Polyethyleneimine-based gene therapy by inhalation.

Abstract

The delivery of genes by inhalation holds promise for the treatment of a wide range of pulmonary and non-pulmonary disorders and offers numerous advantages over more invasive modes of delivery. Subsequent to the cloning of the cystic fibrosis gene, there was great interest in the delivery of genes directly to the lung surfaces by aerosol, and most early efforts focused on the use of non-viral vectors, particularly cationic lipids. Unfortunately, nebulisation shear forces, inefficient penetration of mucous barriers and inhibitory effects of surfactant and other lung-specific features have generally resulted in a lack of therapeutic effect, and much of this work has diminished in recent years as a consequence. Polyethyleneimine (PEI)-based formulations have proven stable during nebulisation and result in nearly 100% efficient transfection throughout the airways, as well as significant, although lower, levels of transfection throughout the lung parenchyma. Most importantly, therapeutic responses have been obtained in several animal lung tumour models when PEI-based complexes of p53 and IL-12 genes were delivered by aerosol. This approach may also prove useful as a means of localised genetic immunisation. In addition, this mode of delivery seems to be associated with surprisingly low toxicity, and results in little or no CpG immunostimulatory response, which has presented a challenge to repeated gene therapy via other modes of delivery.