MSACL 2026 Abstract

Identification of Cystic Fibrosis Biomarkers Using Metabolomic and Lipidomic Approaches and Evaluation of CFTR Modulator Responses

Christiane Auray-Blais (1,3), Asma Farjallah (1), Christelle Bergeron (2,3), Dominic Cliche(2,3), Simon Couillard (2,3), André M. Cantin (2,3)
(1) Division of Medical Genetics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada (2) Department of Medicine, Respiratory Division, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada (3) Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Respiratory Division, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, QC Canada

Christiane Auray-Blais, LL.M., Ph.D. (Presenter) Université de Sherbrooke

Presenter Bio: Christiane Auray-Blais was the Scientific Director of the Provincial Neonatal Urine Screening Program for hereditary metabolic disorders in Sherbrooke, Quebec more than 5 decades. More than 3 700 000 newborns were screened for disorders of amino acids and organic acids. She holds a Ph.D. in radiobiology from the Faculty of Medicine and Health Sciences (FMHS) at the Université de Sherbrooke and postdoctoral studies from Duke University Medical Center in North Carolina, US. She has a master’s degree in Health Law from the Faculty of Law at the Université de Sherbrooke and a bachelor’s degree in biochemistry. She is the author of more than 350 publications, book chapters, abstracts, and articles. She is a full professor in the Medical Genetics Division in the Department of Pediatrics at the FMHS and a researcher at the Clinical Research Centre in Sherbrooke, and in the Mother-Child Axis. She is the Scientific Director for the Waters-CHUS Expertise Centre in Clinical Mass Spectrometry and the Director at the Waters Center of Innovation in Sherbrooke. She is the principal investigator and co-investigator in numerous research grants for various lysosomal storage disorders such as Fabry disease, Gaucher disease, mucopolysaccharidoses, and on Parkinson’s disease, vitamin B12 deficiency in the elderly, etc. She has received awards for her involvement and expertise in preventive genetic medicine.

Relevant Financial Disclosures (within past 24 months, reported on Jun 29, 2026) Salary Université de Sherbrooke Discussing Products? NO, presenter will NOT present educational content related to products/services of the ineligible company(ies) listed above. Conflict mitigation NOT REQUIRED.

INTRODUCTION:
Cystic fibrosis (CF) is a life-limiting autosomal recessive genetic disorder caused by mutations in the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene, which encodes a chloride ion channel expressed in epithelial cells. Dysfunction of CFTR leads to impaired chloride and bicarbonate transport, resulting in dehydration of airway surface liquid and the accumulation of thick, viscous mucus. This abnormal mucus environment promotes chronic bacterial colonization, recurrent respiratory infections, and persistent neutrophil-dominated inflammation. Over time, these processes contribute to progressive lung damage, declining pulmonary function, and increased morbidity and mortality. In addition to pulmonary manifestations, CF affects multiple organs, including the pancreas, liver, and gastrointestinal tract, reflecting its systemic nature. Despite major therapeutic advances, particularly with the development of CFTR modulators, there remains a critical need for robust biomarkers to improve disease characterization, monitor treatment response, and guide personalized therapeutic strategies.

OBJECTIVES:
The primary objective of this study was to identify plasma biomarkers associated with cystic fibrosis using comprehensive untargeted metabolomic and lipidomic approaches. By capturing global metabolic alterations, this work aims to improve early detection, enhance diagnostic precision, and enable more accurate disease monitoring. The secondary objective was to evaluate the biochemical impact of currently available CFTR modulator therapies, including elexacaftor/tezacaftor/ivacaftor (ETI; Trikafta®), tezacaftor/ivacaftor (TI; Symdeko®), and lumacaftor/ivacaftor (LI; Orkambi®), in order to better understand their differential effects on systemic metabolism and identify metabolic signatures associated with therapeutic responses.

RESULTS:
Untargeted metabolomic and lipidomic profiling was performed using liquid chromatography coupled to quadrupole-time-of-flight mass spectrometry (LC-QTOF-MS) to compare untreated cystic fibrosis patients (n = 26) with age- and gender-matched healthy controls (n = 24). Multivariate statistical analyses, including PCA, PLS-DA, and OPLS-DA, demonstrated clear discrimination between groups, indicating significant metabolic perturbations in CF patients. Pathway enrichment analysis revealed marked dysregulation in several key metabolic pathways, including galactose metabolism, glycolysis and gluconeogenesis, bile acid biosynthesis, fatty acid metabolism, steroid hormone biosynthesis, and amino acid catabolism. These alterations reflect disruptions in energy metabolism, lipid homeostasis, and inflammatory signaling.
Evaluation of three CFTR modulator therapies: elexacaftor/tezacaftor/ivacaftor (ETI; Trikafta®, n = 21), tezacaftor/ivacaftor (TI; Symdeko®), and lumacaftor/ivacaftor (LI; Orkambi®, n = 10), revealed distinct metabolic signatures associated with each treatment. Among them, ETI induced the most pronounced metabolic remodeling, with a greater number of significantly altered metabolites and lipids across diverse chemical classes. ETI treatment was consistently associated with downregulation of oxidized fatty acids and oxylipins (e.g., DiHOME derivatives), as well as eicosanoid-related phospholipids, indicating a reduction in lipid peroxidation and inflammatory signaling. In addition, decreases in sphingolipids and membrane-remodeling phospholipids suggest improved membrane stability and reduced cellular stress, including attenuation of endoplasmic reticulum stress. These findings are further supported by evidence of enhanced β-oxidation and normalization of arachidonic acid metabolism, indicating a shift toward improved metabolic efficiency and reduced inflammatory burden. Partial restoration of steroid hormone biosynthesis pathways also suggests broader systemic metabolic recovery under ETI treatment. In contrast, treatment with TI and LI resulted in more modest metabolic changes. While some improvements were observed, several lipid classes, including glycerophospholipids and sphingolipids, as well as amino acid pathways, remained dysregulated. These findings suggest that TI and LI provide only partial correction of the underlying metabolic disturbances in cystic fibrosis, particularly in pathways related to inflammation, oxidative stress, and membrane remodeling.

CONCLUSION:
Overall, this study provides a comprehensive systems-level characterization of metabolic disruptions in cystic fibrosis and highlights the utility of integrated metabolomic and lipidomic profiling for biomarker discovery. The identification of distinct metabolic signatures associated with CFTR modulator therapies, particularly the robust effects observed with ETI, underscores the potential of these approaches to monitor therapeutic response and guide precision medicine strategies. These findings support the integration of metabolomics/lipidomics into translational clinical research and may contribute to the development of novel biomarkers and targeted interventions aimed at improving patient outcomes in cystic fibrosis.

Reference: Farjallah A. et al, Journal of Proteome Research, 2026, 25, 1864-1877.