Using gene editing and nanoparticles to change airway cells needed for cystic fibrosis treatment

A common disease-causing splice site variant was corrected in primary cystic fibrosis airway cells using base editor RNAs.

• Single-cell RNA sequencing showed a significant increase in detectable CFTR transcript levels in most CF airway epithelial cell types.
• There was notable enrichment of CFTR-expressing ionocytes and secretory goblet cells following the correction.
• Edited progenitor basal cell subtypes decreased as a fraction of total cells compared to unedited cells.
• CRISPR base editors delivered by polymeric nanoparticles successfully restored CFTR function to clinically meaningful levels in both immortalized and primary airway cells.
• Polymeric nanoparticles were able to deliver reporter encoding RNA to progenitor airway cells in fully differentiated cultures.
• Vitronectin was identified as a major component of the nanoparticle corona formed in vivo, although pre-incubation with vitronectin did not enhance delivery.

Simplified