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Modification of development by the CFTR gene in utero
S L Morrow1, J E Larson, S Nelson
1Department of Molecular Genetics, Ochsner Medical Foundation, New Orleans, Louisiana, 70121, USA.
Molecular Genetics and Metabolism
|December 16, 1998
Summary
In utero gene therapy using cystic fibrosis transmembrane conductance regulator (CFTR) enhanced lung development and resistance to Pseudomonas aeruginosa infection in rats. This early intervention improved host defense mechanisms against bacterial lung infections.
Area of Science:
- * Developmental biology
- * Gene therapy
- * Respiratory medicine
Background:
- * Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations cause cystic fibrosis, leading to altered lung secretions and increased susceptibility to bacterial infections.
- * In utero gene therapy offers a potential strategy to address developmental defects associated with genetic disorders.
- * Pseudomonas aeruginosa is a common opportunistic pathogen causing severe lung infections, particularly in individuals with cystic fibrosis.
Purpose of the Study:
- * To investigate the effects of in utero delivery of the human CFTR gene on lung development and function in rats.
- * To assess the impact of in utero CFTR gene expression on the susceptibility to Pseudomonas aeruginosa infection.
- * To determine the durability and functional consequences of in utero CFTR gene transfer.
Main Methods:
- * Rats were infected in utero with a recombinant adenovirus carrying the human CFTR gene at 16-17 days gestation.
- * Lung development, morphology, and CFTR protein expression were evaluated post-infection.
- * Secreted glycoconjugates and lipids in the lungs were analyzed.
- * Treated rats were challenged with Pseudomonas aeruginosa to assess resistance and inflammatory responses.
Main Results:
- * In utero CFTR gene transfer altered lung development and morphology, with detectable CFTR protein up to 30 days post-infection.
- * Increased levels of secreted glycoconjugates and lipids were observed in treated lungs.
- * Rats treated in utero with CFTR showed enhanced resistance to Pseudomonas aeruginosa infection, with minimal inflammatory response.
- * Adenovirus transgene was undetectable at the time of bacterial challenge, suggesting long-term functional changes.
Conclusions:
- * In utero expression of the human CFTR gene influences the development and function of lung secretory cells.
- * This early gene therapy approach can enhance host defense mechanisms against bacterial lung infections.
- * In utero CFTR gene transfer may offer a promising strategy for preventing or mitigating lung disease progression in conditions like cystic fibrosis.