Emerging microRNA Therapeutic Approaches for Cystic Fibrosis

Abstract

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and remains the most common life-shortening diseases affecting the exocrine organs. The absence of this channel results in an imbalance of ion concentrations across the cell membrane and results in more abnormal secretion and mucus plugging in the gastrointestinal tract and in the lungs of CF patients. The direct introduction of fully functional CFTR by gene therapy has long been pursued as a therapeutical option to restore CFTR function independent of the specific CFTR mutation, but the different clinical trials failed to propose persuasive evidence of this strategy. The last ten years has led to the development of new pharmacotherapies which can activate CFTR function in a mutation-specific manner. Although approximately 2,000 different disease-associated mutations have been identified, a single codon deletion, F508del, is by far the most common and is present on at least one allele in approximately 70% of the patients in CF populations. This strategy is limited by chemistry, the knowledge on CFTR and the heterogenicity of the patients. New research efforts in CF aim to develop other therapeutical approaches to combine different strategies. Targeting RNA appears as a new and an important opportunity to modulate dysregulated biological processes. Abnormal miRNA activity has been linked to numerous diseases, and over the last decade, the critical role of miRNA in regulating biological processes has fostered interest in how miRNA binds to and interacts explicitly with the target protein. Herein, this review describes the different strategies to identify dysregulated miRNA opens up a new concept and new opportunities to correct CFTR deficiency. This review describes therapeutic applications of antisense techniques currently under investigation in CF.

Treating the Underlying Cystic Fibrosis Transmembrane Conductance Regulator Defect in Patients with Cystic Fibrosis

“…In Europe, 82.4% of CF patients have at least one F508del mutation. 10 Compared with Northern Europe, the frequency of the F508del mutation is much lower in Southern Europe (e.g., 82.57% in Denmark vs. 40.1-60% in Spain, Italy, and Greece), although even there F508del remains the most common mutation. All other mutations are present in only a low percentage of the European CF cohort, but the frequency of a specific mutation may be up to 10 to 15% in specific countries/regions.…”

“…[78][79][80] ASOs are also being developed to increase CFTR protein levels by interfering with microRNAs (miRNAs) that inhibit CFTR transcription. 81,82 Genetic Therapies…”

Novel Anti-Inflammatory Approaches for Cystic Fibrosis Lung Disease: Identification of Molecular Targets and Design of Innovative Therapies

“…The epigenetic regulation role of MUC5AC and MUC5B, the main mucins expressed in the airways, has been thoroughly researched in COPD and have highlighted the implication of methylation and miRNA. Different specific therapies are in progress to modulate the miRNA, and new treatment ways are in progress in CF (Bardin et al, 2018b).…”

“…The possibility of increasing gene expression and protein activity by the use of ASO has become more and more promising in the last years. However, long-term efficacy, safe delivery, and side effects of long-term treatment must be evaluated in order to be applied in patients with CF ( Bardin et al., 2018b ; Vencken et al., 2019 ). Fabbri et al have developed this original concept by modulating the IL-8 expression by increasing miR-93 in BECs during P. aeruginosa infection ( Fabbri et al., 2014 ).…”

Evaluation of miR-155 Expression in Cystic Fibrosis Patients

“…miR-155 is effective on IL-8 expression, and consequently, the up-regulation of miR-155 can promote inflammation in CF patients by driving hyperexpression of IL-8 (7). Previous studies have evaluated miR-155 as a novel therapeutic target for the treatment of CF (13). Figure 1 represents a typical schematic for mir-155 action in CF.…”