The predominant mutation causing cystic fibrosis, a deletion of phenylalanine 508 (Δ508) in the cystic fibrosis transmembrane conductance regulator (CFTR), leads to severe defects in CFTR biogenesis and function. The advanced therapy Trikafta combines the folding corrector tezacaftor (VX-661), the channel potentiator ivacaftor (VX-770), and the dual-function modulator elexacaftor (VX-445). However, it is unclear how elexacaftor exerts its effects, in part because the structure of Δ508 CFTR is unknown. Here, we present cryo–electron microscopy structures of Δ508 CFTR in the absence and presence of CFTR modulators. When used alone, elexacaftor partially rectified interdomain assembly defects in Δ508 CFTR, but when combined with a type I corrector, did so fully. These data illustrate how the different modulators in Trikafta synergistically rescue Δ508 CFTR structure and function. Description How three drugs restore function Cystic fibrosis is caused by defects in a chloride channel crucial for proper fluid balance and secretion. Deletion of a single amino acid, phenylalanine 508 (Δ508), is the most common mutation and leads to misfolding and degradation of the protein before it can reach cell surfaces. Fiedorczuk and Chen determined the structures of the Δ508 channel bound to three drugs that are given in combination therapy to correct folding and potentiate the channel. They uncovered a binding site for one of the drugs, a dual function corrector and potentiator, that was not previously known. The structures showed only a partial correction of folding when only one corrector was provided, but full correction was achieved when type I and III correctors were bound. —MAF Molecular structures reveal how three drugs rectify the effects of the most common CFTR mutant in cystic fibrosis.

Molecular Structures Reveal Synergistic Rescue of Δ508 CFTR by Trikafta Modulators

Background: To date, no consistent data are available on the possible impact of CFTR modulators on glucose metabolism. The aim of this study was to test the hypothesis that treatment with CFTR modulators is associated with an improvement in the key direct determinants of glucose regulation in children and young adults affected by Cystic Fibrosis (CF). Methods: In this study, 21 CF patients aged 10–25 underwent oral glucose tolerance test (OGTT) before and after 12–18 months of treatment with Lumacaftor/Ivacaftor or Elexacaftor-Ivacaftor-Tezacaftor. β-cell function (i.e., first and second phase of insulin secretion measured as derivative and proportional control, respectively) and insulin clearance were estimated by OGTT mathematical modelling. Insulin sensitivity was estimated by the Oral Glucose Sensitivity Index (OGIS). The dynamic interplay between β-cell function, insulin clearance and insulin sensitivity was analysed by vector plots of glucose-stimulated insulin bioavailability vs. insulin sensitivity. Results: No changes in glucose tolerance occurred after either treatment, whereas a significant improvement in pulmonary function and chronic bacterial infection was observed. Beta cell function and insulin clearance did not change in both treatment groups. Insulin sensitivity worsened in the Lumacaftor/Ivacaftor group. The analysis of vector plots confirmed that glucose regulation was stable in both groups. Conclusions: Treatment of CF patients with CFTR modulators does not significantly ameliorate glucose homeostasis and/or any of its direct determinants.

https://www.mdpi.com/2077-0383/11/14/4149/pdf?version=1658052847

Impact of CFTR Modulators on Beta-Cell Function in Children and Young Adults with Cystic Fibrosis

The use of modulator drugs that target the Cystic Fibrosis transmembrane conductance regulator (CFTR) is the final frontier in the treatment of Cystic Fibrosis (CF), a genetic multiorgan disease. F508del is the most common mutation causing defective formation and function of CFTR. Elexacaftor-tezacaftor-ivacaftor is the first triple combination of CFTR modulators. Herein, we report on a one-year case-control study that involved 26 patients with at least one F508del mutation. Patients were assigned to two similar groups, and patients with the worse clinical condition received treatment with the triple combination therapy. The study aimed to define the clinical and especially microbiological implications of treatment administration. The treatment provided significant clinical benefits in terms of respiratory, pancreatic, and sweat function. After one year of therapy, airway infection rates decreased and pulmonary exacerbations were dramatically reduced. Finally, treated patients reported a surprising improvement in their quality of life. The use of triple combination therapy has become essential in most CF people carrying the F508del mutation. Although the clinical and instrumental benefits of treatment are thoroughly known, further investigations are needed to properly define its microbiological respiratory implications and establish the real advantage of life-long treatment with elexacaftor-tezacaftor-ivacaftor.

