Dataset Information

Treatment With LAU-7b Complements CFTR Modulator Therapy by Improving Lung Physiology and Normalizing Lipid Imbalance Associated With CF Lung Disease.

ABSTRACT: Cystic fibrosis (CF) is the most common autosomal recessive genetic disease in Caucasians, affecting more than 100,000 individuals worldwide. It is caused by pathogenic variants in the gene encoding CFTR, an anion channel at the plasma membrane of epithelial and other cells. Many CF pathogenic variants disrupt the biosynthesis and trafficking of CFTR or reduce its ion channel function. The most frequent mutation, loss of a phenylalanine at position 508 (F508del), leads to misfolding, retention in the endoplasmic reticulum, and premature degradation of the protein. The therapeutics available for treating CF lung disease include antibiotics, mucolytics, bronchodilators, physiotherapy, and most recently CFTR modulators. To date, no cure for this life shortening disease has been found. Treatment with the Triple combination drug therapy, TRIKAFTA^®, is composed of three drugs: Elexacaftor (VX-445), Tezacaftor (VX-661) and Ivacaftor (VX-770). This therapy, benefits persons with CF, improving their weight, lung function, energy levels (as defined by reduced fatigue), and overall quality of life. We examined the effect of combining LAU-7b oral treatment and Triple therapy combination on lung function in a F508del^tm1EUR mouse model that displays lung abnormalities relevant to human CF. We assessed lung function, lung histopathology, protein oxidation, lipid oxidation, and fatty acid and lipid profiles in F508del^tm1EUR mice.

SUBMITTER: Centorame A

PROVIDER: S-EPMC9163687 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Treatment With LAU-7b Complements CFTR Modulator Therapy by Improving Lung Physiology and Normalizing Lipid Imbalance Associated With CF Lung Disease.

Centorame Amanda A Dumut Daciana Catalina DC Youssef Mina M Ondra Martin M Kianicka Irenej I Shah Juhi J Paun Radu Alexandru RA Ozdian Tomas T Hanrahan John W JW Gusev Ekaterina E Petrof Basil B Hajduch Marian M Pislariu Radu R De Sanctis Juan Bautista JB Radzioch Danuta D

Frontiers in pharmacology 20220520

Cystic fibrosis (CF) is the most common autosomal recessive genetic disease in Caucasians, affecting more than 100,000 individuals worldwide. It is caused by pathogenic variants in the gene encoding <i>CFTR</i>, an anion channel at the plasma membrane of epithelial and other cells. Many CF pathogenic variants disrupt the biosynthesis and trafficking of CFTR or reduce its ion channel function. The most frequent mutation, loss of a phenylalanine at position 508 (F508del), leads to misfolding, rete ...[more]

PMID: 35668939

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Project description:A deficiency in cystic fibrosis transmembrane conductance regulator (CFTR) function in CF leads to chronic lung disease. CF is associated with abnormalities in fatty acids, ceramides, and cholesterol, their relationship with CF lung pathology is not completely understood. Therefore, we examined the impact of CFTR deficiency on lipid metabolism and pro-inflammatory signaling in airway epithelium using mass spectrometric, protein array. We observed a striking imbalance in fatty acid and ceramide metabolism, associated with chronic oxidative stress under basal conditions in CF mouse lung and well-differentiated bronchial epithelial cell cultures of CFTR knock out pig and CF patients. Cell-autonomous features of all three CF models included high ratios of ω-6- to ω-3-polyunsaturated fatty acids and of long- to very long-chain ceramide species (LCC/VLCC), reduced levels of total ceramides and ceramide precursors. In addition to the retinoic acid analog fenretinide, the anti-oxidants glutathione (GSH) and deferoxamine partially corrected the lipid profile indicating that oxidative stress may promote the lipid abnormalities. CFTR-targeted modulators reduced the lipid imbalance and oxidative stress, confirming the CFTR dependence of lipid ratios. However, despite functional correction of CF cells up to 60% of non-CF in Ussing chamber experiments, a 72-h triple compound treatment (elexacaftor/tezacaftor/ivacaftor surrogate) did not completely normalize lipid imbalance or oxidative stress. Protein array analysis revealed differential expression and shedding of cytokines and growth factors from CF epithelial cells compared to non-CF cells, consistent with sterile inflammation and tissue remodeling under basal conditions, including enhanced secretion of the neutrophil activator CXCL5, and the T-cell activator CCL17. However, treatment with antioxidants or CFTR modulators that mimic the approved combination therapies, ivacaftor/lumacaftor and ivacaftor/tezacaftor/elexacaftor, did not effectively suppress the inflammatory phenotype. We propose that CFTR deficiency causes oxidative stress in CF airway epithelium, affecting multiple bioactive lipid metabolic pathways, which likely play a role in CF lung disease progression. A combination of anti-oxidant, anti-inflammatory and CFTR targeted therapeutics may be required for full correction of the CF phenotype.

Dataset Information

Treatment With LAU-7b Complements CFTR Modulator Therapy by Improving Lung Physiology and Normalizing Lipid Imbalance Associated With CF Lung Disease.

Publications

Treatment With LAU-7b Complements CFTR Modulator Therapy by Improving Lung Physiology and Normalizing Lipid Imbalance Associated With CF Lung Disease.

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