Sodium channel blockers for cystic fibrosis

Burrows, E.; Southern, Kevin W; Noone, Peadar G.

doi:10.1002/14651858.cd005087.pub4

Cited by 15 publications

(9 citation statements)

References 29 publications

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“…Although initial studies showed some promise, beneficial effects could not be confirmed in subsequent studies 268,269 . Inhibition of sodium absorption was initially approached using amiloride, but limited clinical efficacy was demonstrated 270 . More potent and specific inhibitors with a longer half-life are currently being developed.…”

Section: Treatment Of the Basic Defectmentioning

confidence: 99%

Cystic fibrosis

Ratjen

Bell

Rowe

et al. 2015

Nat Rev Dis Primers

468

435

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Cystic fibrosis is an autosomal recessive, monogenetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The gene defect was first described 25 years ago and much progress has been made since then in our understanding of how CFTR mutations cause disease and how this can be addressed therapeutically. CFTR is a transmembrane protein that transports ions across the surface of epithelial cells. CFTR dysfunction affects many organs; however, lung disease is responsible for the vast majority of morbidity and mortality in patients with cystic fibrosis. Prenatal diagnostics, newborn screening and new treatment algorithms are changing the incidence and the prevalence of the disease. Until recently, the standard of care in cystic fibrosis treatment focused on preventing and treating complications of the disease; now, novel treatment strategies directly targeting the ion channel abnormality are becoming available and it will be important to evaluate how these treatments affect disease progression and the quality of life of patients. In this Primer, we summarize the current knowledge, and provide an outlook on how cystic fibrosis clinical care and research will be affected by new knowledge and therapeutic options in the near future. For an illustrated summary of this Primer, visit: http://go.nature.com/4VrefN.

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Section: Treatment Of the Basic Defectmentioning

confidence: 99%

Cystic fibrosis

Ratjen

Bell

Rowe

et al. 2015

Nat Rev Dis Primers

468

435

View full text Add to dashboard Cite

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“…At the moment, the interest in further investigating amiloride and its analogs as possible therapies for the treatment of cystic fibrosis lung disease seems to have fallen since no new data on clinical trials have been published. Furthermore, a recent survey covering four clinical trials with inhaled amiloride failed to demonstrate any beneficial effects by inhalation of sodium channel blockers [47].…”

Section: Amiloride and Its Analogs -Still A Possi-ble Therapy?mentioning

confidence: 99%

Targeting ENaC as a Molecular Suspect in Cystic Fibrosis

Bangel-Ruland

Tomczak²,

Weber³

2015

CDT

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Cystic fibrosis (CF) is the most common life shortening autosomal inherited disorder, affecting 1 in 2500 newborns in the Caucasian population. In CF the lung pathology is associated with dehydration of the airways epithelial surface which in part results from Na(+) hyperabsorption via the epithelial sodium channel (ENaC). The molecular mechanisms of this Na(+) hyperabsorption and its correlation with the underlying genetic defect in the cystic fibrosis transmembrane conductance regulator (CFTR) are not fully understood. However, it is obvious that a reduced Cl(-) secretion by CFTR and an enhanced Na+ absorption through ENaC lead to the so far incurable disease. Therefore, it could be indicated to pursue a double-tracked strategy in that way enabling Cl(-) secretion by a reconstitution of the defect CFTR as well as blocking ENaC to prevent Na(+) hyperabsorption. Since the cloning of CFTR great efforts have been done in delivery of CFTR for the correction of the reduced Cl(-) secretion. Positive benefits for the inhibition of the CF related Na(+) hyperabsorption offer technologies using small molecule inhibitors like ASOs or siRNA, which target translation and knockdown of ENaC, respectively. In this review we discuss possible CFTR/ENaC interactions in the context of CF, describe ENaC structure as well as some of the numerous attempts that were performed to prevent the Na(+) hyperabsorption in CF related lung disease. Thus, we give a short summary of e.g. amiloride therapy approaches and focus on inventive blocking efforts using ASOs and siRNA.

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“…12,13 Three subsequent randomized control trials 14,16 failed to show any benefit of amiloride on respiratory function tests over a 6 to 12 month period (see also Cochrane review 2006). 17 It has been suggested that the lack of clinical benefit of amiloride is due to its short half-life on the airway surface because of rapid absorption. Higher potency sodium channel blockers with longer airway surface half-lives have been developed, most recently a compound called PS552.…”

Section: Therapymentioning

confidence: 99%