Manifestaciones hepáticas en niños con fibrosis quística y uso de moduladores CFTR. ¿Qué debemos monitorizar? / Hepatic manifestations in children with cystic fibrosis and use of CFTR modulators. What should we monitor?

La enfermedad hepática relacionada con fibrosis quística se observa en el 10% de las personas portadoras de la enfermedad. La terapia con moduladores ha mejorado la morbimortalidad, pero teniendo en cuenta que presentan efectos secundarios infrecuentes es necesario monitorizar. Se analiza el algoritmo propuesto por Eldredge et al, que sugiere las decisiones a tomar basado en el resultado de perfil hepático y su aplicación en la práctica clínica.

Cystic fibrosis-related liver disease is seen in 10% of people with the disease. Therapy with modulators has improved morbidity and mortality, but taking into account that they present infrequent side effects, monitoring is necessary. The algorithm proposed by Eldredge et al is analyzed, which suggests the decisions to be made based on the liver profile result and its application in clinical practice.

Real-life experience with a generic formulation of lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for the Phe508del CFTR mutation.

INTRODUCTION: Cystic fibrosis (CF) is the most frequent recessive autosomal disorder in the Caucasian population. It is caused by mutations that result in a deficient or dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) protein activity. Among CFTR modulators, potentiator compounds increase channel opening, whereas corrector compounds increase CFTR quantity in the cell surface. OBJECTIVE: To report real-life effects of a generic formulation of lumacaftor-ivacaftor use in patients with CF homozygous for the Phe508del CFTR mutation. PATIENTS AND METHODS: Clinical variables (body mass index [BMI], pulmonary exacerbations, sweat test, and pulmonary function) were analyzed in 30 CF patients homozygous for the Phe508del CFTR mutation, treated with lumacaftor-ivacaftor for 12 months, at the Respiratory Center of Hospital de Niños Ricardo Gutiérrez. These clinical variables were compared with those before the use of modulators. RESULTS: A total of 30 patients with CF homozygous for the Phe508del CFTR mutation receiving lumacaftor-ivacaftor therapy were included in this study. The median (interquartile range [IQR]) age at the start of treatment was 10.79 (7.08-14.05) years. Nineteen patients were male. Before treatment, median (IQR) sweat chloride concentration was 80 (72-92) mEq/L, and it had decreased to 74 (68-78) mEq/L (p = .05) 12 months after treatment. Median (IQR) BMI z-score improved from -0.33 (-0.86 to 0.21) to -0.13 (-0.66 to 0.54) (p = .003). A spirometry was performed in 28 of 30 patients. Median (IQR) ppFEV1 was 83.5 (71-91) before treatment and 86.5 (67-103) after treatment (p = .38), 73.3% of patients referred decreased sputum production and 40% reported improvement in their dyspnea at 12 months. Severe pulmonary exacerbations significantly decreased from 60% in the year before treatment, to 30% at 12 months after treatment (p = .037); 13 patients showed an improvement in their exacerbation rates, 2 showed an increased rate, and 15 showed no change. CONCLUSIONS: The use of a generic formulation of lumacaftor-ivacaftor in patients homozygous for the Phe508del CFTR mutation was associated with improvement in nutritional status and respiratory symptoms, and a significant reduction in severe pulmonary exacerbations.

Screening by high-throughput sequencing for pathogenic variants in cystic fibrosis: Benefit of introducing personalized therapies.

This short report documented cystic fibrosis transmembrane conductance regulator (CFTR) variants in 37 patients with cystic fibrosis (CF) in the Rio Grande do Norte region of Northeast Brazil. The high-throughput sequencing technology (HTS) genetic testing provided a definitive molecular diagnosis in 31 patients (83.8%). Among them, 25 patients' carriers of the c.1521_1523delCTT variant, categorized as a class 2 mutation, can be currently treated with CFTR modulator drugs. Five children aged 2-5 years could benefit from double lumacaftor/ivacaftor therapy, and 20 patients aged >6 years could be treated with the triple-combination elexacaftor/tezacaftor/ivacaftor therapy. Thus, the identification of pathogenic variants associated with the development of this disease allows for the introduction of therapy with CFTR modulators that favour better patient management.

Fibrosis quística: patogenia bacteriana y moduladores del CFTR (regulador de conductancia transmembranal de la fibrosis quística).

Cystic fibrosis is an autosomal recessive inherited disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). CFTR is a protein that transports ions across the membrane of lung epithelial cells. Loss of its function leads to the production of thick sticky mucus, where various bacterial pathogens can establish and adapt, contributing to the gradual loss of lung function. In this review, evidence of the molecular mechanisms used by Pseudomonas aeruginosa and Burkholderia cenocepacia to survive and persist in the pulmonary environment will be provided. Additionally, new therapeutic strategies based on CFTR function modulators will be described.

