Inhaled ENaC antisense oligonucleotide ameliorates cystic fibrosis-like lung disease in mice

Crosby, Jeff; Zhao, Chenguang; Jiang, Chunhe; Bai, Dong; Katz, Melanie; Greenlee, Sarah; Kawabe, Hiroshi; McCaleb, Michael L.; Rotin, Daniela; Guo, Shuling; Monia, Brett P.

doi:10.1016/j.jcf.2017.05.003

Cited by 73 publications

(72 citation statements)

References 40 publications

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“…These findings have been replicated by others [80], and more recently Ionis Pharmaceuticals reported similar findings in mice following either aerosolized administration or orotracheal instillation of ASOs targeting α-ENaC [81]. The latter study represents the first in vivo application of ASO therapy targeting ENaC in a CF model.…”

Section: Enac Inhibitors In Developmentsupporting

confidence: 70%

The epithelial sodium channel (ENaC) as a therapeutic target for cystic fibrosis

Shei

Peabody

Kaza

et al. 2018

Current Opinion in Pharmacology

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Cystic fibrosis (CF) is a monogenic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR dysfunction is characterized by abnormal mucociliary transport due to a dehydrated airway surface liquid (ASL) and hyperviscous mucus, among other pathologies of host defense. ASL depletion is caused by the absence of CFTR medicated chloride secretion along with continued activity of the epithelial sodium channel (ENaC) activity, which can also be affected by CFTR mediated anion conductance. Therefore, ENaC has been proposed as a therapeutic target to ameliorate ASL dehydration and improve mucus transport. Inhibition of ENaC has been shown to restore ASL hydration and enhance mucociliary transport in induced models of CF lung disease. To date, no therapy inhibiting ENaC has successfully translated to clinical efficacy, in part due to concerns regarding off-target effects, systemic exposure, durability of effect, and adverse effects. Recent efforts have been made to develop novel, rationally designed therapeutics to produce specific, long-lasting inhibition of ENaC activity in the airways while simultaneously minimizing off target fluid transport effects, systemic exposure and side effects. Such approaches comprise next-generation small molecule direct inhibitors, indirect channel-activating protease inhibitors, synthetic peptide analogs, and oligonucleotide-based therapies. These novel therapeutics represent an exciting step forward in the development of ENaC-directed therapies for CF.

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Section: Enac Inhibitors In Developmentsupporting

confidence: 70%

The epithelial sodium channel (ENaC) as a therapeutic target for cystic fibrosis

Shei

Peabody

Kaza

et al. 2018

Current Opinion in Pharmacology

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“…Griesenbach et al could not observe a decrease in ENaC activity after transfection using Genzyme lipid 67 in mice [61], showing that lipid-based transfection is not always suitable. Crosby et al, on the other hand, could successfully decrease ENaC expression and ameliorate inflammation and airway hyperresponsiveness after ENaC ASO inhalation in mice with CF lung disease [62]. However, the pertinence of these findings should be considered with caution, as the murine model of CF often fails to reflect human pulmonary pathology [63].…”

Section: Aso Transfection Successfully Downregulates Enac Activity Inmentioning

confidence: 99%

Chitosan Nanocomplexes for the Delivery of ENaC Antisense Oligonucleotides to Airway Epithelial Cells

et al. 2020

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Nanoscale drug delivery systems exhibit a broad range of applications and promising treatment possibilities for various medical conditions. Nanomedicine is of great interest, particularly for rare diseases still lacking a curative treatment such as cystic fibrosis (CF). CF is defined by a lack of Cl− secretion through the cystic fibrosis transmembrane conductance regulator (CFTR) and an increased Na+ absorption mediated by the epithelial sodium channel (ENaC). The imbalanced ion and water transport leads to pathological changes in many organs, particularly in the lung. We developed a non-viral delivery system based on the natural aminopolysaccharide chitosan (CS) for the transport of antisense oligonucleotides (ASO) against ENaC to specifically address Na+ hyperabsorption. CS–ASO electrostatic self-assembled nanocomplexes were formed at varying positive/negative (P/N) charge ratios and characterized for their physicochemical properties. Most promising nanocomplexes (P/N 90) displayed an average size of ~150 nm and a zeta potential of ~+30 mV. Successful uptake of the nanocomplexes by the human airway epithelial cell line NCI-H441 was confirmed by fluorescence microscopy. Functional Ussing chamber measurements of transfected NCI-H441 cells showed significantly decreased Na+ currents, indicating successful downregulation of ENaC. The results obtained confirm the promising characteristics of CS as a non-viral and non-toxic delivery system and demonstrate the encouraging possibility to target ENaC with ASOs to treat abnormal ion transport in CF.

