T-helper cell-2 (Th2)-mediated allergic immune response leading to inflammation that contributes to permanent lung damage. Corticosteroids and antifungals are the mainstays of therapies for ABPA. However, their long-term use has negative sequelae. The treatment of patients with CF (pwCF) has been revolutionized by the efficacy of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy. Pharmacological improvement in CFTR function with highly effective elexacaftor/tezacaftor/ivacaftor (ETI) provides unprecedented improvements in lung function and other clinical outcomes of pwCF. The mechanism behind the improvement in patient outcomes is a continued topic of investigation as our understanding of the role of CFTR function evolves. As ETI therapy gains traction in CF management, understanding its potential impact on ABPA, especially on the allergic immune response pathways and Af infection becomes increasingly crucial for optimizing patient outcomes. This literature review aims to examine the extent of these findings and expand our understanding of the already published research focusing on the intersection between ABPA therapeutic approaches in CF and the rapid impact of the evolving CFTR modulator landscape. While our literature search yielded limited reports specifically focusing on the role of CFTR modulator therapy on CF-ABPA, findings from epidemiologic and retrospective studies suggest the potential for CFTR modulator therapies to positively influence pulmonary outcomes by addressing the underlying pathophysiology of CF-ABPA, especially by decreasing inflammatory response and Af colonization. Thus, this review highlights the promising scope of CFTR modulator therapy in decreasing the overall prevalence and incidence of CF-ABPA.