(156e) Sputum Penetration and Enhanced Airway Gene Transfer by Mucus Penetrating Synthetic Gene Nanocarriers

No gene delivery system, viral or non-viral, has shown evidence of efficiently penetrating the human mucus barrier; this reality may account in part for the limited success in clinical trials for CF gene therapy to date. Gene carriers that fail to penetrate airway mucus layers are ultimately cleared from the lungs via mucus clearance mechanisms. To potentially overcome this formidable barrier, we developed a synthetic gene delivery platform capable of penetrating human CF sputum while maintaining an ability to provide efficient airway gene transfer in mice and in human airway epithelial cells grown at air-liquid interface. Mucus penetrating gene nanocarriers markedly enhanced particle diffusion in CF sputum, leading to enhanced particle distribution, retention and gene transfer in the mouse airways. Enhanced airway gene transfer by mucus penetrating gene nanocarriers is most likely attributed to the improved mucus penetration, which leads to more uniform distribution and prolonged retention in the lung compared to conventional cationic gene carriers. Pulmonary administration of these nanocarriers exhibited safety and inflammation profile comparable to saline control, whereas conventional cationic gene carriers induced significant toxicity and inflammation.