FETOSCOPIC GENE-THERAPY FOR CONGENITAL LUNG-DISEASE

Fetal gene therapy offers the promise of cure for certain genetic dise ases, like cystic fibrosis and surfactant protein B deficiency. The au thors hypothesized that a fetoscopic approach could attain a high leve l of organ-specific gene transfer to the fetal lung late in gestation. To test this hypothesis the authors examined the efficacy, specificit y, and toxicity of recombinant adenovirus-mediated transfer of the bet a-galactosidase marker gene to the lung of rate gestation fetal sheep using a fetoscopic technique. Twelve fetal sheep of 125 to 135 days' g estation (term, 145 days) underwent fetoscopic bronchoscopy and intrat racheal administration of a replication-deficient adenoviral vector th at transduces the beta-galactosidase marker gene. Escape of administer ed virus was prevented by the fetoscopic deployment of a detachable si licone balloon in the fetal trachea. All fetuses survived until being killed at 2 days after vector delivery far the histopathologic assessm ent of vector efficacy and specificity. Optimal beta-galactosidase tra nsgene expression was observed at a viral titer of 2 x 10(12) particle s per milliliter of administered volume. Expression was greatest in th e distal pulmonary parenchyma, particularly in type II pneumocytes, an d extended out to the pleura. There was no evidence of gene transfer i n either the large conducting airways or in any other fetal organ. The authors have developed a minimally invasive technique for the specifi c pulmonary delivery of gene therapy vectors to the fetus with no asso ciated acute toxicity. Gene transfer to the late gestation fetus for t he treatment of congenital pulmonary disease may be feasible through f etoscopy. Copyright (C) 1997 by W.B. Saunders Company.