Precise Targeting of miRNA Sites Restores CFTR Activity in CF Bronchial Epithelial Cells

Santi, Chiara De; Fernández, Elena Fernández; Gaul, Rachel; Vencken, Sebastian; Glasgow, Arlene; Oglesby, Irene; Hurley, Killian; Hawkins, Finn; Mitash, Nilay; Mu, Fangping; Raoof, Rana; Henshall, David C.; Cutrona, Meritxell B.; Simpson, Jeremy C.; Harvey, Bill; Linnane, Barry; McNally, Paul; Cryan, Sally‐Ann; MacLoughlin, Ronan; Swiatecka‐Urban, Agnieszka; Greene, Catherine M.

doi:10.1016/j.ymthe.2020.02.001

Cited by 43 publications

(36 citation statements)

References 45 publications

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“…Most miRNA-relevant strategies rely on the use of synthetic, sequence-specific molecules that mimic or repress the expression of miRNAs. Some studies have already identified interesting miRNA-based therapeutics (i.e., TSBs targeting the binding sites of miR-223-3p and miR-145-5p) that could be used either alone or in combination with CFTR modulators [ 126 ]. However, several challenges, which include safe and organ-specific delivery, long-term efficacy, as well as side effects of prolonged treatments, need to be overcome.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, TSBs were successfully designed to prevent the binding of miR-9 to the 3’ UTR of ANO1 mRNA [ 57 ]. Recently, De Santi and colleagues reverted the inhibition of CFTR mediated by miRNAs via CFTR-specific TSBs in CF bronchial epithelial cells [ 126 ]. In particular, TSBs targeting the binding sites of miR-223-3p and miR-145-5p in the 3’ UTR were encapsulated in poly-lactic-co-glycolic acid (PLGA) nanoparticles.…”

Section: Therapeutic Modulation Of Micrornas In Cystic Fibrosismentioning

confidence: 99%

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The Multifaceted Roles of MicroRNAs in Cystic Fibrosis

et al. 2020

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Cystic fibrosis (CF) is a lifelong disorder affecting 1 in 3500 live births worldwide. It is a monogenetic autosomal recessive disease caused by loss-of-function mutations in the gene encoding the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR), the impairment of which leads to ionic disequilibria in exocrine organs. This translates into a chronic multisystemic disease characterized by airway obstruction, respiratory infections, and pancreatic insufficiency as well as hepatobiliary and gastrointestinal dysfunction. Molecular characterization of the mutational heterogeneity of CFTR (affected by more than 2000 variants) improved the understanding and management of CF. However, these CFTR variants are linked to different clinical manifestations and phenotypes, and they affect response to treatments. Expanding evidence suggests that multisystemic disease affects CF pathology via impairing either CFTR or proteins regulated by CFTR. Thus, altering the expression of miRNAs in vivo could constitute an appealing strategy for developing new CF therapies. In this review, we will first describe the pathophysiology and clinical management of CF. Then, we will summarize the current knowledge on altered miRNAs in CF patients, with a focus on the miRNAs involved in the deregulation of CFTR and in the modulation of inflammation. We will highlight recent findings on the potential utility of measuring circulating miRNAs in CF as diagnostic, prognostic, and predictive biomarkers. Finally, we will provide an overview on potential miRNA-based therapeutic approaches.

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Section: Resultsmentioning

confidence: 99%

Section: Therapeutic Modulation Of Micrornas In Cystic Fibrosismentioning

confidence: 99%

The Multifaceted Roles of MicroRNAs in Cystic Fibrosis

et al. 2020

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“…Distinct groups have proved that wild-type and mutated p.Phe508del human CFTR is regulated by miR-101-3p, miR-145-5p, miR-223-3p, miR-494-3p,and miR-509-3p ( Glasgow et al., 2018 ). The approaches to inhibit the effect of these miRNAs have demonstrated an increase in CFTR protein expression and activity in BECs ( De Santi et al., 2020 ). This approach is exciting, but further researches are needed to understand the subtility of this regulation better.…”

Section: Novel Anti-inflammatory Approachesmentioning

confidence: 99%

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

Mitri

Bardin

et al. 2020

Front. Pharmacol.

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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.

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“…The majority of male patients with CF and CBAVD have primary infertility (22), suggesting that the CFTR protein has an important role in the development of the male reproductive tract (23). CFTR mutations among patients with CBAVD (58.1%) are common but not as frequent as in patients with unilateral absence of vas deferens (75%), and a normal amount of functional CFTR protein may be required to ensure the normal development of the vas deferens (24).…”

Section: The Cftr Gene and Development Of The Vas Deferensmentioning

confidence: 99%

Mutations of the cystic fibrosis transmembrane conductance regulator gene in males with congenital bilateral absence of the vas deferens: Reproductive implications and genetic counseling (Review)

Cui¹,

Wu²,

Li³

et al. 2020

Mol Med Rep

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congenital bilateral absence of the vas deferens (cBaVd) is predominantly caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. cBaVd accounts for 2-6% of male infertility cases and up to 25% of cases of obstructive azoospermia. With the use of pre-implantation genetic diagnosis, testicular or epididymal sperm aspiration, intracytoplasmic sperm injection and in vitro fertilization, patients affected by cBaVd are able to have children who do not carry CFTR gene mutations, thereby preventing disease. Therefore, genetic counseling should be provided to couples receiving assisted reproductive techniques to discuss the impact of CFTR gene mutations on reproductive health. In the present article, the current literature concerning the CFTR gene and its association with CBAVD is reviewed. Contents 1. Introduction 2. Overview of CFTR structure and function 3. The CFTR gene and development of the vas deferens 4. The CFTR gene in patients with CBAVD 5. Hotspot mutation types in patients with CBAVD 6. Assisted reproductive techniques and genetic counselling 7. Conclusions

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Precise Targeting of miRNA Sites Restores CFTR Activity in CF Bronchial Epithelial Cells

Cited by 43 publications

References 45 publications

The Multifaceted Roles of MicroRNAs in Cystic Fibrosis

The Multifaceted Roles of MicroRNAs in Cystic Fibrosis

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

Mutations of the cystic fibrosis transmembrane conductance regulator gene in males with congenital bilateral absence of the vas deferens: Reproductive implications and genetic counseling (Review)

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