Abstract
Cystic fibrosis (CF) is the most common genetic disorder among Caucasians, estimated to affect more than 70,000 people in the world. Severe and persistent bronchial inflammation and chronic bacterial infection, along with airway mucus obstruction, are hallmarks of CF lung disease and participate in its progression. Anti-inflammatory therapies are, therefore, of particular interest for CF lung disease. Furthermore, a better understanding of the molecular mechanisms involved in airway infection and inflammation in CF has led to the development of new therapeutic approaches that are currently under evaluation by clinical trials. These new strategies dedicated to CF inflammation are designed to treat different dysregulated aspects such as oxidative stress, cytokine secretion, and the targeting of dysregulated pathways. In this review, we summarize the current understanding of the cellular and molecular mechanisms that contribute to abnormal lung inflammation in CF, as well as the new anti-inflammatory strategies proposed to CF patients by exploring novel molecular targets and novel drug approaches.
Highlights
Cystic fibrosis (CF) is the most common lethal monogenic disorder in Caucasians estimated to affect one out of 2.500-4.000 newborns. It is caused by a Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene mutation, which encodes a chloride channel expressed at the apical membrane of the epithelial cells (Riordan et al, 1989)
We have demonstrated that antisense oligonucleotide (ASO)-ANO1 could be used to inhibit the fixation of miR-9 on ANO1 mRNA by a target site blocker, and to activate the alternative chloride channel to compensate CFTR Cldeficiency regardless of the mutation (Sonneville et al, 2017)
Current anti-inflammatory drugs in CF patients have shown little effectiveness, the creation and improvement of new anti-inflammatory drugs for CF lungs has been overlooked for a long time
Summary
Cystic fibrosis (CF) is the most common lethal monogenic disorder in Caucasians estimated to affect one out of 2.500-4.000 newborns. Scientists developed many new symptomatic therapies with either anti-inflammatory properties, antibiotics, or molecules improving mucociliary clearance (mucolytics) in order to treat inflammation, infection, or mucus abnormalities (Figure 2A). The discovery of these new drugs was made possible by the accumulation of knowledge in these three areas. The main treatments remain symptomatic, focusing on different dysregulated clinical manifestations observed in CF patients (pancreatic insufficiency, intestinal malabsorption, and lung deterioration) Their use is limited by insufficient basic scientific knowledge (Figure 2C), which has reduced the number of medicinal products currently on the market (Lopes-Pacheco, 2019). Multiple hypotheses explain the early events leading to the CF lung pathophysiology progression (Jacquot et al, 2008a; Esther et al, 2019)
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