ENHANCED DISTRIBUTION OF ADENOVIRUS-MEDIATED GENE-TRANSFER TO LUNG PARENCHYMA BY PERFLUOROCHEMICAL LIQUID

Although gene therapy holds great promise for the treatment of inherit ed and acquired diseases of the lung, a number of issues including eff icient delivery and distribution of genes to pulmonary target cells mu st still be addressed. In this study we evaluated the use of perfluoro chemical (PFC) liquid as a vehicle for delivery of recombinant adenovi rus (AdCBlacZ) to lungs of juvenile rabbits. Virus was instilled into trachea of rabbits, and 4 days later the lungs were removed, cut into multiple pieces, and assayed for beta-galactosidase (beta-Gal) activit y. Total lung expression of the beta-Gal reporter gene was increased t wo- to three-fold by instillation of the virus (10(11) particles/kg bo dy weight) in saline (1.5 ml/kg) simultaneously with perflubron liquid (15 ml/kg) compared to virus + saline alone (control). Uniformity of beta-Gal activity between lobes was significantly improved by the PFC liquid. In perflubron-treated lungs similar to 45% of the lung pieces had beta-Gal-specific activity values within 50-150% of the mean speci fic activity for the total lung, compared to only similar to 15% of th e pieces in control lungs. More of total lobar beta-Gal activity was r ecovered in the: distal lung tissue (similar to two-fold greater than controls, p < 0.05). Morphological assessment of X-Gal-stained, fresh- frozen lung sections showed increased levels and more complete stainin g of alveolar wall cells in the PFC group. These data indicate that th e PFC liquid perflubron enhances distribution of virus-mediated gene e xpression to the lung parenchyma in healthy rabbits. PFC liquid may be a useful treatment vehicle for accessing distal spaces of the damaged or diseased lung.