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Elexacaftor-Tezacaftor-Ivacaftor as a Final Frontier in the Treatment of Cystic Fibrosis: Definition of the Clinical and Microbiological Implications in a Case-Control Study

The last ten years have been characterized by an enormous step forward in the therapy and management of patients with Cystic Fibrosis (CF), thanks to the development and combination of Cystic Fibrosis Transmembrane Receptor (CFTR) correctors and potentiators. Specifically, the last approved triple combination elexacaftor/tezacaftor/ivacaftor has been demonstrated to improve lung function in CF patients with both homozygous Phe508del and Phe508del/minimal function genotypes. Here we have assessed the effect of elexacaftor/tezacaftor/ivacaftor in patients carrying the Phe508del/minimal function genotype (n = 20) after one year of treatments on liver function and nutrient absorption with a focus on lipid metabolism. We show that weight, BMI, and albumin significantly increase, suggesting a positive impact of the treatment on nutrient absorption. Furthermore, cholesterol levels as a biomarker of lipid metabolism increased significantly after one year of treatment. Most importantly, we suggest that these results were not dependent on the diet composition, possibly indicating that the drug improves the hepatic synthesis and secretion of proteins and cholesterol.

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Cystic Fibrosis Patients with F508del/Minimal Function Genotype: Laboratory and Nutritional Evaluations after One Year of Elexacaftor/Tezacaftor/Ivacaftor Treatment

Cystic fibrosis (CF) is an autosomal recessive condition, deletion of phenylalanine at position 508 (F508del) being the most frequent mutation in CF patients. Kaftrio, also called Trikafta in the USA, (Vertex Pharmaceuticals Inc., Germany) is a licensed modulator therapy for CF patients with at least one F508del mutation [1]. Several clinical trials have demonstrated its efficacy [2]. However, the primary outcome measured in these studies was the change in per cent predicted of forced expiratory volume in 1 s (FEV1), which was in the order of 10%, and thus may have a relatively low sensitivity in predicting efficacy, particularly in more severely affected patients [3]. This is a prospective observation of the effect of Kaftrio initiation in CF. An early and dramatic improvement in the objective measure of 24-h cough monitoring was observed, providing noninvasive, objective evidence of efficacy and compliance in CF. https://bit.ly/3LpnABB

https://openres.ersjournals.com/content/erjor/8/2/00031-2022.full.pdf

Chronic cough in cystic fibrosis: the effect of modulator therapy on objective 24-h cough monitoring

Cystic fibrosis (CF) is a potentially fatal genetic disease that causes serious lung damage. With time, researchers have a more complete understanding of the molecular-biological defects that underlie CF. This knowledge is leading to alternative approaches regarding the treatment of this condition. Trikafta is the third FDA-approved drug that targets the F508del mutation of the CFTR gene. The drug is a combination of three individual drugs which are elexacaftor (ELX), tezacaftor (TEZ), and ivacaftor (IVA). This trio increases the activity of the cystic fibrosis transmembrane conductance regulator (CFTR) protein and reduces the mortality and morbidity rates in CF patients. The effectiveness of Trikafta, seen in clinical trials, outperforms currently available therapies in terms of lung function, quality of life, sweat chloride reduction, and pulmonary exacerbation reduction. The safety and efficacy of CFTR modulators in children with CF have also been studied. Continued evaluation of patient data is needed to confirm its long-term safety and efficacy. In this study, we will focus on reviewing data from clinical trials regarding the benefits of CFTR modulator therapy. We address the impact of Trikafta on lung function, pulmonary exacerbations, and quality of life. Adverse events of the different CFTR modulators are discussed.