La fibrosis quística es una enfermedad hereditaria autosómica recesiva que se origina por mutaciones en el gen regulador de conductancia transmembranal de la fibrosis quística (CFTR, cystic fibrosis transmembrane conductance regulator). El CFTR es una proteína que transporta iones a través de la membrana de las células epiteliales pulmonares. La pérdida de su función conlleva la producción de un moco pegajoso y espeso, donde se pueden establecer y adaptar diversos patógenos bacterianos que contribuyen a la pérdida gradual de la función pulmonar. En este artículo de revisión se dará evidencia de los mecanismos moleculares que utilizan Pseudomonas aeruginosa y Burkholderia cenocepacia para sobrevivir y persistir en el ambiente pulmonar. Adicionalmente, se describirán las nuevas estrategias de terapia a base de moduladores de la función del CFTR.

Fibrosis quística: patogenia bacteriana y moduladores del CFTR (regulador de conductancia transmembranal de la fibrosis quística) / Cystic fibrosis: bacterial pathogenesis and CFTR (cystic fibrosis transmembrane conductance regulator) modulators

Resumen La fibrosis quística es una enfermedad hereditaria autosómica recesiva que se origina por mutaciones en el gen regulador de conductancia transmembranal de la fibrosis quística (CFTR, cystic fibrosis transmembrane conductance regulator). El CFTR es una proteína que transporta iones a través de la membrana de las células epiteliales pulmonares. La pérdida de su función conlleva la producción de un moco pegajoso y espeso, donde se pueden establecer y adaptar diversos patógenos bacterianos que contribuyen a la pérdida gradual de la función pulmonar. En este artículo de revisión se dará evidencia de los mecanismos moleculares que utilizan Pseudomonas aeruginosa y Burkholderia cenocepacia para sobrevivir y persistir en el ambiente pulmonar. Adicionalmente, se describirán las nuevas estrategias de terapia a base de moduladores de la función del CFTR.

Abstract Cystic fibrosis is an autosomal recessive inherited disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). CFTR is a protein that transports ions across the membrane of lung epithelial cells. Loss of its function leads to the production of thick sticky mucus, where various bacterial pathogens can establish and adapt, contributing to the gradual loss of lung function. In this review, evidence of the molecular mechanisms used by Pseudomonas aeruginosa and Burkholderia cenocepacia to survive and persist in the pulmonary environment will be provided. Additionally, new therapeutic strategies based on CFTR function modulators will be described.

Translational Research in Cystic Fibrosis: From Bench to Beside.

Cystic fibrosis is the most common life-limiting recessive genetic disorder in Caucasian populations, characterized by the involvement of exocrine glands, causing multisystemic comorbidities. Since the first descriptions of pancreatic and pulmonary involvement in children, technological development and basic science research have allowed great advances in the diagnosis and treatment of cystic fibrosis. The great search for treatments that acted at the genetic level, despite not having found a cure for this disease, culminated in the creation of CFTR modulators, highly effective medications for certain groups of patients. However, there are still many obstacles behind the treatment of the disease to be discussed, given the wide variety of mutations and phenotypes involved and the difficulty of access that permeate these new therapies around the world.

Net benefit of ivacaftor during prolonged tezacaftor/elexacaftor exposure in vitro.

BACKGROUND: A decrease in the lumacaftor-mediated increase in F508del-CFTR function and expression upon prolonged exposure to ivacaftor (VX-770) has previously been described. However, the efficacy observed with ivacaftor-containing CFTR modulator therapies in vivo is in conflict with these reports. We hypothesized that a portion of the apparent decrease in CFTR function observed after prolonged ivacaftor exposure in vitro was due to an increase in constitutive CFTR-mediated ion transport. METHODS: Human nasal epithelial (HNE) cells were obtained by brushings from three CF individuals homozygous for the F508del CFTR mutation. Differentiated epithelia were pre-treated with prolonged (24 h) exposure to either lumacaftor (VX-809; 3 µM), tezacaftor (VX-661; 3 µM), elexacaftor (VX-445; 3 µM), and/or ivacaftor (0.1-6.4 µM) or DMSO (vehicle control), and CFTR function was assayed by Ussing chamber electrophysiology. RESULTS: In cells treated with lumacaftor, constitutive CFTR activity was not increased at any concentration of co-treatment with ivacaftor. Constitutive CFTR activity was also unchanged in cells treated with the combination of tezacaftor and elexacaftor. An increase in constitutive CFTR activity above the DMSO controls was only observed in cells treated with the combination of tezacaftor and elexacaftor and co-treated with at least 0.1 µM ivacaftor. CONCLUSIONS: These results demonstrate that ivacaftor is a critical component in the triple combination therapy along with tezacaftor and elexacaftor to increase constitutive CFTR function. This work further elucidates the mechanism of action of the effective triple combination therapeutic that is now the primary clinical tool in treating CF.