• Lynda S Ostedgaard, David K Meyerholz, Daniel W Vermeer, Philip H Karp, Lindsey Schneider, Curt D Sigmund, and Michael J Welsh.
• Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
• Proc. Natl. Acad. Sci. U.S.A. 2011 Feb 15; 108 (7): 2921-6.

AbstractGene transfer could provide a novel therapeutic approach for cystic fibrosis (CF), and adeno-associated virus (AAV) is a promising vector. However, the packaging capacity of AAV limits inclusion of the full-length cystic fibrosis transmembrane conductance regulator (CFTR) cDNA together with other regulatory and structural elements. To overcome AAV size constraints, we recently developed a shortened CFTR missing the N-terminal portion of the R domain (residues 708-759, CFTRΔR) and found that it retained regulated anion channel activity in vitro. To test the hypothesis that CFTRΔR could correct in vivo defects, we generated CFTR(-/-) mice bearing a transgene with a fatty acid binding protein promoter driving expression of human CFTRΔR in the intestine (CFTR(-/-);TgΔR). We found that intestinal crypts of CFTR(-/-);TgΔR mice expressed CFTRΔR and the intestine appeared histologically similar to that of WT mice. Moreover, like full-length CFTR transgene, the CFTRΔR transgene produced CFTR Cl(-) currents and rescued the CFTR(-/-) intestinal phenotype. These results indicate that the N-terminal part of the CFTR R domain is dispensable for in vivo intestinal physiology. Thus, CFTRΔR may have utility for AAV-mediated gene transfer in CF.

23 keywords...

hide…