Antisense oligonucleotide targeting of mRNAs encoding ENaC subunits α, β, and γ improves cystic fibrosis-like disease in mice

Abstract

Delivery of ASOs targeting mRNAs encoding each of the three ENaC subunits directly into the lung improved disease phenotypes in a mouse model of CF-like lung disease. These findings suggest that targeting ENaC subunits could be an effective approach for the treatment of CF.

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

“…Antisense technology is being explored as a therapeutic for CF, including strategies to elevate CFTR expression ( 60 , 61 ), modulate other channels in the ion secretion pathway ( 62 , 63 ), and target F508del-CFTR ( 64 ). 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 ( 11 , 25 ).…”

“…The clinical potential of ASOs delivered directly to the respiratory system has been demonstrated for asthma and other inflammatory lung conditions ( 82–85 ). 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 ( 63 , 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 CF-like lung disease model in mice as well as CF patients ( 86 , 88 , 89 ).…”

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

“…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).…”

“…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).…”

“…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). In recent clinical trials, treatment with an ASO drug candidate, eluforsen, which specifically targets the F508del-CFTR mutation, resulted in improved chloride and sodium transport, as measured by a nasal potential difference (NPD), in CF patients when delivered via bilateral intranasal administration three times a week for four weeks (63).…”