Anti-inflammatory effects of elexacaftor/tezacaftor/ivacaftor in adults with cystic fibrosis heterozygous for F508del

Jarosz-Griffiths, Heledd H.; Gillgrass, Lindsey; Caley, Laura R.; Spoletini, Giulia; Clifton, Ian J.; Etherington, Christine; Savic, Sinisa; McDermott, Michael F.; Peckham, Daniel

doi:10.1371/journal.pone.0304555

Cited by 2 publications

(1 citation statement)

References 35 publications

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“…Significant clinical improvements, reduced sweat chloride levels, and a decline in routine serum inflammatory markers were the outcomes when the patients who were heterozygous for F508del treated with ETI combined therapy. Moreover, there was a significant decrease in the amounts of TNF, IL-6, IL-18, and IL-1β in both stimulated peripheral blood mononuclear cells (PBMCs) and CF serum [ 65 ]. ETI treatment for one year has showed significant improvement in BMI, serum biochemical parameters of liver function, and LDL cholesterol level in patients with homozygous f508del.…”

Section: Cftr Modulatorsmentioning

confidence: 99%

Cystic Fibrosis: Understanding Cystic Fibrosis Transmembrane Regulator Mutation Classification and Modulator Therapies

Anwar,

Peng,

Zahid

et al. 2024

ARM

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A common life-threatening hereditary disease, Cystic Fibrosis (CF), affects primarily Caucasian infants. High sweat-salt levels are observed as a result of a single autosomal mutation in chromosome 7 that affects the critical function of the cystic fibrosis transmembrane regulator (CFTR). For establishing tailored treatment strategies, it is important to understand the broad range of CFTR mutations and their impacts on disease pathophysiology. This study thoroughly investigates the six main classes of classification of CFTR mutations based on their functional effects. Each class is distinguished by distinct molecular flaws, such as poor protein synthesis, misfolding, gating defects, conduction defects, and decreased CFTR expression at the apical membrane. Furthermore, this paper focuses on the emerging field of CFTR modulators, which intend to restore CFTR function or mitigate its consequences. These modulators, which are characterized by the mode of action and targeted mutation class, have the potential to provide personalized therapy regimens in CF patients. This review provides valuable insights into the genetic basis of CF pathology, and highlights the potential for precision medicine methods in CF therapy by thoroughly investigating CFTR mutation classification and related modulators.

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Section: Cftr Modulatorsmentioning

confidence: 99%

Cystic Fibrosis: Understanding Cystic Fibrosis Transmembrane Regulator Mutation Classification and Modulator Therapies

Anwar,

Peng,

Zahid

et al. 2024

ARM

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The effect of highly effective modulator therapy on systemic inflammation in cystic fibrosis

Maher,

Cytlak-Chaudhuri,

Aleem

et al. 2024

Preprint

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Background: Despite significant clinical improvements, there is evidence of persisting airway inflammation in people with cystic fibrosis established on Elexacaftor/tezacaftor/ivacaftor (ETI) therapy. As CF is a multi-system disease, systemic immune profiles can reflect local inflammation within the lungs and other organs. Understanding systemic inflammation after ETI therapy may reveal important translational insights. This study aims to profile systemic inflammatory changes and relate these to the well-documented improvements observed with ETI therapy. Methods: We conducted a single-centre longitudinal study with 57 CF subjects initiating ETI therapy. All participants were Phe508del homozygous or Phe508del/minimal function. Blood samples were collected pre-ETI and 3-12 months post-therapy initiation. Analyses included mass spectrometry-based proteomics, a multiplex immunoassay, and flow cytometry for peripheral immune cell counts and phenotype. Controls samples were provided by 29 age- matched healthy controls. Results: Systemic inflammation reduced with ETI therapy; however, the immune profile remained distinct from healthy controls. ETI reduced neutrophil counts and was associated with a more mature, less inflammatory phenotype, as well as a shift toward an immune resolving state associated with increased CD206 expression. Cytokines known to influence neutrophil levels reduced with therapy. Despite ETI therapy, neutrophil and monocyte counts remained elevated compared to healthy controls. There was no obvious association between the ETI-related improvements in systemic inflammation and lung function. Conclusions: Patients with CF show evidence of persisting systemic inflammation despite ETI therapy, this may have long term potentially adverse effects on respiratory and other organ systems.

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Anti-inflammatory effects of elexacaftor/tezacaftor/ivacaftor in adults with cystic fibrosis heterozygous for F508del

Cited by 2 publications

References 35 publications

Cystic Fibrosis: Understanding Cystic Fibrosis Transmembrane Regulator Mutation Classification and Modulator Therapies

Cystic Fibrosis: Understanding Cystic Fibrosis Transmembrane Regulator Mutation Classification and Modulator Therapies

The effect of highly effective modulator therapy on systemic inflammation in cystic fibrosis

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