Gene therapy for inherited lung disorders: an insight into pulmonary defence

This review summarizes the latest developments in viral and nonviral gene delivery systems to the lung, and the problems that have to be overcome. Gene delivery has the potential to offer effective treatment to patients with life-threatening lung diseases such as cystic fibrosis and alpha(1)-antitrypsin deficiency, and could modify gene-environment relationships in asthma and other respiratory diseases. Phase I clinical trials conducted in the early 1990s showed that in principle gene transfer to the lung was safe. Although the preliminary results gave encouraging laboratory data, gene expression from viral or nonviral gene delivery systems was too inefficient or transient to offer clinical benefit. Initial optimism gave way to the realization that gene therapy to the lung was unlikely to be straightforward. The host innate and acquired immune system, which protects against infection from inhaled bacteria and viruses, represents a major barrier to successful gene transfer to the lung. A better understanding of the immunological barriers which exist in the lung may allow the development of pharmacological and/or immunological agents that modulate the host immune system to allow for a more continuous and regulated level of gene expression following gene transfer.