Specific inhibition of epithelial Na<sup>+</sup> channels by antisense oligonucleotides for the treatment of Na<sup>+</sup> hyperabsorption in cystic fibrosis

Sobczak, Katja; Segal, Andrei; Bangel-Ruland, Nadine; Semmler, Judith; Driessche, Willy Van; Lindemann, H.; Heermann, Ralf; Weber, Wolf-Michael

doi:10.1002/jgm.1363

Cited by 11 publications

(21 citation statements)

References 52 publications

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“…To evaluate effects on the function of the ENaC channel, we turned our attention to electrophysiological measurements in human nasal epithelial cells, a system which has previously been used successfully to study the effects of ENaC-targeting ASOs on the function of the channel. 5 Therefore, when human nasal epithelial cells are grown as monolayers and placed in modified Ussing chambers, it is possible to measure changes in transepithelial current through the ENaC channel. Using this system, we were able to demonstrate that GSK2225745-induced suppression of ENaCα mRNA was also associated with marked inhibition of ENaC channel function.…”

Section: Discussionmentioning

confidence: 99%

“…Similar data have previously been published from studies in human-cultured nasal epithelial cells. Therefore, Sobczak and colleagues 5,19 evaluated the effects of an ASO targeting the α-subunit of ENaC. They reported that this ASO was able to significantly inhibit the function of the ENaC channel with duration of action of at least 3 days.…”

Section: Discussionmentioning

confidence: 99%

“…22 Previous workers have shown that the α-subunit is critical for the function of the channel in respiratory epithelia. 4,5,18,23 Therefore, this work focused on the identification of a siRNA-targeting ENaCα.…”

Section: Methodsmentioning

confidence: 99%

“…Previous workers have already demonstrated that ENaC function in airway epithelial cells can be inhibited with both small-interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs) with a long duration of action. 4,5 This long duration of target suppression bodes well for the development of medicines which can be dosed infrequently and thereby reduce patient treatment burden. Moreover, clinical data with inhaled oligonucleotides suggests that systemic exposure is minimal after inhalation.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological Characterization of a Novel ENaCα siRNA (GSK2225745) With Potential for the Treatment of Cystic Fibrosis

Clark

Hughes

Bulsara

et al. 2013

Molecular Therapy - Nucleic Acids

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Lung pathology in cystic fibrosis is linked to dehydration of the airways epithelial surface which in part results from inappropriately raised sodium reabsorption through the epithelial sodium channel (ENaC). To identify a small-interfering RNA (siRNA) which selectively inhibits ENaC expression, chemically modified 21-mer siRNAs targeting human ENaCα were designed and screened. GSK2225745, was identified as a potent inhibitor of ENaCα mRNA (EC50 (half maximal effective concentration) = 0.4 nmol/l, maximum knockdown = 85%) and protein levels in A549 cells. Engagement of the RNA interference (RNAi) pathway was confirmed using 5′ RACE. Further profiling was carried out in therapeutically relevant human primary cells. In bronchial epithelial cells, GSK2225745 elicited potent suppression of ENaCα mRNA (EC50 = 1.6 nmol/l, maximum knockdown = 82%). In human nasal epithelial cells, GSK2225745 also produced potent and long-lasting (≥72 hours) suppression of ENaCα mRNA levels which was associated with significant inhibition of ENaC function (69% inhibition of amiloride-sensitive current in cells treated with GSK2225745 at 10 nmol/l). GSK2225745 showed no evidence for potential to stimulate toll-like receptor (TLR)3, 7 or 8. In vivo, topical delivery of GSK2225745 in a lipid nanoparticle formulation to the airways of mice resulted in significant inhibition of the expression of ENaCα in the lungs. In conclusion, GSK2225745 is a potent inhibitor of ENaCα expression and warrants further evaluation as a potential novel inhaled therapeutic for cystic fibrosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pharmacological Characterization of a Novel ENaCα siRNA (GSK2225745) With Potential for the Treatment of Cystic Fibrosis

Clark

Hughes

Bulsara

et al. 2013

Molecular Therapy - Nucleic Acids

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“…Since ENaC activation has been shown to depend on several trypsin-family serine peptidases [51,52], therapeutic approaches based on protease inhibitors are also being pursued [53]. Another approach to selectively downregulate ENaC involves usage of small interference (si) RNAs to downeregulate its expression levels [54][55][56] and, given the rapid developments in siRNA therapeutics targeted to the lung [57], this strategy may become feasible in the shortterm. However, since ENaC cannot be fully blocked, given the associated risk of hypotension and other symptoms associated with psuedohypoaldosteronism (PHA1), all ENaC targeted therapies must might under tight control.…”

Section: Manipulating Other Ionic Conductances To Restore Airway Surfmentioning

confidence: 98%

Targeting CFTR: How to Treat Cystic Fibrosis by CFTR-Repairing Therapies

Amaral

2011

CDT

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Several novel compounds recently appeared as promising leads to develop effective drugs against the basic defect in Cystic fibrosis (CF) and the first rationale therapies for CF relying on the understanding of the basic defect started to hit the clinical setting. Most of these efforts are focused on correcting the F508del mutation (occurring in ≈90% of CF patients) which causes misfolding of the CF transmembrane conductance regulator (CFTR) protein, the intracellular retention of such abnormal conformation by the endoplasmic reticulum quality control and premature degradation, thus precluding CFTR from reaching the cell membrane where it normally functions as a cAMP-stimulated Cl- channel. Here, several rationale therapeutic strategies are briefly reviewed, namely, mutation-specific (or "CFTR-repairing") approaches (with a particular focus on the cellular defect associated with F508del-CFTR), manipulation of other ionic (non-CFTR) conductances and gene therapy. Still more innovative strategies, such as manipulation of the proteostasis network, displacement of molecular chaperones, targeting mutant CFTR by in silico small-molecule screens and systems biology approaches are also discussed.

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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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Specific inhibition of epithelial Na⁺ channels by antisense oligonucleotides for the treatment of Na⁺ hyperabsorption in cystic fibrosis

Cited by 11 publications

References 52 publications

Pharmacological Characterization of a Novel ENaCα siRNA (GSK2225745) With Potential for the Treatment of Cystic Fibrosis

Pharmacological Characterization of a Novel ENaCα siRNA (GSK2225745) With Potential for the Treatment of Cystic Fibrosis

Targeting CFTR: How to Treat Cystic Fibrosis by CFTR-Repairing Therapies

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

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Specific inhibition of epithelial Na+ channels by antisense oligonucleotides for the treatment of Na+ hyperabsorption in cystic fibrosis

Cited by 11 publications

References 52 publications

Pharmacological Characterization of a Novel ENaCα siRNA (GSK2225745) With Potential for the Treatment of Cystic Fibrosis

Pharmacological Characterization of a Novel ENaCα siRNA (GSK2225745) With Potential for the Treatment of Cystic Fibrosis

Targeting CFTR: How to Treat Cystic Fibrosis by CFTR-Repairing Therapies

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

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Specific inhibition of epithelial Na⁺ channels by antisense oligonucleotides for the treatment of Na⁺ hyperabsorption in cystic fibrosis