| First Author | Ostedgaard LS | Year | 2011 |
| Journal | Proc Natl Acad Sci U S A | Volume | 108 |
| Issue | 7 | Pages | 2921-6 |
| PubMed ID | 21285372 | Mgi Jnum | J:169220 |
| Mgi Id | MGI:4940124 | Doi | 10.1073/pnas.1019752108 |
| Citation | Ostedgaard LS, et al. (2011) Cystic fibrosis transmembrane conductance regulator with a shortened R domain rescues the intestinal phenotype of CFTR-/- mice. Proc Natl Acad Sci U S A 108(7):2921-6 |
| abstractText | Gene 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, CFTRDeltaR) and found that it retained regulated anion channel activity in vitro. To test the hypothesis that CFTRDeltaR could correct in vivo defects, we generated CFTR(-/-) mice bearing a transgene with a fatty acid binding protein promoter driving expression of human CFTRDeltaR in the intestine (CFTR(-/-);TgDeltaR). We found that intestinal crypts of CFTR(-/-);TgDeltaR mice expressed CFTRDeltaR and the intestine appeared histologically similar to that of WT mice. Moreover, like full-length CFTR transgene, the CFTRDeltaR 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, CFTRDeltaR may have utility for AAV-mediated gene transfer in CF. |
