A truncated CFTR protein rescues endogenous DeltaF508-CFTR and corrects chloride transport in mice.

Cystic fibrosis (CF) is most frequently associated with deletion of phenylalanine at position 508 (DeltaF508) in the CF transmembrane conductance regulator (CFTR) protein. The DeltaF508-CFTR mutant protein exhibits a folding defect that affects its processing and impairs chloride-channel function. This study aimed to determine whether CFTR fragments approximately half the size of wild-type CFTR and complementary to the portion of CFTR bearing the mutation can specifically rescue the processing of endogenous DeltaF508-CFTR in vivo. cDNA encoding CFTR fragments were delivered to human airway epithelial cells and mice harboring endogenous DeltaF508-CFTR. Delivery of small CFTR fragments, which do not act as chloride channels by themselves, rescue DeltaF508-CFTR. Therefore, we can speculate that the presence of the CFTR fragment, which does not harbor a mutation, might facilitate intermolecular interactions. The rescue of CFTR was evident by the restoration of chloride transport in human CFBE41o- bronchial epithelial cells expressing DeltaF508-CFTR in vitro. More important, nasal administration of an adenovirus expressing a complementary CFTR fragment restored some degree of CFTR activity in the nasal airways of DeltaF508 homozygous mice in vivo. These findings identify complementary protein fragments as a viable in vivo approach for correcting disease-causing misfolding of plasma membrane proteins.