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“…Antisense technology is being explored as a therapeutic for CF, including strategies to elevate CFTR expression (59,60), modulate other channels in the ion secretion pathway (61,62), and target F508del-CFTR (63). Although splicing mutations account for a significant portion of CF cases, splice-switching ASOs have only been tested for two such mutations, CFTR c.3718-2477 C>T and c.2647+5G>A Pulmonary disease severity has been linked to the amount of aberrant splicing in patients, with small differences in -Ex splicing correlating with comparatively large differences in pulmonary function, as determined by the percent predicted forced expiratory volume (ppFEV1) (15,67).…”

Section: Discussionmentioning

confidence: 99%

“…The clinical potential of ASOs delivered directly to the respiratory system has been demonstrated for asthma and other inflammatory lung conditions (82)(83)(84)(85). Unlike in vitro cell culture systems, which typically require transfection reagents for efficient delivery, naked ASOs have been successfully delivered to the lung, where they access multiple cell types including airway epithelial cells (62,83,86,87). Specific to CF, aerosolization of ASOs has shown promise as an effective delivery modality to CFTR expressing lung epithelial cells in both a CFlike lung disease model in mice as well as CF patients (86,88,89).…”

Section: Importantly Treatment With Aso- In Combination With the Momentioning

confidence: 99%

Antisense oligonucleotide-mediated correction ofCFTRsplicing improves chloride secretion in cystic fibrosis patient-derived bronchial epithelial cells

Michaels

Bridges

Hastings

2020

Preprint

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Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, encoding an anion channel that conducts chloride and bicarbonate across epithelial membranes. Mutations that disrupt pre-mRNA splicing occur in more than 15% of CF cases. One common CFTR splicing mutation is CFTR c.3718-2477C>T (3849+10kbC>T), which creates a new 5' splice site, resulting in splicing to a cryptic exon with a premature termination codon.Splice-switching antisense oligonucleotides (ASOs) have emerged as an effective therapeutic strategy to block aberrant splicing. We test an ASO targeting the CFTR c.3718-2477C>T mutation and show that it effectively blocks aberrant splicing in primary bronchial epithelial (hBE) cells from CF patients with the mutation. ASO treatment results in long-term improvement in CFTR activity in hBE cells, as demonstrated by a recovery of chloride secretion and apical membrane conductance.We also show that the ASO is more effective at recovering chloride secretion in our assay than ivacaftor, the potentiator treatment currently available to these patients.Our findings demonstrate the utility of ASOs in correcting CFTR expression and channel activity in a manner expected to be therapeutic in patients.

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Inhaled ENaC antisense oligonucleotide ameliorates cystic fibrosis-like lung disease in mice

Abstract: Our results demonstrate that antisense inhibition of ENaC in airway epithelial cells could be an effective and safe approach for the prevention and reversal of lung symptoms in CF and potentially other inflammatory diseases of the lung.

Cited by 73 publications

References 40 publications

The epithelial sodium channel (ENaC) as a therapeutic target for cystic fibrosis

The epithelial sodium channel (ENaC) as a therapeutic target for cystic fibrosis

Chitosan Nanocomplexes for the Delivery of ENaC Antisense Oligonucleotides to Airway Epithelial Cells

Antisense oligonucleotide-mediated correction ofCFTRsplicing improves chloride secretion in cystic fibrosis patient-derived bronchial epithelial cells

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