MicroRNA-9 downregulates the ANO1 chloride channel and contributes to cystic fibrosis lung pathology

Sonneville, Florence; Ruffin, Manon; Coraux, Christelle; Rousselet, Nathalie; Rouzic, Philippe Le; Blouquit-Laye, Sabine; Corvol, Harriet; Tabary, Olivier

doi:10.1038/s41467-017-00813-z

Cited by 63 publications

(59 citation statements)

References 42 publications

(50 reference statements)

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“…The calcium-activated chloride ion channel, ANO1, has also been shown to contribute to CF pathology and is downregulated in CF epithelium [126]. ANO1 is targeted by miR-9, which is increased in fully differentiated bronchial epithelial cells from CF patients [127].…”

Section: Mirnas In Cfmentioning

confidence: 99%

Alpha-1 Antitrypsin—A Target for MicroRNA-Based Therapeutic Development for Cystic Fibrosis

Hunt

Glasgow

Humphreys

et al. 2020

IJMS

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Cystic fibrosis (CF) is an autosomal recessive genetic disorder arising from mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Disruption to normal ion homeostasis in the airway results in impaired mucociliary clearance, leaving the lung more vulnerable to recurrent and chronic bacterial infections. The CF lung endures an excess of neutrophilic inflammation, and whilst neutrophil serine proteases are a crucial part of the innate host defence to infection, a surplus of neutrophil elastase (NE) is understood to create a net destructive effect. Alpha-1 antitrypsin (A1AT) is a key antiprotease in the control of NE protease activity but is ineffective in the CF lung due to the huge imbalance of NE levels. Therapeutic strategies to boost levels of protective antiproteases such as A1AT in the lung remain an attractive research strategy to limit the damage from excess protease activity. microRNAs are small non-coding RNA molecules that bind specific cognate sequences to inhibit expression of target mRNAs. The inhibition of miRNAs which target the SERPINA1 (A1AT-encoding gene) mRNA represents a novel therapeutic approach for CF inflammation. This could involve the delivery of antagomirs that bind and sequester the target miRNA, or target site blockers that bind miRNA recognition elements within the target mRNA to prevent miRNA interaction. Therefore, miRNA targeted therapies offer an alternative strategy to drive endogenous A1AT production and thus supplement the antiprotease shield of the CF lung.

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Section: Mirnas In Cfmentioning

confidence: 99%

Alpha-1 Antitrypsin—A Target for MicroRNA-Based Therapeutic Development for Cystic Fibrosis

Hunt

Glasgow

Humphreys

et al. 2020

IJMS

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“…For viral infections, MucilAir™-Pool airway epithelia were reconstituted with a mixture of human nasal cells isolated from 14 different donors, and cultured at the air-liquid interface (ALI) in MucilAir™ culture medium (EP04MM), ready-to-use, chemically defined, serum-free (Epithelix Sàrl, Geneva, Switzerland), in 24-well plates with 6.5-mm Transwell ® inserts (cat #3470, Corning Incorporated, Tweksbury, USA). The MucilAir™ models are stable for months and generate reproducible data in several domains, such as toxicology, therapeutic drug study or disease model (Baxter et al, 2015), (Balogh Sivars et al, 2017), (Rocca et al, 2016), (Sonneville et al, 2017).…”

Section: Mucilair™ Culturingmentioning

confidence: 99%

Antiviral drug screening by assessing epithelial functions and innate immune responses in human 3D airway epithelium model

et al. 2018

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Respiratory viral infections cause mild to severe diseases, such as common cold, bronchiolitis and pneumonia and are associated with substantial burden for society. To test new molecules for shortening, alleviating the diseases or to develop new therapies, relevant human in vitro models are mandatory. MucilAir™, a human standardized air-liquid interface 3D airway epithelial culture holds in vitro specific mechanisms to counter invaders comparable to the in vivo situation, such as mucus production, mucociliary clearance, and secretion of defensive molecules. The objective of this study was to test the relevance of such a model for the discovery and validation of antiviral drugs. Fully differentiated 3D nasal epithelium cultures were inoculated with picornaviruses, a coronavirus and influenza A viruses in the absence or in the presence of reference antiviral drugs. Results showed that, rupintrivir efficiently inhibits the replication of respiratory picornaviruses in a dose dependent manner and prevents the impairment of the mucociliary clearance. Similarly, oseltamivir reduced the replication of influenza A viruses in a dose dependent manner and prevented the impairment of the epithelial barrier function and cytotoxicity until 4 days of infection. In addition we found that Rhinovirus B14, C15 and influenza A(H1N1) induce significant increase of β Defensins 2 and Cathelicidin release with different time course. These results reveal that a large panel of epithelial functions is modified upon viral infection and validate MucilAir™ as a pertinent tool for pre-clinical antiviral drug testing.

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“…They improve mucociliary clearance, decrease inflammation or fight infection 2 . One of the new therapeutic strategies proposed in the literature is based on the stimulation of an alternative pathway to that involving CFTR for the transfer of chloride ions, such as that induced by the chloride channel ANO1 (Anoctamin-1, also called TMEM16A [transmembrane protein 16A]) ( Caputo et al, 2008 ; Schroeder et al, 2008 ; Yang et al, 2008 ; Sonneville et al, 2017 ), which could also participate in the activation of CFTR in the cell membrane ( Benedetto et al, 2017 ). Another proposed emerging approach is based on modulating the expression of the microRNAs that regulate target RNAs such as CFTR.…”

Section: Cystic Fibrosis and Therapeutic Approachesmentioning

confidence: 99%

Emerging microRNA Therapeutic Approaches for Cystic Fibrosis

et al. 2018

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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.

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MicroRNA-9 downregulates the ANO1 chloride channel and contributes to cystic fibrosis lung pathology

Cited by 63 publications

References 42 publications

Alpha-1 Antitrypsin—A Target for MicroRNA-Based Therapeutic Development for Cystic Fibrosis

Alpha-1 Antitrypsin—A Target for MicroRNA-Based Therapeutic Development for Cystic Fibrosis

Antiviral drug screening by assessing epithelial functions and innate immune responses in human 3D airway epithelium model

Emerging microRNA Therapeutic Approaches for Cystic Fibrosis

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