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A truncated CFTR protein rescues endogenous F508-CFTR and corrects chloride transport in mice

Estelle Cormet-Boyaka^*,1, Jeong S. Hong, Bakhram K. Berdiev, James A. Fortenberry, Jessica Rennolds^*, J. P. Clancy^||, Dale J. Benos^#, Prosper N. Boyaka and Eric J. Sorscher

^* Division of Pulmonary, Critical Care and Sleep Medicine and

Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA; and

Department of Cell Biology,

Department of Medicine,

^|| Department of Pediatrics, and

^# Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama, USA

¹ Correspondence: Division of Pulmonary Critical Care and Sleep Medicine, The Ohio State University, Columbus, OH 43201, USA. E-mail: estelle.boyaka{at}osumc.edu

Cystic fibrosis (CF) is most frequently associated with deletion of phenylalanine at position 508 (F508) in the CF transmembrane conductance regulator (CFTR) protein. The F508-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 F508-CFTR in vivo. cDNA encoding CFTR fragments were delivered to human airway epithelial cells and mice harboring endogenous F508-CFTR. Delivery of small CFTR fragments, which do not act as chloride channels by themselves, rescue F508-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 F508-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 F508 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.—Cormet-Boyaka, E., Hong, J. S., Berdiev, B. K., Fortenberry, J. A., Rennolds, J., Clancy, J. P., Benos, D. J., Boyaka, P. N., Sorscher, E. J. A truncated CFTR protein rescues endogenous F508-CFTR and corrects chloride transport in mice.

Key Words: cystic fibrosis • in vivo rescue • processing • transcomplementation