The Cystic Fibrosis-Like Airway Surface Layer Is not a Significant Barrier for Delivery of Eluforsen to Airway Epithelial Cells
| Autor: | N. Henig, Brinks, de Jager M, K. Lipinska, Brian Button, B. Matthee, Beumer W, Alessandra Livraghi-Butrico |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Pulmonary and Respiratory Medicine
Male Pathology medicine.medical_specialty Time Factors Cystic Fibrosis Mucociliary clearance Oligonucleotides Pharmaceutical Science Cystic Fibrosis Transmembrane Conductance Regulator medicine.disease_cause Cystic fibrosis Mice In vivo Administration Inhalation medicine Animals Humans Pharmacology (medical) Tissue Distribution Lung Cells Cultured Original Research Inhalation Pseudomonas aeruginosa Chemistry Epithelial Cells respiratory system Oligonucleotides Antisense medicine.disease Mucus Mice Inbred C57BL medicine.anatomical_structure Biofilms Sputum Female medicine.symptom |
| Zdroj: | J Aerosol Med Pulm Drug Deliv |
| ISSN: | 1941-2703 |
| Popis: | Background: Eluforsen (previously known as QR-010) is a 33-mer antisense oligonucleotide under development for oral inhalation in cystic fibrosis (CF) patients with the delta F508 mutation. Previous work has shown that eluforsen restores CF transmembrane conductance regulator (CFTR) function in vitro and in vivo. To be effective, eluforsen has first to reach its primary target, the lung epithelial cells. Therefore, it has to diffuse through the CF airway surface layer (ASL), which in CF is characterized by the presence of thick and viscous mucus, impaired mucociliary clearance, and persistent infections. The goal of this study was to assess delivery of eluforsen through CF-like ASL. Methods and Results: First, air-liquid interface studies with cultured primary airway epithelial cells revealed that eluforsen rapidly diffuses through CF-like mucus at clinically relevant doses when nebulized once or repeatedly, over a range of testing doses. Furthermore, eluforsen concentrations remained stable in CF patient sputum for at least 48 hours, and eluforsen remained intact in the presence of various inhaled CF medications for at least 24 hours. When testing biodistribution of eluforsen after orotracheal administration in vivo, no differences in lung, liver, trachea, and kidney eluforsen concentration were observed between mice with a CF-like lung phenotype (ENaC-overexpressing mice) and control wild-Type (WT) littermates. Also, eluforsen was visualized in the airway epithelial cell layer of CF-like muco-obstructed mice and WT littermates. Finally, studies of eluforsen uptake and binding to bacteria prevalent in CF lungs, and diffusion through bacterial biofilms showed that eluforsen was stable and not absorbed by, or bound to bacteria. In addition, eluforsen was found to be able to penetrate Pseudomonas aeruginosa biofilms. Conclusions: The thickened and concentrated CF ASL does not constitute a significant barrier for delivery of eluforsen, and feasibility of oral inhalation of eluforsen is supported by these data. |
| Databáze: | OpenAIRE |
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