GENE-THERAPY FOR CYSTIC-FIBROSIS USING AD ENOVIRUS VECTORS

Mutations in the CFTR gene are responsible for the clinical manifestat ions of cystic fibrosis (CF). Since approximately 95% of the morbidity and mortality related to the disease arise from pulmonary complicatio ns, the primary target for gene therapy of CF is the respiratory epith elium, in which reversal of tile CF phenotype can be envisaged. In the past few years, CF has thus emerged as an early experimental model fo r human gene therapies utilizing the first generation (E1-deleted) rec ombinant adenoviruses. The efforts undertaken to implement a safe and efficient transfer of the CFTR gene to the airways of animals and CF p atients are also stimulating a more precise understanding of the immun ology of the virus in the respiratory environment. Several groups have undertaken large studies in the airways of mice, cotton rats, Rhesus monkeys and baboons to assess efficiency of gene transfer as well as s afety parameters. Such preclinical studies have shown that biological efficacy of gene delivery could be achieved for few weeks without sign s of severe toxicity depending of the virus dose which was administere d. These results have encouraged the design of several clinical trials involving CF patients which at present are underway. The large body o f data collected during these last years has highlighted the limitatio ns of the first generation of adenovirus vectors (mainly the Immunores ponses elicited by the host), but also stimulated improvements in vect or engineering and in knowledge of adenovirus biology. Both approaches will provide more rational strategies to treat cystic fibrosis by gen etic means.