Transfer of a cathelicidin peptide antibiotic gene restores bacterial killing in a cystic fibrosis xenograft model

Recent studies suggest that the gene defect in cystic fibrosis (CF) leads t o a breach in innate immunity. We describe a novel genetic strategy for rev ersing the CF-specific defect of antimicrobial activity by transferring a g ene encoding a secreted cathelicidin peptide antibiotic into the airway epi thelium grown in a human bronchial xenograft model. The airway surface flui d (ASF) from CF xenografts failed to kill Pseudomonas aeruginosa or Staphyl ococcus aureus. Partial reconstitution of CF transmembrane conductance regu lator expression after adenovirus-mediated gene transfer restored the antim icrobial activity of ASF from CF xenografts to normal levels. Exposure of C F xenografts to an adenovirus expressing the human cathelicidin LL-37/hCAP- 18 increased levels of this peptide in the ASF three- to fourfold above the normal concentrations, which were equivalent in ASF from CF and normal xen ografts before gene transfer. The increase of LL-37 was sufficient to resto re bacterial killing to normal levels. The data presented describe an alter native genetic approach to the treatment of CF based on enhanced expression of an endogenous antimicrobial peptide and provide strong evidence that ex pression of antimicrobial peptides indeed protects against bacterial infect ion.