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Correction of lethal intestinal defect in a mouse model of cystic fibrosis by human CFTR
1Children's Hospital Medical Center, Division of Pulmonary Biology, Cincinnati, OH 45229-3039.
Abstract:
Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). A potential animal model of CF, the CFTR-/- mouse, has had limited utility because most mice die from intestinal obstruction during the first month of life. Human CFTR (hCFTR) was expressed in CFTR-/- mice under the control of the rat intestinal fatty acid-binding protein gene promoter. The mice survived and showed functional correction of ileal goblet cell and crypt cell hyperplasia and cyclic adenosine monophosphate-stimulated chloride secretion. These results support the concept that transfer of the hCFTR gene may be a useful strategy for correcting physiologic defects in patients with CF.
Insights
Cystic fibrosis (CF) gene therapy using human CFTR (hCFTR) in CFTR-/- mice corrected intestinal defects and improved survival. This study demonstrates hCFTR gene transfer as a promising strategy for treating CF physiological abnormalities.
Area of Science:
- Genetics
- Physiology
- Animal Models
Background:
- Cystic fibrosis (CF) is a genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.
- The CFTR-/- mouse model of CF has limited utility due to early mortality from intestinal obstruction.
Purpose of the Study:
- To assess the therapeutic potential of expressing human CFTR (hCFTR) in CFTR-/- mice.
- To evaluate the functional correction of intestinal defects in a CF mouse model.
Main Methods:
- Human CFTR (hCFTR) was expressed in CFTR-/- mice using the rat intestinal fatty acid-binding protein gene promoter.
- Survival rates, ileal goblet cell and crypt cell hyperplasia, and cyclic adenosine monophosphate-stimulated chloride secretion were assessed.
Main Results:
- Mice expressing hCFTR demonstrated improved survival rates.
- Functional correction of ileal goblet cell and crypt cell hyperplasia was observed.
- Restoration of cyclic adenosine monophosphate-stimulated chloride secretion was confirmed.
Conclusions:
- Expression of hCFTR in CFTR-/- mice rescues the lethal phenotype and corrects key intestinal defects.
- Gene transfer of hCFTR is a viable strategy for addressing CF-related physiological abnormalities.