A Review of Trikafta: Triple Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulator Therapy

Chronic obstructive pulmonary disease (COPD) has remained a leading cause of death worldwide and is expected to increase its burden on the healthcare system in the coming future. Numerous clinical trials have been conducted over the years and as a result, many drugs became a part of the treatment protocols of COPD. Currently, there are also several drugs under development. This review will help future researchers to grasp salient features of previous studies and use them in their future trials in order to reduce the morbidity and mortality of COPD. Randomized control trials provide strong evidence for any hypothesis in a research study. This review focuses on major COPD trials in the last two decades including TORCH, UPLIFT, POET, WISDOM, and TIOSPIR. It showcases the main clinical question, primary outcome, and result of these five trials.

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A Review of Clinical Trials That Contributed to Chronic Obstructive Pulmonary Disease Treatment Protocols

Background Community-acquired pneumonia (CAP) is associated with significant morbidity and mortality. Non-invasive ventilation (NIV) and invasive mechanical ventilation (IMV) are most important interventions for patients with severe CAP associated with respiratory failure. We analysed utilization trends and predictors of non-invasive and invasive ventilation in patients hospitalized with CAP. Methods Nationwide Inpatient Sample and Healthcare Cost and Utilization Project data for years 2008-2017 were analysed. Adult hospitalizations due to CAP were identified by previously validated International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) and International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) codes. We then utilized the Cochran-Armitage trend test and multivariate survey logistic regression models to analyse temporal incidence trends, predictors, and outcomes. We used SAS 9.4 software (SAS Institute Inc., Cary, NC, USA) for analysing data. Results Out of a total of 8,385,861 hospitalizations due to CAP, ventilation assistance was required in 552,395 (6.6%). The overall ventilation use increased slightly; however, IMV utilization decreased, while NIV utilization increased. In multivariable regression analysis, males, Asian/others and weekend admissions were associated with higher odds of any ventilation utilization. Concurrent diagnoses of septicemia, congestive heart failure, alcoholism, chronic lung diseases, pulmonary circulatory diseases, diabetes mellitus, obesity and cancer were associated with increased odds of requiring ventilation assistance. Ventilation requirement was associated with high odds of in-hospital mortality and discharge to facility. Conclusion The use of NIV among CAP patients has increased while IMV use has decreased over the years. We observed numerous factors linked with a higher use of ventilation support. The requirement of ventilation support is also associated with very high chances of mortality and morbidity.

Utilization Trends and Predictors of Non-invasive and Invasive Ventilation During Hospitalization Due to Community-Acquired Pneumonia

Infective endocarditis (IE) is relatively uncommon; however, when it is diagnosed, it is usually among those with known cardiac valvular abnormalities. The most common pathogens that cause endocarditis are streptococci (mainly viridans), enterococci, and other streptococci species. An extremely rare pathogen that could cause IE is Granulicatella. This gram-positive coccus classically inhabits human mucosal surfaces and only rarely causes disease. We present an incredibly rare case of a 74-year-old female with a bioprosthetic aortic valve replacement, who presented with headache and weakness and was subsequently found to have recurrent Granulicatella adiacens infective endocarditis.

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Jude ElSaygh

Papers

A Review of Trikafta: Triple Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulator Therapy

A Review of Clinical Trials That Contributed to Chronic Obstructive Pulmonary Disease Treatment Protocols

Utilization Trends and Predictors of Non-invasive and Invasive Ventilation During Hospitalization Due to Community-Acquired Pneumonia

Granulicatella adiacens Endocarditis of a Bioprosthetic Aortic Valve

Tumefactive Multiple Sclerosis: Challenges With Treatment Modalities